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Sample records for l-type ca current

  1. Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents.

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    Chih-Chieh Yu

    Full Text Available Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear.To test the hypothesis that apamin does not inhibit any major cardiac ion currents.We studied human embryonic kidney (HEK 293 cells that expressed human voltage-gated Na+, K+ and Ca2+ currents and isolated rabbit ventricular myocytes. Whole-cell patch clamp techniques were used to determine ionic current densities before and after apamin administration.Ca2+ currents (CACNA1c+CACNB2b were not affected by apamin (500 nM (data are presented as median [25th percentile;75th percentile] (from -16 [-20;-10] to -17 [-19;-13] pA/pF, P = NS, but were reduced by nifedipine to -1.6 [-3.2;-1.3] pA/pF (p = 0.008. Na+ currents (SCN5A were not affected by apamin (from -261 [-282;-145] to -268 [-379;-132] pA/pF, P = NS, but were reduced by flecainide to -57 [-70;-47] pA/pF (p = 0.018. None of the major K+ currents (IKs, IKr, IK1 and Ito were inhibited by 500 nM of apamin (KCNQ1+KCNE1, from 28 [20]; [37] to 23 [18]; [32] pA/pF; KCNH2+KCNE2, from 28 [24]; [30] to 27 [24]; [29] pA/pF; KCNJ2, from -46 [-48;-40] to -46 [-51;-35] pA/pF; KCND3, from 608 [505;748] to 606 [454;684]. Apamin did not inhibit the INa or ICaL in isolated rabbit ventricular myocytes (INa, from -67 [-75;-59] to -68 [-71;-59] pA/pF; ICaL, from -16 [-17;-14] to -14 [-15;-13] pA/pF, P = NS for both.Apamin does not inhibit human cardiac Na+ currents, L-type Ca2+ currents or other major K+ currents. These findings indicate that apamin is a specific SK current inhibitor in hearts as well as in other organs.

  2. Direct interaction of CaVβ with actin up-regulates L-type calcium currents in HL-1 cardiomyocytes.

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    Stölting, Gabriel; de Oliveira, Regina Campos; Guzman, Raul E; Miranda-Laferte, Erick; Conrad, Rachel; Jordan, Nadine; Schmidt, Silke; Hendriks, Johnny; Gensch, Thomas; Hidalgo, Patricia

    2015-02-20

    Expression of the β-subunit (CaVβ) is required for normal function of cardiac L-type calcium channels, and its up-regulation is associated with heart failure. CaVβ binds to the α1 pore-forming subunit of L-type channels and augments calcium current density by facilitating channel opening and increasing the number of channels in the plasma membrane, by a poorly understood mechanism. Actin, a key component of the intracellular trafficking machinery, interacts with Src homology 3 domains in different proteins. Although CaVβ encompasses a highly conserved Src homology 3 domain, association with actin has not yet been explored. Here, using co-sedimentation assays and FRET experiments, we uncover a direct interaction between CaVβ and actin filaments. Consistently, single-molecule localization analysis reveals streaklike structures composed by CaVβ2 that distribute over several micrometers along actin filaments in HL-1 cardiomyocytes. Overexpression of CaVβ2-N3 in HL-1 cells induces an increase in L-type current without altering voltage-dependent activation, thus reflecting an increased number of channels in the plasma membrane. CaVβ mediated L-type up-regulation, and CaVβ-actin association is prevented by disruption of the actin cytoskeleton with cytochalasin D. Our study reveals for the first time an interacting partner of CaVβ that is directly involved in vesicular trafficking. We propose a model in which CaVβ promotes anterograde trafficking of the L-type channels by anchoring them to actin filaments in their itinerary to the plasma membrane. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Direct Interaction of CaVβ with Actin Up-regulates L-type Calcium Currents in HL-1 Cardiomyocytes*

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    Stölting, Gabriel; de Oliveira, Regina Campos; Guzman, Raul E.; Miranda-Laferte, Erick; Conrad, Rachel; Jordan, Nadine; Schmidt, Silke; Hendriks, Johnny; Gensch, Thomas; Hidalgo, Patricia

    2015-01-01

    Expression of the β-subunit (CaVβ) is required for normal function of cardiac L-type calcium channels, and its up-regulation is associated with heart failure. CaVβ binds to the α1 pore-forming subunit of L-type channels and augments calcium current density by facilitating channel opening and increasing the number of channels in the plasma membrane, by a poorly understood mechanism. Actin, a key component of the intracellular trafficking machinery, interacts with Src homology 3 domains in different proteins. Although CaVβ encompasses a highly conserved Src homology 3 domain, association with actin has not yet been explored. Here, using co-sedimentation assays and FRET experiments, we uncover a direct interaction between CaVβ and actin filaments. Consistently, single-molecule localization analysis reveals streaklike structures composed by CaVβ2 that distribute over several micrometers along actin filaments in HL-1 cardiomyocytes. Overexpression of CaVβ2-N3 in HL-1 cells induces an increase in L-type current without altering voltage-dependent activation, thus reflecting an increased number of channels in the plasma membrane. CaVβ mediated L-type up-regulation, and CaVβ-actin association is prevented by disruption of the actin cytoskeleton with cytochalasin D. Our study reveals for the first time an interacting partner of CaVβ that is directly involved in vesicular trafficking. We propose a model in which CaVβ promotes anterograde trafficking of the L-type channels by anchoring them to actin filaments in their itinerary to the plasma membrane. PMID:25533460

  4. Reduced density and altered regulation of rat atrial L-type Ca2+ current in heart failure.

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    Bond, Richard C; Bryant, Simon M; Watson, Judy J; Hancox, Jules C; Orchard, Clive H; James, Andrew F

    2017-03-01

    Constitutive regulation by PKA has recently been shown to contribute to L-type Ca 2+ current ( I CaL ) at the ventricular t-tubule in heart failure. Conversely, reduction in constitutive regulation by PKA has been proposed to underlie the downregulation of atrial I CaL in heart failure. The hypothesis that downregulation of atrial I CaL in heart failure involves reduced channel phosphorylation was examined. Anesthetized adult male Wistar rats underwent surgical coronary artery ligation (CAL, N =10) or equivalent sham-operation (Sham, N =12). Left atrial myocytes were isolated ~18 wk postsurgery and whole cell currents recorded (holding potential=-80 mV). I CaL activated by depolarizing pulses to voltages from -40 to +50 mV were normalized to cell capacitance and current density-voltage relations plotted. CAL cell capacitances were ~1.67-fold greater than Sham ( P ≤ 0.0001). Maximal I CaL conductance ( G max ) was downregulated more than 2-fold in CAL vs. Sham myocytes ( P 50% more effectively in CAL than in Sham so that differences in I CaL density were abolished. Differences between CAL and Sham G max were not abolished by calyculin A (100 nmol/l), suggesting that increased protein dephosphorylation did not account for I CaL downregulation. Treatment with either H-89 (10 μmol/l) or AIP (5 μmol/l) had no effect on basal currents in Sham or CAL myocytes, indicating that, in contrast to ventricular myocytes, neither PKA nor CaMKII regulated basal I CaL Expression of the L-type α 1C -subunit, protein phosphatases 1 and 2A, and inhibitor-1 proteins was unchanged. In conclusion, reduction in PKA-dependent regulation did not contribute to downregulation of atrial I CaL in heart failure. NEW & NOTEWORTHY Whole cell recording of L-type Ca 2+ currents in atrial myocytes from rat hearts subjected to coronary artery ligation compared with those from sham-operated controls reveals marked reduction in current density in heart failure without change in channel subunit

  5. Effects of itopride hydrochloride on the delayed rectifier K+ and L-type CA2+ currents in guinea-pig ventricular myocytes.

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    Morisawa, T; Hasegawa, J; Hama, R; Kitano, M; Kishimoto, Y; Kawasaki, H

    1999-01-01

    The effects of itopride hydrochloride, a new drug used to regulate motility in the gastrointestinal tract, on the delayed rectifier K+ current (I(K)) and the L-type Ca2+ current (I(Ca)) were evaluated in guinea-pig ventricular myocytes at concentrations of 1, 10 and 100 microM to determine whether the drug has a proarrhythmic effect through blockade of I(K). Itopride did not affect I(K) at concentrations of 100 microM or less, and no significant effects of 1, 10 or 100 microM itopride were observed on the inward rectifier K+ current (I(K1)) responsible for the resting potential and final repolarization phase of the action potential. We next investigated the effects of itopride on L-type Ca2+ current (I(Ca)). Significant inhibition of I(Ca) was observed at itopride concentrations greater than 10 microM. These results suggested that itopride hydrochloride has an inhibitory effect on I(Ca) at concentrations much higher than those in clinical use.

  6. Single-channel L-type Ca2+ currents in chicken embryo semicircular canal type I and type II hair cells.

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    Zampini, Valeria; Valli, Paolo; Zucca, Giampiero; Masetto, Sergio

    2006-08-01

    Few data are available concerning single Ca channel properties in inner ear hair cells and particularly none in vestibular type I hair cells. By using the cell-attached configuration of the patch-clamp technique in combination with the semicircular canal crista slice preparation, we determined the elementary properties of voltage-dependent Ca channels in chicken embryo type I and type II hair cells. The pipette solutions included Bay K 8644. With 70 mM Ba(2+) in the patch pipette, Ca channel activity appeared as very brief openings at -60 mV. Ca channel properties were found to be similar in type I and type II hair cells; therefore data were pooled. The mean inward current amplitude was -1.3 +/- 0.1 (SD) pA at - 30 mV (n = 16). The average slope conductance was 21 pS (n = 20). With 5 mM Ba(2+) in the patch pipette, very brief openings were already detectable at -80 mV. The mean inward current amplitude was -0.7 +/- 0.2 pA at -40 mV (n = 9). The average slope conductance was 11 pS (n = 9). The mean open time and the open probability increased significantly with depolarization. Ca channel activity was still present and unaffected when omega-agatoxin IVA (2 microM) and omega-conotoxin GVIA (3.2 microM) were added to the pipette solution. Our results show that types I and II hair cells express L-type Ca channels with similar properties. Moreover, they suggest that in vivo Ca(2+) influx might occur at membrane voltages more negative than -60 mV.

  7. Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs.

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    Jae Gon Kim

    Full Text Available The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD prolongation that involves increase in late L-type Ca2+ current (ICaL caused by a decrease in Ca2+-dependent inactivation (CDI. Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.

  8. Bioactive Natural Product and Superacid Chemistry for Lead Compound Identification: A Case Study of Selective hCA III and L-Type Ca2+ Current Inhibitors for Hypotensive Agent Discovery

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    Hélène Carreyre

    2017-05-01

    Full Text Available Dodoneine (Ddn is one of the active compounds identified from Agelanthus dodoneifolius, which is a medicinal plant used in African pharmacopeia and traditional medicine for the treatment of hypertension. In the context of a scientific program aiming at discovering new hypotensive agents through the original combination of natural product discovery and superacid chemistry diversification, and after evidencing dodoneine’s vasorelaxant effect on rat aorta, superacid modifications allowed us to generate original analogues which showed selective human carbonic anhydrase III (hCA III and L-type Ca2+ current inhibition. These derivatives can now be considered as new lead compounds for vasorelaxant therapeutics targeting these two proteins.

  9. Oestrogen directly inhibits the cardiovascular L-type Ca2+ channel Cav1.2

    International Nuclear Information System (INIS)

    Ullrich, Nina D.; Koschak, Alexandra; MacLeod, Kenneth T.

    2007-01-01

    Oestrogen can modify the contractile function of vascular smooth muscle and cardiomyocytes. The negative inotropic actions of oestrogen on the heart and coronary vasculature appear to be mediated by L-type Ca 2+ channel (Ca v 1.2) inhibition, but the underlying mechanisms remain elusive. We tested the hypothesis that oestrogen directly inhibits the cardiovascular L-type Ca 2+ current, I CaL . The effect of oestrogen on I CaL was measured in Ca v 1.2-transfected HEK-293 cells using the whole-cell patch-clamp technique. The current revealed typical activation and inactivation profiles of nifedipine- and cadmium-sensitive I CaL . Oestrogen (50 μM) rapidly reduced I CaL by 50% and shifted voltage-dependent activation and availability to more negative potentials. Furthermore, oestrogen blocked the Ca 2+ channel in a rate-dependent way, exhibiting higher efficiency of block at higher stimulation frequencies. Our data suggest that oestrogen inhibits I CaL through direct interaction of the steroid with the channel protein

  10. Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes.

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    Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun; Ledford, Hannah A; Lee, Jeong Han; Sirish, Padmini; Dai, Gu; Jian, Zhong; Chuang, Frank; Brust-Mascher, Ingrid; Yamoah, Ebenezer N; Chen-Izu, Ye; Izu, Leighton T; Chiamvimonvat, Nipavan

    2018-03-16

    Small-conductance Ca 2+ -activated K + (SK) channels regulate the excitability of cardiomyocytes by integrating intracellular Ca 2+ and membrane potentials on a beat-to-beat basis. The inextricable interplay between activation of SK channels and Ca 2+ dynamics suggests the pathology of one begets another. Yet, the exact mechanistic underpinning for the activation of cardiac SK channels remains unaddressed. Here, we investigated the intracellular Ca 2+ microdomains necessary for SK channel activation. SK currents coupled with Ca 2+ influx via L-type Ca 2+ channels (LTCCs) continued to be elicited after application of caffeine, ryanodine or thapsigargin to deplete SR Ca 2+ store, suggesting that LTCCs provide the immediate Ca 2+ microdomain for the activation of SK channels in cardiomyocytes. Super-resolution imaging of SK2, Ca v 1.2 Ca 2+ channel, and ryanodine receptor 2 (RyR2) was performed to quantify the nearest neighbor distances (NND) and localized the three molecules within hundreds of nanometers. The distribution of NND between SK2 and RyR2 as well as SK2 and Ca v 1.2 was bimodal, suggesting a spatial relationship between the channels. The activation mechanism revealed by our study paved the way for the understanding of the roles of SK channels on the feedback mechanism to regulate the activities of LTCCs and RyR2 to influence local and global Ca 2+ signaling.

  11. Cytoskeleton, L-type Ca2+ and stretch activated channels in injured skeletal muscle

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    Fabio Francini

    2013-07-01

    Full Text Available The extra-sarcomeric cytoskeleton (actin microfilaments and anchoring proteins is involved in maintaining the sarco-membrane stiffness and integrity and in turn the mechanical stability and function of the intra- and sub-sarcoplasmic proteins. Accordingly, it regulates Ca2+ entry through the L-type Ca2+ channels and the mechano-sensitivity of the stretch activated channels (SACs. Moreover, being intra-sarcomeric cytoskeleton bound to costameric proteins and other proteins of the sarcoplasma by intermediate filaments, as desmin, it integrates the properties of the sarcolemma with the skeletal muscle fibres contraction. The aim of this research was to compare the cytoskeleton, SACs and the ECC alterations in two different types of injured skeletal muscle fibres: by muscle denervation and mechanical overload (eccentric contraction. Experiments on denervation were made in isolated Soleus muscle of male Wistar rats; forced eccentric-contraction (EC injury was achieved in Extensor Digitorum Longus muscles of Swiss mice. The method employed conventional intracellular recording with microelectrodes inserted in a single fibre of an isolated skeletal muscle bundle. The state of cytoskeleton was evaluated by recording SAC currents and by evaluating the resting membrane potential (RMP value determined in current-clamp mode. The results demonstrated that in both injured skeletal muscle conditions the functionality of L-type Ca2+ current, ICa, was affected. In parallel, muscle fibres showed an increase of the resting membrane permeability and of the SAC current. These issues, together with a more depolarized RMP are an index of altered cytoskeleton. In conclusion, we found a symilar alteration of ICa, SAC and cytoskeleton in both injured skeletal muscle conditions.

  12. Rock Tea extract (Jasonia glutinosa) relaxes rat aortic smooth muscle by inhibition of L-type Ca(2+) channels.

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    Valero, Marta Sofía; Oliván-Viguera, Aida; Garrido, Irene; Langa, Elisa; Berzosa, César; López, Víctor; Gómez-Rincón, Carlota; Murillo, María Divina; Köhler, Ralf

    2015-12-01

    In traditional herbal medicine, Rock Tea (Jasonia glutinosa) is known for its prophylactic and therapeutic value in various disorders including arterial hypertension. However, the mechanism by which Rock Tea exerts blood pressure-lowering actions has not been elucidated yet. Our aim was to demonstrate vasorelaxing effects of Rock Tea extract and to reveal its possible action mechanism. Isometric myography was conducted on high-K+-precontracted rings from rat thoracic aorta and tested extracts at concentrations of 0.5-5 mg/ml. Whole-cell patch-clamp experiments were performed in rat aortic vascular smooth muscle cells (line A7r5) to determine blocking effects on L-type Ca(2+) channels. Rock Tea extract relaxed the aorta contracted by high [K+] concentration dependently with an EC50 of ≈2.4 mg/ml and produced ≈75 % relaxation at the highest concentration tested. The L-type Ca(2+) channel blocker, verapamil (10(-6) M), had similar effects. Rock Tea extract had no effect in nominally Ca(2+)-free high-K(+) buffer but significantly inhibited contractions to re-addition of Ca(2+). Rock Tea extract inhibited the contractions induced by the L-type Ca(2+) channel activator Bay K 8644 (10(-5) M) and by phenylephrine (10(-6) M). Rock Tea extract and Y-27632 (10(-6) M), Rho-kinase inhibitor, had similar effects and the respective effects were not additive. Patch-clamp experiments demonstrated that Rock Tea extract (2.5 mg/ml) virtually abolished L-type Ca(2+) currents in A7r5. We conclude that Rock Tea extract produced vasorelaxation of rat aorta and that this relaxant effect is mediated by inhibition of L-type Ca(2+) channels. Rock Tea extracts may be of phytomedicinal value for prevention and adjuvant treatment of hypertension and other cardiovascular diseases.

  13. Endogenous testosterone increases L-type Ca2+ channel expression in porcine coronary smooth muscle.

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    Bowles, D K; Maddali, K K; Ganjam, V K; Rubin, L J; Tharp, D L; Turk, J R; Heaps, C L

    2004-11-01

    Evidence indicates that gender and sex hormonal status influence cardiovascular physiology and pathophysiology. We recently demonstrated increased L-type voltage-gated Ca2+ current (ICa,L) in coronary arterial smooth muscle (CASM) of male compared with female swine. The promoter region of the L-type voltage-gated Ca2+ channel (VGCC) (Cav1.2) gene contains a hormone response element that is activated by testosterone. Thus the purpose of the present study was to determine whether endogenous testosterone regulates CASM ICa,L through regulation of VGCC expression and activity. Sexually mature male and female Yucatan swine (7-8 mo; 35-45 kg) were obtained from the breeder. Males were left intact (IM, n=8), castrated (CM, n=8), or castrated with testosterone replacement (CMT, n=8; 10 mg/day Androgel). Females remained gonad intact (n=8). In right coronary arteries, both Cav1.2 mRNA and protein were greater in IM compared with intact females. Cav1.2 mRNA and protein were reduced in CM compared with IM and restored in CMT. In isolated CASM, both peak and steady-state ICa were reduced in CM compared with IM and restored in CMT. In males, a linear relationship was found between serum testosterone levels and ICa. In vitro, both testosterone and the nonaromatizable androgen, dihydrotestosterone, increased Cav1.2 expression. Furthermore, this effect was blocked by the androgen receptor antagonist cyproterone. We conclude that endogenous testosterone is a primary regulator of Cav1.2 expression and activity in coronary arteries of males.

  14. 12-lipoxygenase regulates hippocampal long-term potentiation by modulating L-type Ca2+ channels

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    DeCostanzo, Anthony J.; Voloshyna, Iryna; Rosen, Zev B.; Feinmark, Steven J.; Siegelbaum, Steven A.

    2010-01-01

    Although long-term potentiation (LTP) has been intensely studied, there is disagreement as to which molecules mediate and modulate LTP. This is partly due to the presence of mechanistically distinct forms of LTP that are induced by different patterns of stimulation and that depend on distinct Ca2+ sources. Here we report a novel role for the arachidonic acid-metabolizing enzyme 12-lipoxygenase (12-LO) in LTP at CA3-CA1 hippocampal synapses that is dependent on the pattern of tetanic stimulation. We find that 12-LO activity is required for the induction of LTP in response to a theta-burst stimulation (TBS) protocol, which depends on Ca2+ influx through both NMDA receptors and L-type voltage-gated Ca2+ channels. In contrast, LTP induced by 100 Hz tetanic stimulation, which requires Ca2+ influx through NMDA receptors but not L-type channels, does not require 12-LO. We find that 12-LO regulates LTP by enhancing postsynaptic somatodendritic Ca2+ influx through L-type channels during theta burst stimulation, an action exerted via 12(S)-HPETE, a downstream metabolite of 12-LO. These results help define the role of a long-disputed signaling enzyme in LTP. PMID:20130191

  15. Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear.

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    Busquet, Perrine; Hetzenauer, Alfred; Sinnegger-Brauns, Martina J; Striessnig, Jörg; Singewald, Nicolas

    2008-05-01

    Dihydropyridine (DHP) L-type Ca(2+) channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca(V)1.2 and Ca(V)1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca(V)1.2 LTCCs (Ca(V)1.2DHP(-/-) mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca(V)1.2DHP(-/-) mice, indicating that it is mediated by Ca(V)1.2, but not by Ca(V)1.3 LTCCs. Supporting this conclusion, Ca(V)1.3-deficient mice (Ca(V)1.3(-/-)) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca(V)1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca(V)1.2DHP(-/-) mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca(V)1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca(V)1.3) is not sufficient to accelerate extinction of conditioned fear in mice.

  16. Intermolecular failure of L-type Ca2+ channel and ryanodine receptor signaling in hypertrophy.

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    Ming Xu

    2007-02-01

    Full Text Available Pressure overload-induced hypertrophy is a key step leading to heart failure. The Ca(2+-induced Ca(2+ release (CICR process that governs cardiac contractility is defective in hypertrophy/heart failure, but the molecular mechanisms remain elusive. To examine the intermolecular aspects of CICR during hypertrophy, we utilized loose-patch confocal imaging to visualize the signaling between a single L-type Ca(2+ channel (LCC and ryanodine receptors (RyRs in aortic stenosis rat models of compensated (CHT and decompensated (DHT hypertrophy. We found that the LCC-RyR intermolecular coupling showed a 49% prolongation in coupling latency, a 47% decrease in chance of hit, and a 72% increase in chance of miss in DHT, demonstrating a state of "intermolecular failure." Unexpectedly, these modifications also occurred robustly in CHT due at least partially to decreased expression of junctophilin, indicating that intermolecular failure occurs prior to cellular manifestations. As a result, cell-wide Ca(2+ release, visualized as "Ca(2+ spikes," became desynchronized, which contrasted sharply with unaltered spike integrals and whole-cell Ca(2+ transients in CHT. These data suggested that, within a certain limit, termed the "stability margin," mild intermolecular failure does not damage the cellular integrity of excitation-contraction coupling. Only when the modification steps beyond the stability margin does global failure occur. The discovery of "hidden" intermolecular failure in CHT has important clinical implications.

  17. Attenuated response of L-type calcium current to nitric oxide in atrial fibrillation.

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    Rozmaritsa, Nadiia; Christ, Torsten; Van Wagoner, David R; Haase, Hannelore; Stasch, Johannes-Peter; Matschke, Klaus; Ravens, Ursula

    2014-03-01

    Nitric oxide (NO) synthesized by cardiomyocytes plays an important role in the regulation of cardiac function. Here, we studied the impact of NO signalling on calcium influx in human right atrial myocytes and its relation to atrial fibrillation (AF). Right atrial appendages (RAAs) were obtained from patients in sinus rhythm (SR) and AF. The biotin-switch technique was used to evaluate endogenous S-nitrosylation of the α1C subunit of L-type calcium channels. Comparing SR to AF, S-nitrosylation of Ca(2+) channels was similar. Direct effects of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) on L-type calcium current (ICa,L) were studied in cardiomyocytes with standard voltage-clamp techniques. In SR, ICa,L increased with SNAP (100 µM) by 48%, n/N = 117/56, P < 0.001. The SNAP effect on ICa,L involved activation of soluble guanylate cyclase and protein kinase A. Specific inhibition of phosphodiesterase (PDE)3 with cilostamide (1 µM) enhanced ICa,L to a similar extent as SNAP. However, when cAMP was elevated by PDE3 inhibition or β-adrenoceptor stimulation, SNAP reduced ICa,L, pointing to cGMP-cAMP cross-regulation. In AF, the stimulatory effect of SNAP on ICa,L was attenuated, while its inhibitory effect on isoprenaline- or cilostamide-stimulated current was preserved. cGMP elevation with SNAP was comparable between the SR and AF group. Moreover, the expression of PDE3 and soluble guanylate cyclase was not reduced in AF. NO exerts dual effects on ICa,L in SR with an increase of basal and inhibition of cAMP-stimulated current, and in AF NO inhibits only stimulated ICa,L. We conclude that in AF, cGMP regulation of PDE2 is preserved, but regulation of PDE3 is lost.

  18. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome

    DEFF Research Database (Denmark)

    Cordeiro, Jonathan M; Marieb, Mark; Pfeiffer, Ryan

    2009-01-01

    S in which loss of function is caused by accelerated inactivation of I(Ca). The proband, a 32 year old male, displayed a Type I ST segment elevation in two right precordial ECG leads following a procainamide challenge. EP study was positive with induction of polymorphic VT/VF. Interrogation of implanted ICD...... significantly faster in mutant channels between 0 and + 20 mV. Action potential voltage clamp experiments showed that total charge was reduced by almost half compared to WT. We report the first BrS mutation in CaCNB2b resulting in accelerated inactivation of L-type calcium channel current. Our results suggest...

  19. Role of voltage-gated L-type Ca2+ channel isoforms for brain function.

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    Striessnig, J; Koschak, A; Sinnegger-Brauns, M J; Hetzenauer, A; Nguyen, N K; Busquet, P; Pelster, G; Singewald, N

    2006-11-01

    Voltage-gated LTCCs (L-type Ca2+ channels) are established drug targets for the treatment of cardiovascular diseases. LTCCs are also expressed outside the cardiovascular system. In the brain, LTCCs control synaptic plasticity in neurons, and DHP (dihydropyridine) LTCC blockers such as nifedipine modulate brain function (such as fear memory extinction and depression-like behaviour). Voltage-sensitive Ca2+ channels Cav1 .2 and Cav1.3 are the predominant brain LTCCs. As DHPs and other classes of organic LTCC blockers inhibit both isoforms, their pharmacological distinction is impossible and their individual contributions to defined brain functions remain largely unknown. Here, we summarize our recent experiments with two genetically modified mouse strains, which we generated to explore the individual biophysical features of Cav1.2 and Cav1.3 LTCCs and to determine their relative contributions to various physiological peripheral and neuronal functions. The results described here also allow predictions about the pharmacotherapeutic potential of isoform-selective LTCC modulators.

  20. Bradykinin induced a positive chronotropic effect via stimulation of T- and L-type calcium currents in heart cells.

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    El-Bizri, Nesrine; Bkaily, Ghassan; Wang, Shimin; Jacques, Danielle; Regoli, Domenico; D'Orléans-Juste, Pedro; Sukarieh, Rami

    2003-03-01

    Using Fluo-3 calcium dye confocal microscopy and spontaneously contracting embryonic chick heart cells, bradykinin (10(-10) M) was found to induce positive chronotropic effects by increasing the frequency of the transient increase of cytosolic and nuclear free Ca2+. Pretreatment of the cells with either B1 or B2 receptor antagonists (R126 and R817, respectively) completely prevented bradykinin (BK) induced positive chronotropic effects on spontaneously contracting single heart cells. Using the whole-cell voltage clamp technique and ionic substitution to separate the different ionic current species, our results showed that BK (10(-6) M) had no effect on fast Na+ inward current and delayed outward potassium current. However, both L- and T-type Ca2+ currents were found to be increased by BK in a dose-dependent manner (10(-10)-10(-7) M). The effects of BK on T- and L-type Ca2+ currents were partially blocked by the B1 receptor antagonist [Leu8]des-Arg9-BK (R592) (10(-7) M) and completely reversed by the B2 receptor antagonist D-Arg[Hyp3,D-Phe7,Leu8]BK (R-588) (10(-7) M) or pretreatment with pertussis toxin (PTX). These results demonstrate that BK induced a positive chronotropic effect via stimulation of T- and L-type Ca2+ currents in heart cells mainly via stimulation of B2 receptor coupled to PTX-sensitive G-proteins. The increase of both types of Ca2+ current by BK in heart cells may explain the positive inotropic and chronotropic effects of this hormone.

  1. Phosphorylation of Ser1928 mediates the enhanced activity of the L-type Ca2+ channel Cav1.2 by the β2-adrenergic receptor in neurons.

    Science.gov (United States)

    Qian, Hai; Patriarchi, Tommaso; Price, Jennifer L; Matt, Lucas; Lee, Boram; Nieves-Cintrón, Madeline; Buonarati, Olivia R; Chowdhury, Dhrubajyoti; Nanou, Evanthia; Nystoriak, Matthew A; Catterall, William A; Poomvanicha, Montatip; Hofmann, Franz; Navedo, Manuel F; Hell, Johannes W

    2017-01-24

    The L-type Ca 2+ channel Ca v 1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving β-adrenergic receptors (βARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylates Ser 1928 in Ca v 1.2 in vitro and in vivo, including in rodents and humans. However, S1928A knock-in (KI) mice have normal PKA-mediated L-type channel regulation in the heart, indicating that Ser 1928 is not required for regulation of cardiac Ca v 1.2 by PKA in this tissue. We report that augmentation of L-type currents by PKA in neurons was absent in S1928A KI mice. Furthermore, S1928A KI mice failed to induce long-term potentiation in response to prolonged theta-tetanus (PTT-LTP), a form of synaptic plasticity that requires Ca v 1.2 and enhancement of its activity by the β 2 -adrenergic receptor (β 2 AR)-cAMP-PKA cascade. Thus, there is an unexpected dichotomy in the control of Ca v 1.2 by PKA in cardiomyocytes and hippocampal neurons. Copyright © 2017, American Association for the Advancement of Science.

  2. Citalopram inhibits L-type calcium channel current in rat cardiomyocytes in culture

    Czech Academy of Sciences Publication Activity Database

    Hamplová-Peichlová, J.; Krůšek, Jan; Paclt, I.; Slavíček, J.; Lisá, Věra; Vyskočil, František

    2002-01-01

    Roč. 51, č. 3 (2002), s. 317-321 ISSN 0862-8408 R&D Projects: GA AV ČR IAA7011902; GA ČR GA305/02/1333 Institutional research plan: CEZ:AV0Z5011922 Keywords : citalopram * amitriptyline * L-type calcium channel current Subject RIV: ED - Physiology Impact factor: 0.984, year: 2002

  3. Role of L-Type Ca[superscript 2+] Channel Isoforms in the Extinction of Conditioned Fear

    Science.gov (United States)

    Busquet, Perrine; Hetzenauer, Alfred; Sinnegger-Brauns, Martina J.; Striessnig, Jorg; Singewald, Nicolas

    2008-01-01

    Dihydropyridine (DHP) L-type Ca[superscript 2+] channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the…

  4. Orexin-A potentiates L-type calcium/barium currents in rat retinal ganglion cells.

    Science.gov (United States)

    Liu, F; Weng, S-J; Yang, X-L; Zhong, Y-M

    2015-10-01

    Two neuropeptides, orexin-A and orexin-B (also called hypocretin-1 and -2), have been implicated in sleep/wake regulation, feeding behaviors via the activation of two subtypes of G-protein-coupled receptors: orexin 1 and orexin 2 receptors (OX1R and OX2R). While the expression of orexins and orexin receptors is immunohistochemically revealed in retinal neurons, the function of these peptides in the retina is largely unknown. Using whole-cell patch-clamp recordings in rat retinal slices, we demonstrated that orexin-A increased L-type-like barium currents (IBa,L) in ganglion cells (GCs), and the effect was blocked by the selective OX1R antagonist SB334867, but not by the OX2R antagonist TCS OX2 29. The orexin-A effect was abolished by intracellular dialysis of GDP-β-S/GPAnt-2A, a Gq protein inhibitor, suggesting the mediation of Gq. Additionally, during internal dialysis of the phosphatidylinositol (PI)-phospholipase C (PLC) inhibitor U73122, orexin-A did not change the IBa,L of GCs, whereas the orexin-A effect persisted in the presence of the phosphatidylcholine (PC)-PLC inhibitor D609. The orexin-A-induced potentiation was not seen with internal infusion of Ca(2+)-free solution or when inositol 1,4,5-trisphosphate (IP3)-sensitive Ca(2+) release from intracellular stores was blocked by heparin/xestospongins-C. Moreover, the orexin-A effect was mimicked by the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate, but was eliminated when PKC was inhibited by bisindolylmaleimide IV (Bis-IV)/Gö6976. Neither adenosine 3',5'-cyclic monophosphate (cAMP)-protein kinase A (PKA) nor guanosine 3',5'-cyclic monophosphate (cGMP)-protein kinase G (PKG) signaling pathway was likely involved, as orexin-A persisted to potentiate the IBa,L of GCs no matter these two pathways were activated or inhibited. These results suggest that, by activating OX1R, orexin-A potentiates the IBa,L of rat GCs through a distinct Gq/PI-PLC/IP3/Ca(2+)/PKC signaling pathway. Copyright

  5. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

    Science.gov (United States)

    Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

    2003-03-01

    The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

  6. Localization of Rod Bipolar Cells in the Mammalian Retina Using an Antibody Against the α1c L-type Ca2+ Channel

    International Nuclear Information System (INIS)

    Huh, Yu-Jin; Choi, Jae-Sik; Jeon, Chang-Jin

    2015-01-01

    Bipolar cells transmit stimuli via graded changes in membrane potential and neurotransmitter release is modulated by Ca 2+ influx through L-type Ca 2+ channels. The purpose of this study was to determine whether the α 1 c subunit of L-type voltage-gated Ca 2+ channel (α 1 c L-type Ca 2+ channel) colocalizes with protein kinase C alpha (PKC-α), which labels rod bipolar cells. Retinal whole mounts and vertical sections from mouse, hamster, rabbit, and dog were immunolabeled with antibodies against PKC-α and α 1 c L-type Ca 2+ channel, using fluorescein isothiocyanate (FITC) and Cy5 as visualizing agents. PKC-α-immunoreactive cells were morphologically identical to rod bipolar cells as previously reported. Their cell bodies were located within the inner nuclear layer, dendritic processes branched into the outer plexiform layer, and axons extended into the inner plexiform layer. Immunostaining showed that α 1 c L-type Ca 2+ channel colocalized with PKC-α in rod bipolar cells. The identical expression of PKC-α and α 1 c L-type Ca 2+ channel indicates that the α 1 c L-type Ca 2+ channel has a specific role in rod bipolar cells, and the antibody against the α 1 c L-type Ca 2+ channel may be a useful marker for studying the distribution of rod bipolar cells in mouse, hamster, rabbit, and dog retinas

  7. CaV1.3 L-type Ca2+ channels modulate depression-like behaviour in mice independent of deaf phenotype.

    Science.gov (United States)

    Busquet, Perrine; Nguyen, Ngoc Khoi; Schmid, Eduard; Tanimoto, Naoyuki; Seeliger, Mathias W; Ben-Yosef, Tamar; Mizuno, Fengxia; Akopian, Abram; Striessnig, Jörg; Singewald, Nicolas

    2010-05-01

    Mounting evidence suggests that voltage-gated L-type Ca2+ channels can modulate affective behaviour. We therefore explored the role of CaV1.3 L-type Ca2+ channels in depression- and anxiety-like behaviours using CaV1.3-deficient mice (CaV1.3-/-). We showed that CaV1.3-/- mice displayed less immobility in the forced swim test as well as in the tail suspension test, indicating an antidepressant-like phenotype. Locomotor activity in the home cage or a novel open-field test was not influenced. In the elevated plus maze (EPM), CaV1.3-/- mice entered the open arms more frequently and spent more time there indicating an anxiolytic-like phenotype which was, however, not supported in the stress-induced hyperthermia test. By performing parallel experiments in Claudin 14 knockout mice (Cldn14-/-), which like CaV1.3-/- mice are congenitally deaf, an influence of deafness on the antidepressant-like phenotype could be ruled out. On the other hand, a similar EPM behaviour indicative of an anxiolytic phenotype was also found in the Cldn14-/- animals. Using electroretinography and visual behavioural tasks we demonstrated that at least in mice, CaV1.3 channels do not significantly contribute to visual function. However, marked morphological changes were revealed in synaptic ribbons in the outer plexiform layer of CaV1.3-/- retinas by immunohistochemistry suggesting a possible role of this channel type in structural plasticity at the ribbon synapse. Taken together, our findings indicate that CaV1.3 L-type Ca2+ channels modulate depression-like behaviour but are not essential for visual function. The findings raise the possibility that selective modulation of CaV1.3 channels could be a promising new therapeutic concept for the treatment of mood disorders.

  8. Conservation of cardiac L-type Ca2+ channels and their regulation in Drosophila: A novel genetically-pliable channelopathic model.

    Science.gov (United States)

    Limpitikul, Worawan B; Viswanathan, Meera C; O'Rourke, Brian; Yue, David T; Cammarato, Anthony

    2018-04-21

    Dysregulation of L-type Ca 2+ channels (LTCCs) underlies numerous cardiac pathologies. Understanding their modulation with high fidelity relies on investigating LTCCs in their native environment with intact interacting proteins. Such studies benefit from genetic manipulation of endogenous channels in cardiomyocytes, which often proves cumbersome in mammalian models. Drosophila melanogaster, however, offers a potentially efficient alternative as it possesses a relatively simple heart, is genetically pliable, and expresses well-conserved genes. Fluorescence in situ hybridization confirmed an abundance of Ca-α1D and Ca-α1T mRNA in fly myocardium, which encode subunits that specify hetero-oligomeric channels homologous to mammalian LTCCs and T-type Ca 2+ channels, respectively. Cardiac-specific knockdown of Ca-α1D via interfering RNA abolished cardiac contraction, suggesting Ca-α1D (i.e. A1D) represents the primary functioning Ca 2+ channel in Drosophila hearts. Moreover, we successfully isolated viable single cardiomyocytes and recorded Ca 2+ currents via patch clamping, a feat never before accomplished with the fly model. The profile of Ca 2+ currents recorded in individual cells when Ca 2+ channels were hypomorphic, absent, or under selective LTCC blockage by nifedipine, additionally confirmed the predominance of A1D current across all activation voltages. T-type current, activated at more negative voltages, was also detected. Lastly, A1D channels displayed Ca 2+ -dependent inactivation, a critical negative feedback mechanism of LTCCs, and the current through them was augmented by forskolin, an activator of the protein kinase A pathway. In sum, the Drosophila heart possesses a conserved compendium of Ca 2+ channels, suggesting that the fly may serve as a robust and effective platform for studying cardiac channelopathies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability.

    Science.gov (United States)

    Pedrozo, Zully; Criollo, Alfredo; Battiprolu, Pavan K; Morales, Cyndi R; Contreras-Ferrat, Ariel; Fernández, Carolina; Jiang, Nan; Luo, Xiang; Caplan, Michael J; Somlo, Stefan; Rothermel, Beverly A; Gillette, Thomas G; Lavandero, Sergio; Hill, Joseph A

    2015-06-16

    L-type calcium channel activity is critical to afterload-induced hypertrophic growth of the heart. However, the mechanisms governing mechanical stress-induced activation of L-type calcium channel activity are obscure. Polycystin-1 (PC-1) is a G protein-coupled receptor-like protein that functions as a mechanosensor in a variety of cell types and is present in cardiomyocytes. We subjected neonatal rat ventricular myocytes to mechanical stretch by exposing them to hypo-osmotic medium or cyclic mechanical stretch, triggering cell growth in a manner dependent on L-type calcium channel activity. RNAi-dependent knockdown of PC-1 blocked this hypertrophy. Overexpression of a C-terminal fragment of PC-1 was sufficient to trigger neonatal rat ventricular myocyte hypertrophy. Exposing neonatal rat ventricular myocytes to hypo-osmotic medium resulted in an increase in α1C protein levels, a response that was prevented by PC-1 knockdown. MG132, a proteasomal inhibitor, rescued PC-1 knockdown-dependent declines in α1C protein. To test this in vivo, we engineered mice harboring conditional silencing of PC-1 selectively in cardiomyocytes (PC-1 knockout) and subjected them to mechanical stress in vivo (transverse aortic constriction). At baseline, PC-1 knockout mice manifested decreased cardiac function relative to littermate controls, and α1C L-type calcium channel protein levels were significantly lower in PC-1 knockout hearts. Whereas control mice manifested robust transverse aortic constriction-induced increases in cardiac mass, PC-1 knockout mice showed no significant growth. Likewise, transverse aortic constriction-elicited increases in hypertrophic markers and interstitial fibrosis were blunted in the knockout animals PC-1 is a cardiomyocyte mechanosensor that is required for cardiac hypertrophy through a mechanism that involves stabilization of α1C protein. © 2015 American Heart Association, Inc.

  10. Anion-sensitive regions of L-type CaV1.2 calcium channels expressed in HEK293 cells.

    Directory of Open Access Journals (Sweden)

    Norbert Babai

    2010-01-01

    Full Text Available L-type calcium currents (I(Ca are influenced by changes in extracellular chloride, but sites of anion effects have not been identified. Our experiments showed that CaV1.2 currents expressed in HEK293 cells are strongly inhibited by replacing extracellular chloride with gluconate or perchlorate. Variance-mean analysis of I(Ca and cell-attached patch single channel recordings indicate that gluconate-induced inhibition is due to intracellular anion effects on Ca(2+ channel open probability, not conductance. Inhibition of CaV1.2 currents produced by replacing chloride with gluconate was reduced from approximately 75%-80% to approximately 50% by omitting beta subunits but unaffected by omitting alpha(2delta subunits. Similarly, gluconate inhibition was reduced to approximately 50% by deleting an alpha1 subunit N-terminal region of 15 residues critical for beta subunit interactions regulating open probability. Omitting beta subunits with this mutant alpha1 subunit did not further diminish inhibition. Gluconate inhibition was unchanged with expression of different beta subunits. Truncating the C terminus at AA1665 reduced gluconate inhibition from approximately 75%-80% to approximately 50% whereas truncating it at AA1700 had no effect. Neutralizing arginines at AA1696 and 1697 by replacement with glutamines reduced gluconate inhibition to approximately 60% indicating these residues are particularly important for anion effects. Expressing CaV1.2 channels that lacked both N and C termini reduced gluconate inhibition to approximately 25% consistent with additive interactions between the two tail regions. Our results suggest that modest changes in intracellular anion concentration can produce significant effects on CaV1.2 currents mediated by changes in channel open probability involving beta subunit interactions with the N terminus and a short C terminal region.

  11. L-Type Voltage-Gated Ca2+ Channels Regulate Synaptic-Activity-Triggered Recycling Endosome Fusion in Neuronal Dendrites

    Directory of Open Access Journals (Sweden)

    Brian G. Hiester

    2017-11-01

    Full Text Available The repertoire and abundance of proteins displayed on the surface of neuronal dendrites are tuned by regulated fusion of recycling endosomes (REs with the dendritic plasma membrane. While this process is critical for neuronal function and plasticity, how synaptic activity drives RE fusion remains unexplored. We demonstrate a multistep fusion mechanism that requires Ca2+ from distinct sources. NMDA receptor Ca2+ initiates RE fusion with the plasma membrane, while L-type voltage-gated Ca2+ channels (L-VGCCs regulate whether fused REs collapse into the membrane or reform without transferring their cargo to the cell surface. Accordingly, NMDA receptor activation triggered AMPA-type glutamate receptor trafficking to the dendritic surface in an L-VGCC-dependent manner. Conversely, potentiating L-VGCCs enhanced AMPA receptor surface expression only when NMDA receptors were also active. Thus L-VGCCs play a role in tuning activity-triggered surface expression of key synaptic proteins by gating the mode of RE fusion.

  12. The L-Type Voltage-Gated Calcium Channel Ca [subscript V] 1.2 Mediates Fear Extinction and Modulates Synaptic Tone in the Lateral Amygdala

    Science.gov (United States)

    Temme, Stephanie J.; Murphy, Geoffrey G.

    2017-01-01

    L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca[subscript V]1.2 and Ca[subscript V] 1.3, using transgenic mice have…

  13. Regulation of Ca2+ influx by a protein kinase C activator in chromaffin cells: differential role of P/Q- and L-type Ca2+ channels.

    Science.gov (United States)

    Sena, C M; Santos, R M; Boarder, M R; Rosário, L M

    1999-02-05

    Phorbol esters reduce depolarization-evoked Ca2+ influx in adrenal chromaffin cells, suggesting that voltage-sensitive Ca2+ channels (VSCCs) are inhibited by protein kinase C-mediated phosphorylation. We now address the possibility that L- and P/Q-type Ca2+ channel subtypes might be differentially involved in phorbol ester action. In bovine chromaffin cells, short-term (10 min) incubations with phorbol 12-myristate 13-acetate (PMA) inhibited early high K+-evoked rises in cytosolic free Ca2+ concentration ([Ca2+]i) and the early component of the depolarization-evoked Mn2+ quenching of fura-2 fluorescence in a dose-dependent manner (IC50: 18 and 7 nM; maximal inhibitions: 45 and 48%, respectively). The protein kinase C inhibitor staurosporine (100 nM) reverted the inhibitory action of PMA. PMA (0.1-1 microM) inhibited the early and late phases of the ionomycin (2 microM)-evoked [Ca2+]i transients by 14-23%. Omega-agatoxin IVA, a blocker of P/Q-type Ca2+ channels, inhibited high K+-evoked [Ca2+]i rises in a dose-dependent fashion (IC50 = 50 nM). In contrast, 0.1 microM omega-conotoxin GVIA, a blocker of N-type channels, was without effect. A sizeable (< 45%) component of early Ca2+ influx persisted in the combined presence of omega-agatoxin IVA (100 nM) and nitrendipine (1 microM). Simultaneous exposure to omega-agatoxin IVA and PMA inhibited both the early [Ca2+]i transients and Mn2+ quenching to a much greater extent than each drug separately. Inhibition of the [Ca2+]i transients by nitrendipine and PMA did not significantly exceed that produced by PMA alone. It is concluded that phorbol ester-mediated activation of protein kinase C inhibits preferentially L-type VSCCs over P/Q type channels in adrenal chromaffin cells. However, the possibility cannot be ruled out that dihydropyridine-resistant, non-P/Q type channels might also be negatively regulated by protein kinase C. This may represent an important pathway for the specific control of VSCCs by protein kinase C

  14. Electrophysiological properties of myocytes isolated from the mouse atrioventricular node: L-type ICa, IKr, If, and Na-Ca exchange.

    Science.gov (United States)

    Choisy, Stéphanie C; Cheng, Hongwei; Orchard, Clive H; James, Andrew F; Hancox, Jules C

    2015-11-01

    The atrioventricular node (AVN) is a key component of the cardiac pacemaker-conduction system. This study investigated the electrophysiology of cells isolated from the AVN region of adult mouse hearts, and compared murine ionic current magnitude with that of cells from the more extensively studied rabbit AVN. Whole-cell patch-clamp recordings of ionic currents, and perforated-patch recordings of action potentials (APs), were made at 35-37°C. Hyperpolarizing voltage commands from -40 mV elicited a Ba(2+)-sensitive inward rectifier current that was small at diastolic potentials. Some cells (Type 1; 33.4 ± 2.2 pF; n = 19) lacked the pacemaker current, If, whilst others (Type 2; 34.2 ± 1.5 pF; n = 21) exhibited a clear If, which was larger than in rabbit AVN cells. On depolarization from -40 mV L-type Ca(2+) current, IC a,L, was elicited with a half maximal activation voltage (V0.5) of -7.6 ± 1.2 mV (n = 24). IC a,L density was smaller than in rabbit AVN cells. Rapid delayed rectifier (IK r) tail currents sensitive to E-4031 (5 μmol/L) were observed on repolarization to -40 mV, with an activation V0.5 of -10.7 ± 4.7 mV (n = 8). The IK r magnitude was similar in mouse and rabbit AVN. Under Na-Ca exchange selective conditions, mouse AVN cells exhibited 5 mmol/L Ni-sensitive exchange current that was inwardly directed negative to the holding potential (-40 mV). Spontaneous APs (5.2 ± 0.5 sec(-1); n = 6) exhibited an upstroke velocity of 37.7 ± 16.2 V/s and ceased following inhibition of sarcoplasmic reticulum Ca(2+) release by 1 μmol/L ryanodine, implicating intracellular Ca(2+) cycling in murine AVN cell electrogenesis. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  15. Effects of induced Na+/Ca2+ exchanger overexpression on the spatial distribution of L-type Ca2+ channels and junctophilin-2 in pressure-overloaded hearts.

    Science.gov (United States)

    Ujihara, Yoshihiro; Mohri, Satoshi; Katanosaka, Yuki

    2016-11-25

    The Na + /Ca 2+ exchanger 1 (NCX1) is an essential Ca 2+ efflux system in cardiomyocytes. Although NCX1 is distributed throughout the sarcolemma, a subpopulation of NCX1 is localized to transverse (T)-tubules. There is growing evidence that T-tubule disorganization is a causal event that shifts the transition from hypertrophy to heart failure (HF). However, the detailed molecular mechanisms have not been clarified. Previously, we showed that induced NCX1 expression in pressure-overloaded hearts attenuates defective excitation-contraction coupling and HF progression. Here, we examined the effects of induced NCX1 overexpression on the spatial distribution of L-type Ca 2+ channels (LTCCs) and junctophilin-2 (JP2), a structural protein that connects the T-tubule and sarcoplasmic reticulum membrane, in pressure-overloaded hearts. Quantitative analysis showed that the regularity of NCX1 localization was significantly decreased at 8 weeks after transverse aortic constriction (TAC)-surgery; however, T-tubule organization and the regularities of LTCC and JP2 immunofluorescent signals were maintained at this time point. These observations demonstrated that release of NCX1 from the T-tubule area occurred before the onset of T-tubule disorganization and LTCC and JP2 mislocalization. Moreover, induced NCX1 overexpression at 8 weeks post-TAC not only recovered NCX1 regularity but also prevented the decrease in LTCC and JP2 regularities at 16 weeks post-TAC. These results suggested that NCX1 may play an important role in the proper spatial distribution of LTCC and JP2 in T-tubules in the context of pressure-overloading. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Functional properties of a newly identified C-terminal splice variant of Cav1.3 L-type Ca2+ channels.

    Science.gov (United States)

    Bock, Gabriella; Gebhart, Mathias; Scharinger, Anja; Jangsangthong, Wanchana; Busquet, Perrine; Poggiani, Chiara; Sartori, Simone; Mangoni, Matteo E; Sinnegger-Brauns, Martina J; Herzig, Stefan; Striessnig, Jörg; Koschak, Alexandra

    2011-12-09

    An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Ca(v)1.3 L-type Ca(2+) channels (Ca(v)1.3(L)) is a major determinant of their voltage- and Ca(2+)-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca(v)1.3(42A) channels that activate at a more negative voltage range and exhibit more pronounced Ca(2+)-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca(v)1.3(43S)) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca(v)1.3(42A), still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Ca(v)1.3(43S) also activated at more negative voltages like Ca(v)1.3(42A) but Ca(2+)-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca(v)1.3(L). The presence of the proximal C terminus in Ca(v)1.3(43S) channels preserved their modulation by distal C terminus-containing Ca(v)1.3- and Ca(v)1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca(2+) influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca(v)1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca(2+) channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca(2+) accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca(2+)-induced neurodegenerative processes.

  17. EGF suppresses hydrogen peroxide induced Ca2+ influx by inhibiting L-type channel activity in cultured human corneal endothelial cells.

    Science.gov (United States)

    Mergler, Stefan; Pleyer, Uwe; Reinach, Peter; Bednarz, Jürgen; Dannowski, Haike; Engelmann, Katrin; Hartmann, Christian; Yousif, Tarik

    2005-02-01

    Endogenous generated hydrogen peroxide during eye bank storage limits viability. We determined in cultured human corneal endothelial cells (HCEC) whether: (1) this oxidant induces elevations in intracellular calcium concentration [Ca2+]i; (2) epidermal growth factor (EGF) medium supplementation has a protective effect against peroxide mediated rises in [Ca2+]i. Whereas pathophysiological concentrations of H2O2 (10 mM) induced irreversible large increases in [Ca2+]i, lower concentrations (up to 1 mM) had smaller effects, which were further reduced by exposure to either 5 microM nifedipine or EGF (10 ng ml(-1)). EGF had a larger protective effect against H2O2-induced rises in [Ca2+]i than nifedipine. In addition, icilin, the agonist for the temperature sensitive transient receptor potential protein, TRPM8, had complex dose-dependent effects (i.e. 10 and 50 microM) on [Ca2+]i. At 10 microM, it reversibly elevated [Ca2+]i whereas at 50 microM an opposite effect occurred suggesting complex effects of temperature on endothelial viability. Taken together, H2O2 induces rises in [Ca2+]i that occur through increases in Ca2+ permeation along plasma membrane pathways that include L-type Ca2+ channels as well as other EGF-sensitive pathways. As EGF overcomes H2O2-induced rises in [Ca2+]i, its presence during eye bank storage could improve the outcome of corneal transplant surgery.

  18. Functional Properties of a Newly Identified C-terminal Splice Variant of Cav1.3 L-type Ca2+ Channels*

    Science.gov (United States)

    Bock, Gabriella; Gebhart, Mathias; Scharinger, Anja; Jangsangthong, Wanchana; Busquet, Perrine; Poggiani, Chiara; Sartori, Simone; Mangoni, Matteo E.; Sinnegger-Brauns, Martina J.; Herzig, Stefan; Striessnig, Jörg; Koschak, Alexandra

    2011-01-01

    An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Cav1.3 L-type Ca2+ channels (Cav1.3L) is a major determinant of their voltage- and Ca2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Cav1.342A channels that activate at a more negative voltage range and exhibit more pronounced Ca2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Cav1.343S) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Cav1.342A, still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Cav1.343S also activated at more negative voltages like Cav1.342A but Ca2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Cav1.3L. The presence of the proximal C terminus in Cav1.343S channels preserved their modulation by distal C terminus-containing Cav1.3- and Cav1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Cav1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca2+-induced neurodegenerative processes. PMID:21998310

  19. Vasoconstriction triggered by hydrogen sulfide: Evidence for Na+,K+,2Cl-cotransport and L-type Ca2+ channel-mediated pathway.

    Science.gov (United States)

    Orlov, Sergei N; Gusakova, Svetlana V; Smaglii, Liudmila V; Koltsova, Svetlana V; Sidorenko, Svetalana V

    2017-12-01

    This study examined the dose-dependent actions of hydrogen sulfide donor sodium hydrosulphide (NaHS) on isometric contractions and ion transport in rat aorta smooth muscle cells (SMC). Isometric contraction was measured in ring aortas segments from male Wistar rats. Activity of Na + /K + -pump and Na + ,K + ,2Cl - cotransport was measured in cultured endothelial and smooth muscle cells from the rat aorta as ouabain-sensitive and ouabain-resistant, bumetanide-sensitive components of the 86 Rb influx, respectively. NaHS exhibited the bimodal action on contractions triggered by modest depolarization ([K + ] o =30 mM). At 10 -4 M, NaHS augmented contractions of intact and endothelium-denuded strips by ~ 15% and 25%, respectively, whereas at concentration of 10 -3  M it decreased contractile responses by more than two-fold. Contractions evoked by 10 -4  M NaHS were completely abolished by bumetanide, a potent inhibitor of Na + ,K + ,2Cl - cotransport, whereas the inhibition seen at 10 -3  M NaHS was suppressed in the presence of K + channel blocker TEA. In cultured SMC, 5×10 -5  M NaHS increased Na + ,K + ,2Cl - - cotransport without any effect on the activity of this carrier in endothelial cells. In depolarized SMC, 45 Ca influx was enhanced in the presence of 10 -4  M NaHS and suppressed under elevation of [NaHS] up to 10 -3  M. 45 Ca influx triggered by 10 -4  M NaHS was abolished by bumetanide and L-type Ca 2+ channel blocker nicardipine. Our results strongly suggest that contractions of rat aortic rings triggered by low doses of NaHS are mediated by activation of Na + ,K + ,2Cl - cotransport and Ca 2+ influx via L-type channels.

  20. Estradiol up-regulates L-type Ca2+ channels via membrane-bound estrogen receptor/phosphoinositide-3-kinase/Akt/cAMP response element-binding protein signaling pathway.

    Science.gov (United States)

    Yang, Xiaoyan; Mao, Xiaofang; Xu, Gao; Xing, Shasha; Chattopadhyay, Ansuman; Jin, Si; Salama, Guy

    2018-05-01

    In long QT syndrome type 2, women are more prone than men to the lethal arrhythmia torsades de pointes. We previously reported that 17β-estradiol (E2) up-regulates L-type Ca 2+ channels and current (I Ca,L ) (∼30%) in rabbit ventricular myocytes by a classic genomic mechanism mediated by estrogen receptor-α (ERα). In long QT syndrome type 2 (I Kr blockade or bradycardia), the higher Ca 2+ influx via I Ca,L causes Ca 2+ overload, spontaneous sarcoplasmic reticulum Ca 2+ release, and reactivation of I Ca,L that triggers early afterdepolarizations and torsades de pointes. The purpose of this study was to investigate the molecular mechanisms whereby E2 up-regulates I Ca,L , which are poorly understood. H9C2 and rat myocytes were incubated with E2 ± ER antagonist, or inhibitors of downstream transcription factors, for 24 hours, followed by western blots of Cav1.2α1C and voltage-clamp measurements of I Ca,L . Incubation of H9C2 cells with E2 (10-100 nM) increased I Ca,L density and Cav1.2α1C expression, which were suppressed by the ER antagonist ICI182,780 (1 μM). Enhanced I Ca,L and Cav1.2α1C expression by E2 was suppressed by inhibitors of phosphoinositide-3-kinase (Pi3K) (30 μM LY294002; P L via plasma membrane ER and by activating Pi3K, Akt, and CREB signaling. The promoter regions of the CACNA1C gene (human-rabbit-rat) contain adjacent/overlapping binding sites for p-CREB and ERα, which suggests a synergistic regulation by these pathways. Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  1. C-terminal modulatory domain controls coupling of voltage-sensing to pore opening in Cav1.3 L-type Ca(2+) channels.

    Science.gov (United States)

    Lieb, Andreas; Ortner, Nadine; Striessnig, Jörg

    2014-04-01

    Activity of voltage-gated Cav1.3 L-type Ca(2+) channels is required for proper hearing as well as sinoatrial node and brain function. This critically depends on their negative activation voltage range, which is further fine-tuned by alternative splicing. Shorter variants miss a C-terminal regulatory domain (CTM), which allows them to activate at even more negative potentials than C-terminally long-splice variants. It is at present unclear whether this is due to an increased voltage sensitivity of the Cav1.3 voltage-sensing domain, or an enhanced coupling of voltage-sensor conformational changes to the subsequent opening of the activation gate. We studied the voltage-dependence of voltage-sensor charge movement (QON-V) and of current activation (ICa-V) of the long (Cav1.3L) and a short Cav1.3 splice variant (Cav1.342A) expressed in tsA-201 cells using whole cell patch-clamp. Charge movement (QON) of Cav1.3L displayed a much steeper voltage-dependence and a more negative half-maximal activation voltage than Cav1.2 and Cav3.1. However, a significantly higher fraction of the total charge had to move for activation of Cav1.3 half-maximal conductance (Cav1.3: 68%; Cav1.2: 52%; Cav3.1: 22%). This indicated a weaker coupling of Cav1.3 voltage-sensor charge movement to pore opening. However, the coupling efficiency was strengthened in the absence of the CTM in Cav1.342A, thereby shifting ICa-V by 7.2 mV to potentials that were more negative without changing QON-V. We independently show that the presence of intracellular organic cations (such as n-methyl-D-glucamine) induces a pronounced negative shift of QON-V and a more negative activation of ICa-V of all three channels. These findings illustrate that the voltage sensors of Cav1.3 channels respond more sensitively to depolarization than those of Cav1.2 or Cav3.1. Weak coupling of voltage sensing to pore opening is enhanced in the absence of the CTM, allowing short Cav1.342A splice variants to activate at lower voltages

  2. Coassembly of big conductance Ca2+-activated K+ channels and L-type voltage-gated Ca2+ channels in rat brain

    DEFF Research Database (Denmark)

    Grunnet, Morten; Kaufmann, Walter A

    2004-01-01

    Based on electrophysiological studies, Ca(2+)-activated K(+) channels and voltage-gated Ca(2+) channels appear to be located in close proximity in neurons. Such colocalization would ensure selective and rapid activation of K(+) channels by local increases in the cytosolic calcium concentration...

  3. Heparin/heparan sulfates bind to and modulate neuronal L-type (Cav1.2) voltage-dependent Ca2+ channels

    DEFF Research Database (Denmark)

    Garau, Gianpiero; Magotti, Paola; Heine, Martin

    2015-01-01

    Our previous studies revealed that L-type voltage-dependent Ca2+ channels (Cav1.2 L-VDCCs) are modulated by the neural extracellular matrix backbone, polyanionic glycan hyaluronic acid. Here we used isothermal titration calorimetry and screened a set of peptides derived from the extracellular......M), integrating their enthalpic and entropic binding contributions. Interaction between heparin and recombinant as well as native full-length neuronal Cav1.2α1 channels was confirmed using the heparin–agarose pull down assay. Whole cell patch clamp recordings in HEK293 cells transfected with neuronal Cav1.......2 channels revealed that enzymatic digestion of highly sulfated heparan sulfates with heparinase 1 affects neither voltage-dependence of channel activation nor the level of steady state inactivation, but did speed up channel inactivation. Treatment of hippocampal cultures with heparinase 1 reduced the firing...

  4. Increased expression of the auxiliary beta(2-subunit of ventricular L-type Ca(2+ channels leads to single-channel activity characteristic of heart failure.

    Directory of Open Access Journals (Sweden)

    Roger Hullin

    2007-03-01

    Full Text Available Increased activity of single ventricular L-type Ca(2+-channels (L-VDCC is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation.By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1 or beta(3 isoforms, beta(2a and beta(2b induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V1.2 also reveal increased single-channel activity and sarcolemmal beta(2 expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase", reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2 expression. Additional evidence for the cause-effect relationship between beta(2-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V1.2 and inducible beta(2 cardiac overexpression. Here in non-failing hearts induction of beta(2-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure.Our study presents evidence of the pathobiochemical relevance of beta(2-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.

  5. L-type Ca²⁺ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory.

    Science.gov (United States)

    Degoulet, M; Stelly, C E; Ahn, K-C; Morikawa, H

    2016-03-01

    Drug addiction is driven, in part, by powerful and enduring memories of sensory cues associated with drug intake. As such, relapse to drug use during abstinence is frequently triggered by an encounter with drug-associated cues, including the drug itself. L-type Ca(2+) channels (LTCCs) are known to regulate different forms of synaptic plasticity, the major neural substrate for learning and memory, in various brain areas. Long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA) may contribute to the increased motivational valence of drug-associated cues triggering relapse. In this study, using rat brain slices, we found that isradipine, a general LTCC antagonist used as antihypertensive medication, not only blocks the induction of NMDAR LTP but also promotes the reversal of previously induced LTP in the VTA. In behaving rats, isradipine injected into the VTA suppressed the acquisition of cocaine-paired contextual cue memory assessed using a conditioned place preference (CPP) paradigm. Furthermore, administration of isradipine or a CaV1.3 subtype-selective LTCC antagonist (systemic or intra-VTA) before a single extinction or reinstatement session, while having no immediate effect at the time of administration, abolished previously acquired cocaine and alcohol (ethanol) CPP on subsequent days. Notably, CPP thus extinguished cannot be reinstated by drug re-exposure, even after 2 weeks of withdrawal. These results suggest that LTCC blockade during exposure to drug-associated cues may cause unlearning of the increased valence of those cues, presumably via reversal of glutamatergic synaptic plasticity in the VTA.

  6. Astragalus Granule Prevents Ca2+ Current Remodeling in Heart Failure by the Downregulation of CaMKII

    Directory of Open Access Journals (Sweden)

    Sinai Li

    2017-01-01

    Full Text Available Background. Astragalus was broadly used for treating heart failure (HF and arrhythmias in East Asia for thousands of years. Astragalus granule (AG, extracted from Astragalus, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca2+ current (ICa-L in HF mice by the downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII. Methods. HF mice were induced by thoracic aortic constriction (TAC. After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP and ICa-L. The expressions of L-type calcium channel alpha 1C subunit (Cav1.2, CaMKII, and phosphorylated protein kinase A (p-PKA were examined by western blot. Results. The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered ICa-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG-related shortened repolarization time, decreased peak ICa-L, accelerated ICa-L inactivation, and positive frequency-dependent ICa-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart. Conclusion. AG treatment protected the failing heart against electrical remodeling and ICa-L remodeling by downregulating CaMKII.

  7. Sensitivity of Rabbit Ventricular Action Potential and Ca2+ Dynamics to Small Variations in Membrane Currents and Ion Diffusion Coefficients

    Directory of Open Access Journals (Sweden)

    Yuan Hung Lo

    2013-01-01

    Full Text Available Little is known about how small variations in ionic currents and Ca2+ and Na+ diffusion coefficients impact action potential and Ca2+ dynamics in rabbit ventricular myocytes. We applied sensitivity analysis to quantify the sensitivity of Shannon et al. model (Biophys. J., 2004 to 5%–10% changes in currents conductance, channels distribution, and ion diffusion in rabbit ventricular cells. We found that action potential duration and Ca2+ peaks are highly sensitive to 10% increase in L-type Ca2+ current; moderately influenced by 10% increase in Na+-Ca2+ exchanger, Na+-K+ pump, rapid delayed and slow transient outward K+ currents, and Cl− background current; insensitive to 10% increases in all other ionic currents and sarcoplasmic reticulum Ca2+ fluxes. Cell electrical activity is strongly affected by 5% shift of L-type Ca2+ channels and Na+-Ca2+ exchanger in between junctional and submembrane spaces while Ca2+-activated Cl−-channel redistribution has the modest effect. Small changes in submembrane and cytosolic diffusion coefficients for Ca2+, but not in Na+ transfer, may alter notably myocyte contraction. Our studies highlight the need for more precise measurements and further extending and testing of the Shannon et al. model. Our results demonstrate usefulness of sensitivity analysis to identify specific knowledge gaps and controversies related to ventricular cell electrophysiology and Ca2+ signaling.

  8. PDGF-induced migration of synthetic vascular smooth muscle cells through c-Src-activated L-type Ca2+ channels with full-length CaV1.2 C-terminus.

    Science.gov (United States)

    Guo, Xiaoguang; Kashihara, Toshihide; Nakada, Tsutomu; Aoyama, Toshifumi; Yamada, Mitsuhiko

    2018-06-01

    In atherosclerosis, vascular smooth muscle cells (VSMC) migrate from the media toward the intima of the arteries in response to cytokines, such as platelet-derived growth factor (PDGF). However, molecular mechanism underlying the PDGF-induced migration of VSMCs remains unclear. The migration of rat aorta-derived synthetic VSMCs, A7r5, in response to PDGF was potently inhibited by a Ca V 1.2 channel inhibitor, nifedipine, and a Src family tyrosine kinase (SFK)/Abl inhibitor, bosutinib, in a less-than-additive manner. PDGF significantly increased Ca V 1.2 channel currents without altering Ca V 1.2 protein expression levels in A7r5 cells. This reaction was inhibited by C-terminal Src kinase, a selective inhibitor of SFKs. In contractile VSMCs, the C-terminus of Ca V 1.2 is proteolytically cleaved into proximal and distal C-termini (PCT and DCT, respectively). Clipped DCT is noncovalently reassociated with PCT to autoinhibit the channel activity. Conversely, in synthetic A7r5 cells, full-length Ca V 1.2 (Ca V 1.2FL) is expressed much more abundantly than truncated Ca V 1.2. In a heterologous expression system, c-Src activated Ca V 1.2 channels composed of Ca V 1.2FL but not truncated Ca V 1.2 (Ca V 1.2Δ1763) or Ca V 1.2Δ1763 plus clipped DCT. Further, c-Src enhanced the coupling efficiency between the voltage-sensing domain and activation gate of Ca V 1.2FL channels by phosphorylating Tyr1709 and Tyr1758 in PCT. Compared with Ca V 1.2Δ1763, c-Src could more efficiently bind to and phosphorylate Ca V 1.2FL irrespective of the presence or absence of clipped DCT. Therefore, in atherosclerotic lesions, phenotypic switching of VSMCs may facilitate pro-migratory effects of PDGF on VSMCs by suppressing posttranslational Ca V 1.2 modifications.

  9. L-type calcium channel CaV 1.2 in transgenic mice overexpressing human AbetaPP751 with the London (V717I) and Swedish (K670M/N671L) mutations.

    Science.gov (United States)

    Willis, Michael; Kaufmann, Walter A; Wietzorrek, Georg; Hutter-Paier, Birgit; Moosmang, Sven; Humpel, Christian; Hofmann, Franz; Windisch, Manfred; Knaus, Hans-Günther; Marksteiner, Josef

    2010-01-01

    Cumulative evidence indicates that amyloid-beta peptides exert some of their neurodegenerative effects through modulation of L-type voltage gated calcium channels, which play key roles in a diverse range of CNS functions. In this study we examined the expression of CaV1.2 L-type voltage gated calcium channels in transgenic mice overexpressing human AbetaPP751 with the London (V717I) and Swedish (K670M/N671L) mutations by immunohistochemistry in light and electron microscopy. In hippocampal layers of wild type and transgenic mice, CaV1.2 channels were predominantly localized to somato-dendritic domains of neurons, and to astrocytic profiles with an age-dependent increase in labeling density. In transgenic animals, CaV1.2-like immunoreactive clusters were found in neuronal profiles in association with amyloid-beta plaques. Both the number and density of these clusters depended upon age of animals and number of plaques. The most striking difference between wild type and transgenic mice was the age-dependent expression of CaV1.2 channels in reactive astrocytes. At the age of 6 month, CaV1.2 channels were rarely detected in reactive astrocytes of transgenic mice, but an incremental number of CaV1.2 expressing reactive astrocytes was found with increasing age of animals and number of amyloid-beta plaques. This study demonstrates that CaV1.2 channels are highly expressed in reactive astrocytes of 12-months of age transgenic mice, which might be a consequence of the increasing amyloid burden. Further studies should clarify which functional implications are associated with the higher availability of CaV1.2 channels in late stage Alzheimer's disease.

  10. Hypoxic augmentation of Ca2+ channel currents requires a functional electron transport chain.

    Science.gov (United States)

    Brown, Stephen T; Scragg, Jason L; Boyle, John P; Hudasek, Kristin; Peers, Chris; Fearon, Ian M

    2005-06-10

    The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid beta (Abeta) peptide-mediated increases in voltage-gated L-type Ca(2+) channel activity contribute to the Ca(2+) dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O(2) levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca(2+) channel alpha(1C) subunits during CH and exposure to Abeta-(1-40). In wild-type (rho(+)) HEK 293 cells expressing recombinant L-type alpha(1C) subunits, Ca(2+) currents were enhanced by prolonged (24 h) exposure to either CH (6% O(2)) or Abeta-(1-40) (50 nm). By contrast the response to CH was absent in rho(0) cells in which the mitochondrial electron transport chain (ETC) was depleted following long term treatment with ethidium bromide or in rho(+) cells cultured in the presence of 1 microm rotenone. CH was mimicked in rho(0) cells by the exogenous production of O2(-.). by xanthine/xanthine oxidase. Furthermore Abeta-(1-40) enhanced currents in rho(0) cells to a degree similar to that seen in cells with an intact ETC. The antioxidants ascorbate (200 microm) and Trolox (500 microm) ablated the effect of CH in rho(+) cells but were without effect on Abeta-(1-40)-mediated augmentation of Ca(2+) current in rho(0) cells. Thus oxidant production in the mitochondrial ETC is a critical factor, acting upstream of amyloid beta peptide production in the up-regulation of Ca(2+) channels in response to CH.

  11. Differential contribution of Ca2+ sources to day and night BK current activation in the circadian clock.

    Science.gov (United States)

    Whitt, Joshua P; McNally, Beth A; Meredith, Andrea L

    2018-02-05

    Large conductance K + (BK) channels are expressed widely in neurons, where their activation is regulated by membrane depolarization and intracellular Ca 2+ (Ca 2+ i ). To enable this regulation, BK channels functionally couple to both voltage-gated Ca 2+ channels (VGCCs) and channels mediating Ca 2+ release from intracellular stores. However, the relationship between BK channels and their specific Ca 2+ source for particular patterns of excitability is not well understood. In neurons within the suprachiasmatic nucleus (SCN)-the brain's circadian clock-BK current, VGCC current, and Ca 2+ i are diurnally regulated, but paradoxically, BK current is greatest at night when VGCC current and Ca 2+ i are reduced. Here, to determine whether diurnal regulation of Ca 2+ is relevant for BK channel activation, we combine pharmacology with day and night patch-clamp recordings in acute slices of SCN. We find that activation of BK current depends primarily on three types of channels but that the relative contribution changes between day and night. BK current can be abrogated with nimodipine during the day but not at night, establishing that L-type Ca 2+ channels (LTCCs) are the primary daytime Ca 2+ source for BK activation. In contrast, dantrolene causes a significant decrease in BK current at night, suggesting that nighttime BK activation is driven by ryanodine receptor (RyR)-mediated Ca 2+ i release. The N- and P/Q-type Ca 2+ channel blocker ω-conotoxin MVIIC causes a smaller reduction of BK current that does not differ between day and night. Finally, inhibition of LTCCs, but not RyRs, eliminates BK inactivation, but the BK β2 subunit was not required for activation of BK current by LTCCs. These data reveal a dynamic coupling strategy between BK channels and their Ca 2+ sources in the SCN, contributing to diurnal regulation of SCN excitability. © 2018 Whitt et al.

  12. Ca(2+) currents and voltage responses in Type I and Type II hair cells of the chick embryo semicircular canal.

    Science.gov (United States)

    Masetto, Sergio; Zampini, Valeria; Zucca, Giampiero; Valli, Paolo

    2005-11-01

    Type I and Type II hair cells, and Type II hair cells located in different zones of the semicircular canal crista, express different patterns of voltage-dependent K channels, each one specifically shaping the hair cell receptor potential. We report here that, close to hatching, chicken embryo semicircular canal Type I and Type II hair cells express a similar voltage-dependent L-type calcium current (I(Ca)), whose main features are: activation above -60 mV, fast activation kinetics, and scarce inactivation. I(Ca) should be already active at rest in Zone 1 Type II hair cells, whose resting membrane potential was on average slightly less negative than -60 mV. Conversely, I(Ca) would not be active at rest in Type II hair cells from Zone 2 and 3, nor in Type I hair cells, since their resting membrane potential was significantly more negative than -60 mV. However, even small depolarising currents would activate I(Ca) steadily in Zone 2 and 3 Type II hair cells, but not in Type I hair cells because of the robust repolarising action of their specific array of K(+) currents. The implications of the present findings in the afferent discharge are discussed.

  13. F-actin-based Ca signaling-a critical comparison with the current concept of Ca signaling.

    Science.gov (United States)

    Lange, Klaus; Gartzke, Joachim

    2006-11-01

    A short comparative survey on the current idea of Ca signaling and the alternative concept of F-actin-based Ca signaling is given. The two hypotheses differ in one central aspect, the mechanism of Ca storage. The current theory rests on the assumption of Ca-accumulating endoplasmic/sarcoplasmic reticulum-derived vesicles equipped with an ATP-dependent Ca pump and IP3- or ryanodine-sensitive channel-receptors for Ca-release. The alternative hypothesis proceeds from the idea of Ca storage at the high-affinity binding sites of actin filaments. Cellular sites of F-actin-based Ca storage are microvilli and the submembrane cytoskeleton. Several specific features of Ca signaling such as store-channel coupling, quantal Ca release, spiking and oscillations, biphasic and "phasic" uptake kinetics, and Ca-induced Ca release (CICR), which are not adequately described by the current concept, are inherent properties of the F-actin system and its dynamic state of treadmilling. Copyright 2006 Wiley-Liss, Inc.

  14. Stac gets the skeletal L-type calcium channel unstuck

    Czech Academy of Sciences Publication Activity Database

    Weiss, Norbert

    2015-01-01

    Roč. 34, č. 2 (2015), s. 101-103 ISSN 0231-5882 Institutional support: RVO:61388963 Keywords : calcium channel * L-type calcium channel * Ca(v)1.1 channel * Stac adaptor protein * excitation- contraction coupling * trafficking Subject RIV: CE - Biochemistry Impact factor: 0.892, year: 2015

  15. High-Frequency Stimulation-Induced Synaptic Potentiation in Dorsal and Ventral CA1 Hippocampal Synapses: The Involvement of NMDA Receptors, mGluR5, and (L-Type) Voltage-Gated Calcium Channels

    Science.gov (United States)

    Papatheodoropoulos, Costas; Kouvaros, Stylianos

    2016-01-01

    The ability of the ventral hippocampus (VH) for long-lasting long-term potentiation (LTP) and the mechanisms underlying its lower ability for shortlasting LTP compared with the dorsal hippocampus (DH) are unknown. Using recordings of field excitatory postsynaptic potentials (EPSPs) from the CA1 field of adult rat hippocampal slices, we found that…

  16. CaV 3.1 and CaV 3.3 account for T-type Ca2+ current in GH3 cells

    Directory of Open Access Journals (Sweden)

    M.A. Mudado

    2004-06-01

    Full Text Available T-type Ca2+ channels are important for cell signaling by a variety of cells. We report here the electrophysiological and molecular characteristics of the whole-cell Ca2+ current in GH3 clonal pituitary cells. The current inactivation at 0 mV was described by a single exponential function with a time constant of 18.32 ± 1.87 ms (N = 16. The I-V relationship measured with Ca2+ as a charge carrier was shifted to the left when we applied a conditioning pre-pulse of up to -120 mV, indicating that a low voltage-activated current may be present in GH3 cells. Transient currents were first activated at -50 mV and peaked around -20 mV. The half-maximal voltage activation and the slope factors for the two conditions are -35.02 ± 2.4 and 6.7 ± 0.3 mV (pre-pulse of -120 mV, N = 15, and -27.0 ± 0.97 and 7.5 ± 0.7 mV (pre-pulse of -40 mV, N = 9. The 8-mV shift in the activation mid-point was statistically significant (P < 0.05. The tail currents decayed bi-exponentially suggesting two different T-type Ca2+ channel populations. RT-PCR revealed the presence of a1G (CaV3.1 and a1I (CaV3.3 T-type Ca2+ channel mRNA transcripts.

  17. L-type calcium channels refine the neural population code of sound level

    Science.gov (United States)

    Grimsley, Calum Alex; Green, David Brian

    2016-01-01

    The coding of sound level by ensembles of neurons improves the accuracy with which listeners identify how loud a sound is. In the auditory system, the rate at which neurons fire in response to changes in sound level is shaped by local networks. Voltage-gated conductances alter local output by regulating neuronal firing, but their role in modulating responses to sound level is unclear. We tested the effects of L-type calcium channels (CaL: CaV1.1–1.4) on sound-level coding in the central nucleus of the inferior colliculus (ICC) in the auditory midbrain. We characterized the contribution of CaL to the total calcium current in brain slices and then examined its effects on rate-level functions (RLFs) in vivo using single-unit recordings in awake mice. CaL is a high-threshold current and comprises ∼50% of the total calcium current in ICC neurons. In vivo, CaL activates at sound levels that evoke high firing rates. In RLFs that increase monotonically with sound level, CaL boosts spike rates at high sound levels and increases the maximum firing rate achieved. In different populations of RLFs that change nonmonotonically with sound level, CaL either suppresses or enhances firing at sound levels that evoke maximum firing. CaL multiplies the gain of monotonic RLFs with dynamic range and divides the gain of nonmonotonic RLFs with the width of the RLF. These results suggest that a single broad class of calcium channels activates enhancing and suppressing local circuits to regulate the sensitivity of neuronal populations to sound level. PMID:27605536

  18. A critical comparison of the current view of Ca signaling with the novel concept of F-actin-based Ca signaling.

    Science.gov (United States)

    Lange, Klaus; Gartzke, Joachim

    2006-01-01

    A detailed comparative survey on the current idea of Ca signaling and the alternative concept of F-actin-based Ca signaling is given. The two hypotheses differ in one central aspect - the mechanism of Ca storage. The current theory rests on the assumption of Ca-accumulating vesicles derived from the endoplasmic/ sarcoplasmic reticulum, which are equipped with an ATP-dependent Ca pump and IP3- or ryanodine-sensitive Ca-release channels/receptors. The alternative hypothesis proceeds from the idea of Ca storage at the high-affinity binding sites of F-actin subunits. Several prominent features of Ca signaling, which are not adequately described by the current concept, are inherent properties of the F-actin system and its dynamic state of treadmilling. F-actin is the only known biological Ca-binding system that has been proven by in vitro experiments to work within the physiological range of Ca concentrations and the only system that meets all necessary conditions to function as receptor-operated Ca store and as a coupling device between the Ca store and the store-operated Ca influx pathway. The most important properties of Ca signaling, such as store-channel coupling, quantal Ca release, spiking and oscillations, biphasic and "phasic" uptake kinetics, and Ca-induced Ca release, turn out to be systematic features of the new concept but remain unexplained by the classical vesicle storage hypothesis. A number of novel findings, specifically recent reports about direct effects of actin-specific toxins on Ca stores, have strengthened the new concept. The concept of F-actin-based Ca signaling combined with the notion of microvillar regulation of ion and substrate fluxes opens new aspects and far-reaching consequences, not only for cellular Ca signaling but also for various other cell functions, and represents an opportunity to connect several fields of cell physiology on the basis of a common mechanism.

  19. Currents of thermally stimulated depolarization in CaIn2S4 single crystals

    International Nuclear Information System (INIS)

    Tagiev, B.G.; Tagiev, O.B.; Dzhabbarov, R.B.; Musaeva, N.N.

    1996-01-01

    The results of investigation into currents of thermally stimulated depolarization in CaIn 2 S 4 monocrystals are presented for the first time. Spectra of thermally stimulated depolarization for In-CaIn S4 -In structures are measured under T=99 K at various rates of heat, times of polarization and times of expectation following switching off of electrical field up to beginning of measurements of shorting. The main parameters of capture cross section, partial factor, concentration of traps, are determined. It is determined that one may observed a biomolecular mechanism with a strong secondary capture in CaIn 2 S 4 monocrystals. 9 refs.; 4 figs

  20. A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis.

    Directory of Open Access Journals (Sweden)

    Jessica A Hennessey

    Full Text Available Mutations in CACNA1C that increase current through the CaV1.2 L-type Ca2+ channel underlie rare forms of long QT syndrome (LQTS, and Timothy syndrome (TS. We identified a variant in CACNA1C in a male child of Filipino descent with arrhythmias and extracardiac features by candidate gene sequencing and performed functional expression studies to electrophysiologically characterize the effects of the variant on CaV1.2 channels. As a baby, the subject developed seizures and displayed developmental delays at 30 months of age. At age 5 years, he displayed a QTc of 520 ms and experienced recurrent VT. Physical exam at 17 years of age was notable for microcephaly, short stature, lower extremity weakness and atrophy with hyperreflexia, spastic diplegia, multiple dental caries and episodes of rhabdomyolysis. Candidate gene sequencing identified a G>C transversion at position 5731 of CACNA1C (rs374528680 predicting a glycine>arginine substitution at residue 1911 (p.G1911R of CaV1.2. The allele frequency of this variant is 0.01 in Malays, but absent in 984 Caucasian alleles and in the 1000 genomes project. In electrophysiological analyses, the variant decreased voltage-dependent inactivation, thus causing a gain of function of CaV1.2. We also observed a negative shift of V1/2 of activation and positive shift of V1/2 of channel inactivation, resulting in an increase of the window current. Together, these suggest a gain-of-function effect on CaV1.2 and suggest increased susceptibility for arrhythmias in certain clinical settings. The p.G1911R variant was also identified in a case of sudden unexplained infant death (SUID, for which an increasing number of clinical observations have demonstrated can be associated with arrhythmogenic mutations in cardiac ion channels. In summary, the combined effects of the CACNA1C variant to diminish voltage-dependent inactivation of CaV1.2 and increase window current expand our appreciation of mechanisms by which a gain of

  1. CNTF inhibits high voltage activated Ca2+ currents in fetal mouse cortical neurones

    DEFF Research Database (Denmark)

    Holm, Ninna R; Christophersen, Palle; Hounsgaard, Jørn

    2002-01-01

    of the alpha-subunit glycerophosphatidylinositol anchor of the receptor eliminated the response. The CNTF effect was not elicited through pertussis toxin-sensitive G proteins. Other neurotrophic factors like neurotrophin-3 and insulin-like growth factor-I had no effect on the Ca2+ currents. These results may...

  2. Ca2+-currents in human induced pluripotent stem cell-derived cardiomyocytes - effects of two different culture conditions

    Directory of Open Access Journals (Sweden)

    Ahmet Umur Uzun

    2016-09-01

    Full Text Available Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM provide a unique opportunity to study human heart physiology and pharmacology and repair injured hearts. The suitability of hiPSC-CM critically depends on how closely they share physiological properties of human adult cardiomyocytes (CM. Here we investigated whether a 3D engineered heart tissue (EHT culture format favors maturation and addressed the L-type Ca2+-current (ICa,L as a readout. The results were compared with hiPSC-CM cultured in conventional monolayer (ML and to our previous data from human adult atrial and ventricular CM obtained when identical patch-clamp protocols were used. HiPSC-CM were 2-3 fold smaller than adult CM, independently of culture format (capacitance ML 45±1 pF (n=289, EHT 45±1 pF (n=460, atrial CM 87±3 pF (n=196, ventricular CM 126±8 pF (n=50. Only 88% of ML cells showed ICa, but all EHT. Basal ICa density was 10±1 pA/pF (n=207 for ML and 12±1 pA/pF (n=361 for EHT and was larger than in adult CM (7±1 pA/pF (p<0.05, n=196 for atrial CM and 6±1 pA/pF (p<0.05, n=47 for ventricular CM. However, ML and EHT showed robust T-type Ca2+-currents (ICa,T. While (--Bay K 8644, that activates ICa,L directly, increased ICa,L to the same extent in ML and EHT, β1- and β2-adrenoceptor effects were marginal in ML, but of same size as (--Bay K 8644 in EHT. The opposite was true for serotonin receptors. Sensitivity to β1 and β2-adrenoceptor stimulation was the same in EHT as in adult CM (-logEC50: 5.9 and 6.1 for norepinephrine (NE and epinephrine (Epi, respectively, but very low concentrations of Rp-8-Br-cAMPS were sufficient to suppress effects (-logEC50: 5.3 and 5.3 respectively for NE and Epi. Taken together, hiPSC-CM express ICa,L at the same density as human adult CM, but, in contrast, possess robust ICa,T. Increased effects of catecholamines in EHT suggest more efficient maturation.

  3. Gestational hypothyroidism-induced changes in L-type calcium channels of rat aorta smooth muscle and their impact on the responses to vasoconstrictors

    Directory of Open Access Journals (Sweden)

    Katayoun Sedaghat

    2015-02-01

    Conclusion: This study suggests that in hypothyroid offspring L-type Ca2+ channels are less functional, while intracellular Ca2+ handling systems are less modified by low levels of maternal thyroid hormones.

  4. Calcium current activation kinetics in isolated pyramidal neurones of the Ca1 region of the mature guinea-pig hippocampus.

    Science.gov (United States)

    Kay, A R; Wong, R K

    1987-11-01

    1. Neurones were isolated from the CA1 region of the guinea-pig hippocampus and subjected to the whole-cell mode of voltage clamping, to determine the kinetics of voltage-gated Ca2+ channel activation. 2. Isolated neurones had an abbreviated morphology, having lost most of the distal dendritic tree during the isolation procedure. The electrical compactness of the cells facilitates voltage clamp analysis. 3. Block of sodium and potassium currents revealed a persistent current activated on depolarization above -40 mV, which inactivated slowly when the intracellular medium contained EGTA. The current was blocked by Co2+ and Cd2+, augmented by increases in Ca2+ and could be carried by Ba2+, suggesting that the current is borne by Ca2+. 4. Steady-state activation of the Ca2+ current was found to be well described by the Boltzman equation raised to the second power. 5. The open channel's current-voltage (I-V) relationship rectified in the inward direction and was consistent with the constant-field equation. 6. The kinetics of Ca2+ current onset followed m2 kinetics throughout the range of its activation. Tail current kinetics were in accord with this model. A detailed Hodgkin-Huxley model was derived, defining the activation of this current. 7. The kinetics of the currents observed in this regionally and morphologically defined class of neurones were consistent with the existence of a single kinetic class of channels.

  5. Critical current density of BiSrCaCuO superconductors: effect of surface barriers

    International Nuclear Information System (INIS)

    Konczykowski, M.; Chikumoto, N.

    1992-01-01

    Effects of surface barriers on vortex motion in BiSrCaCuO-2212 high-temperature superconducting crystals is summarized. Characteristic features of this phenomenon appear in the hysteresis loop (shape of its ascending and descending branches), in the effect of 2.5 MeV electron irradiation, and in flux creep measurements (magnetization dependence to the crystal lateral dimension, size of the flux-creep barrier and the crossover as a function of temperature and time persistent current density). (A.B.). 25 refs., 3 figs

  6. Role of action potential configuration and the contribution of Ca2+ and K+ currents to isoprenaline-induced changes in canine ventricular cells

    Science.gov (United States)

    Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, PP

    2012-01-01

    BACKGROUND AND PURPOSE Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca2+ current (ICa), slow delayed rectifier K+ current (IKs) and fast delayed rectifier K+ current (IKr) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. EXPERIMENTAL APPROACH Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. KEY RESULTS In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the IKr blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the IKs blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the ICa blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating ICa followed by a rise in IKs, both currents increased with increasing the cycle length. CONCLUSIONS AND IMPLICATIONS The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of IKs– but not IKr– may be responsible for the observed shortening of action potentials. PMID:22563726

  7. Cell cycle-dependent activity of the volume- and Ca2+-activated anion currents in Ehrlich lettre ascites cells

    DEFF Research Database (Denmark)

    Klausen, Thomas Kjaer; Bergdahl, Andreas; Christophersen, Palle

    2007-01-01

    Recent evidence implicates the volume-regulated anion current (VRAC) and other anion currents in control or modulation of cell cycle progression; however, the precise involvement of anion channels in this process is unclear. Here, Cl- currents in Ehrlich Lettre Ascites (ELA) cells were monitored...... during cell cycle progression, under three conditions: (i) after osmotic swelling (i.e., VRAC), (ii) after an increase in the free intracellular Ca2+ concentration (i.e., the Ca2+-activated Cl- current, CaCC), and (iii) under steady-state isotonic conditions. The maximal swelling-activated VRAC current......+ in the pipette), was unaltered from G0 to G1, but decreased in early S phase. A novel high-affinity anion channel inhibitor, the acidic di-aryl-urea NS3728, which inhibited both VRAC and CaCC, attenuated ELA cell growth, suggesting a possible mechanistic link between cell cycle progression and cell cycle...

  8. Evidence of the Current Collector Effect: Study of the SOFC Cathode Material Ca3Co4O9+d

    NARCIS (Netherlands)

    Rolle, A.; Thoréton, V.; Rozier, P.; Capoen, E.; Mentré, O.; Boukamp, Bernard A.; Daviero-Minaud, S.

    2012-01-01

    In the study of the performance of solid oxide fuel cell (SOFC) electrodes, the possible influence of the applied current collector is often not mentioned or recognized. In this article, as part of an optimization study of the potentially attractive Ca3Co4O9+δ cathode material (Ca349), special

  9. Quantitative analysis of the Ca2+ -dependent regulation of delayed rectifier K+ current IKs in rabbit ventricular myocytes.

    Science.gov (United States)

    Bartos, Daniel C; Morotti, Stefano; Ginsburg, Kenneth S; Grandi, Eleonora; Bers, Donald M

    2017-04-01

    [Ca 2+ ] i enhanced rabbit ventricular slowly activating delayed rectifier K + current (I Ks ) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol. Rabbit ventricular rapidly activating delayed rectifier K + current (I Kr ) amplitude and voltage dependence were unaffected by high [Ca 2+ ] i . When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca 2+ transient or when [Ca 2+ ] i was buffered to 500 nm. The slowly activating delayed rectifier K + current (I Ks ) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca 2+ ([Ca 2+ ] i ) and β-adrenergic receptor (β-AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca 2+ ] i dependence of I Ks in steady-state conditions and with dynamically changing membrane potential and [Ca 2+ ] i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole-cell patch clamp. With intracellular pipette solutions that controlled free [Ca 2+ ] i , we found that raising [Ca 2+ ] i from 100 to 600 nm produced similar increases in I Ks as did β-AR activation, and the effects appeared additive. Both β-AR activation and high [Ca 2+ ] i increased maximally activated tail I Ks , negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well-established mathematical model of the rabbit myocyte. In both AP-clamp experiments and simulations, I Ks recorded during a normal physiological Ca 2+ transient was similar to I Ks measured with [Ca 2+ ] i clamped at 500-600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca 2+ ] i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca 2+ ] i , in the submembrane or

  10. Mg/Ca Ratios in Coralline Red Algae as Temperature Proxies for Reconstructing Labrador Current Variability

    Science.gov (United States)

    Gamboa, G.; Hetzinger, S.; Halfar, J.; Zack, T.; Kunz, B.; Adey, W.

    2009-05-01

    Marine ecosystems and fishery productivity in the Northwestern Atlantic have been considerably affected by regional climate and oceanographic changes. Fluctuations of North Atlantic marine climate have been linked in part to a dominant pattern of atmospheric circulation known as the North Atlantic Oscillation, which has a strong influence on transport variability of the Labrador Current (LC). The cold LC originates in the Labrador Sea and flows southbound along the Eastern Canadian coastline causing an important cooling effect on marine waters off the Canadian Atlantic provinces. Although interdecadal and interannual variability of sea surface temperatures (SST) in the LC system have been documented, a long-term pattern has not been identified. In order to better understand the observed ecosystem changes and their relationship with climate variability in the Northwestern Atlantic, a century-scale reconstruction of spatial and temporal variations of the LC is needed. This, however, requires reliable long-term and high-resolution SST records, which are not available from short instrumental observations. Here we present the first century-scale SST reconstructions from the Northwest Atlantic using long-lived coralline red algae. Coralline red algae have a high-Mg calcite skeleton, live in shallow water worldwide and develop annual growth bands. It has previously been demonstrated that subannual resolution SSTs can be obtained from coralline red algal Mg/Ca ratios, a commonly used paleotemperature proxy. Specimens of the long-lived coralline red algae Clathromorphum compactum were collected alive in August 2008 along a latitudinal transect spanning the southern extent of LC flow in Nova Scotia and Newfoundland. This collection is supplemented with specimens from the same region collected in the 1960's. In order to reconstruct spatial and temporal patterns of the LC, selected samples of C. compactum were analyzed for Mg/Ca using Laser Ablation Inductively-Coupled Plasma

  11. Turtle Flexion Reflex Motor Patterns Show Windup, Mediated Partly by L-type Calcium Channels

    Directory of Open Access Journals (Sweden)

    Keith P. Johnson

    2017-10-01

    Full Text Available Windup is a form of multisecond temporal summation in which identical stimuli, delivered seconds apart, trigger increasingly strong neuronal responses. L-type Ca2+ channels have been shown to play an important role in the production of windup of spinal cord neuronal responses, initially in studies of turtle spinal cord and later in studies of mammalian spinal cord. L-type Ca2+ channels have also been shown to contribute to windup of limb withdrawal reflex (flexion reflex in rats, but flexion reflex windup has not previously been described in turtles and its cellular mechanisms have not been studied. We studied windup of flexion reflex motor patterns, evoked with weak mechanical and electrical stimulation of the dorsal hindlimb foot skin and assessed via a hip flexor (HF nerve recording, in spinal cord-transected and immobilized turtles in vivo. We found that an L-type Ca2+ channel antagonist, nifedipine, applied at concentrations of 50 μM or 100 μM to the hindlimb enlargement spinal cord, significantly reduced windup of flexion reflex motor patterns, while lower concentrations of nifedipine had no such effect. Nifedipine similarly reduced the amplitude of an individual flexion reflex motor pattern evoked by a stronger mechanical stimulus, in a dose-dependent manner, suggesting that L-type Ca2+ channels contribute to each flexion reflex as well as to multisecond summation of flexion reflex responses in turtles. We also found that we could elicit flexion reflex windup consistently using a 4-g von Frey filament, which is not usually considered a nociceptive stimulus. Thus, it may be that windup can be evoked by a wide range of tactile stimuli and that L-type calcium channels contribute to multisecond temporal summation of diverse tactile stimuli across vertebrates.

  12. Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase.

    Science.gov (United States)

    Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

    2016-11-01

    Inward rectifier K + channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP 2 ). Stimulation of the Ca 2+ -sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both G q/11 , which decreases PIP 2 , and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP 2 . How membrane PIP 2 levels are regulated by CaR activation and whether these changes modulate inward rectifier K + are unknown. In this study, we found that activation of CaR by the allosteric agonist, NPSR568, increased inward rectifier K + current (I K1 ) in guinea pig ventricular myocytes and currents mediated by Kir2.1 channels exogenously expressed in HEK293T cells with a similar sensitivity. Moreover, using the fluorescent PIP 2 reporter tubby-R332H-cYFP to monitor PIP 2 levels, we found that CaR activation in HEK293T cells increased membrane PIP 2 concentrations. Pharmacological studies showed that both phospholipase C (PLC) and PI-4-K are activated by CaR stimulation with the latter played a dominant role in regulating membrane PIP 2 and, thus, Kir currents. These results provide the first direct evidence that CaR activation upregulates currents through inward rectifier K + channels by accelerating PIP 2 synthesis. The regulation of I K1 plays a critical role in the stability of the electrical properties of many excitable cells, including cardiac myocytes and neurons. Further, synthetic allosteric modulators that increase CaR activity have been used to treat hyperparathyroidism, and negative CaR modulators are of potential importance in the treatment of osteoporosis. Thus, our results provide further insight into the roles played by CaR in the cardiovascular system and are potentially valuable for heart disease treatment and drug safety.

  13. Intracellular Ca(2+) release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal.

    Science.gov (United States)

    Zhu, Mei Hong; Sung, Tae Sik; O'Driscoll, Kate; Koh, Sang Don; Sanders, Kenton M

    2015-04-15

    Interstitial cells of Cajal (ICC) provide pacemaker activity in gastrointestinal muscles that underlies segmental and peristaltic contractions. ICC generate electrical slow waves that are due to large-amplitude inward currents resulting from anoctamin 1 (ANO1) channels, which are Ca(2+)-activated Cl(-) channels. We investigated the hypothesis that the Ca(2+) responsible for the stochastic activation of ANO1 channels during spontaneous transient inward currents (STICs) and synchronized activation of ANO1 channels during slow wave currents comes from intracellular Ca(2+) stores. ICC, obtained from the small intestine of Kit(+/copGFP) mice, were studied under voltage and current clamp to determine the effects of blocking Ca(2+) uptake into stores and release of Ca(2+) via inositol 1,4,5-trisphosphate (IP3)-dependent and ryanodine-sensitive channels. Cyclocpiazonic acid, thapsigargin, 2-APB, and xestospongin C inhibited STICs and slow wave currents. Ryanodine and tetracaine also inhibited STICs and slow wave currents. Store-active compounds had no direct effects on ANO1 channels expressed in human embryonic kidney-293 cells. Under current clamp, store-active drugs caused significant depolarization of ICC and reduced spontaneous transient depolarizations (STDs). After block of ryanodine receptors with ryanodine and tetracaine, repolarization did not restore STDs. ANO1 expressed in ICC has limited access to cytoplasmic Ca(2+) concentration, suggesting that pacemaker activity depends on Ca(2+) dynamics in restricted microdomains. Our data from studies of isolated ICC differ somewhat from studies on intact muscles and suggest that release of Ca(2+) from both IP3 and ryanodine receptors is important in generating pacemaker activity in ICC. Copyright © 2015 the American Physiological Society.

  14. Intracellular Ca2+ release from endoplasmic reticulum regulates slow wave currents and pacemaker activity of interstitial cells of Cajal

    Science.gov (United States)

    Zhu, Mei Hong; Sung, Tae Sik; O'Driscoll, Kate; Koh, Sang Don

    2015-01-01

    Interstitial cells of Cajal (ICC) provide pacemaker activity in gastrointestinal muscles that underlies segmental and peristaltic contractions. ICC generate electrical slow waves that are due to large-amplitude inward currents resulting from anoctamin 1 (ANO1) channels, which are Ca2+-activated Cl− channels. We investigated the hypothesis that the Ca2+ responsible for the stochastic activation of ANO1 channels during spontaneous transient inward currents (STICs) and synchronized activation of ANO1 channels during slow wave currents comes from intracellular Ca2+ stores. ICC, obtained from the small intestine of Kit+/copGFP mice, were studied under voltage and current clamp to determine the effects of blocking Ca2+ uptake into stores and release of Ca2+ via inositol 1,4,5-trisphosphate (IP3)-dependent and ryanodine-sensitive channels. Cyclocpiazonic acid, thapsigargin, 2-APB, and xestospongin C inhibited STICs and slow wave currents. Ryanodine and tetracaine also inhibited STICs and slow wave currents. Store-active compounds had no direct effects on ANO1 channels expressed in human embryonic kidney-293 cells. Under current clamp, store-active drugs caused significant depolarization of ICC and reduced spontaneous transient depolarizations (STDs). After block of ryanodine receptors with ryanodine and tetracaine, repolarization did not restore STDs. ANO1 expressed in ICC has limited access to cytoplasmic Ca2+ concentration, suggesting that pacemaker activity depends on Ca2+ dynamics in restricted microdomains. Our data from studies of isolated ICC differ somewhat from studies on intact muscles and suggest that release of Ca2+ from both IP3 and ryanodine receptors is important in generating pacemaker activity in ICC. PMID:25631870

  15. L-Type Calcium Channel Inhibition Contributes to the Proarrhythmic Effects of Aconitine in Human Cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Jianjun Wu

    Full Text Available Aconitine (ACO is well-known for causing lethal ventricular tachyarrhythmias. While cardiac Na+ channel opening during repolarization has long been documented in animal cardiac myocytes, the cellular effects and mechanism of ACO in human remain unexplored. This study aimed to assess the proarrhythmic effects of ACO in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs. ACO concentration-dependently (0.3 ~ 3.0 μM shortened the action potentials (AP durations (APD in ventricular-like hiPSC-CMs by > 40% and induced delayed after-depolarization. Laser-scanning confocal calcium imaging analysis showed that ACO decreased the duration and amplitude of [Ca2+]i transients and increased in the beating frequencies by over 60%. Moreover, ACO was found to markedly reduce the L-type calcium channel (LTCC currents (ICa,L in hiPSC-CMs associated with a positive-shift of activation and a negative shift of inactivation. ACO failed to alter the peak and late Na+ currents (INa in hiPSC-CMs while it drastically increased the late INa in Guinea-pig ventricular myocytes associated with enhanced activation/delayed inactivation of INa at -55 mV~ -85 mV. Further, the effects of ACO on ICa,L, INa and the rapid delayed rectifier potassium current (Ikr were validated in heterologous expression systems by automated voltage-clamping assays and a moderate suppression of Ikr was observed in addition to concentration-dependent ICa,L inhibition. Lastly, increased beating frequency, decreased Ca2+ wave and shortened field potential duration were recorded from hiPSC-CMs by microelectrode arrays assay. In summary, our data demonstrated that LTCC inhibition could play a main role in the proarrhythmic action of ACO in human cardiomyocytes.

  16. Attenuation of hypoxic current by intracellular applications of ATP regenerating agents in hippocampal CA1 neurons of rat brain slices.

    Science.gov (United States)

    Chung, I; Zhang, Y; Eubanks, J H; Zhang, L

    1998-10-01

    Hypoxia-induced outward currents (hyperpolarization) were examined in hippocampal CA1 neurons of rat brain slices, using the whole-cell recording technique. Hypoxic episodes were induced by perfusing slices with an artificial cerebrospinal fluid aerated with 5% CO2/95% N2 rather than 5% CO2/95% O2, for about 3 min. The hypoxic current was consistently and reproducibly induced in CA1 neurons dialysed with an ATP-free patch pipette solution. This current manifested as an outward shift in the holding current in association with increased conductance, and it reversed at -78 +/- 2.5 mV, with a linear I-V relation in the range of -100 to -40 mV. To provide extra energy resources to individual neurons recorded, agents were added to the patch pipette solution, including MgATP alone, MgATP + phosphocreatine + creatine kinase, or MgATP + creatine. In CA1 neurons dialysed with patch solutions including these agents, hypoxia produced small outward currents in comparison with those observed in CA1 neurons dialysed with the ATP-free solution. Among the above agents examined, whole-cell dialysis with MgATP + creatine was the most effective at decreasing the hypoxic outward currents. We suggest that the hypoxic hyperpolarization is closely related to energy metabolism in individual CA1 neurons, and that the energy supply provided by phosphocreatine metabolism may play a critical role during transient metabolic stress.

  17. A computational model of the ionic currents, Ca2+ dynamics and action potentials underlying contraction of isolated uterine smooth muscle.

    Directory of Open Access Journals (Sweden)

    Wing-Chiu Tong

    2011-04-01

    Full Text Available Uterine contractions during labor are discretely regulated by rhythmic action potentials (AP of varying duration and form that serve to determine calcium-dependent force production. We have employed a computational biology approach to develop a fuller understanding of the complexity of excitation-contraction (E-C coupling of uterine smooth muscle cells (USMC. Our overall aim is to establish a mathematical platform of sufficient biophysical detail to quantitatively describe known uterine E-C coupling parameters and thereby inform future empirical investigations of physiological and pathophysiological mechanisms governing normal and dysfunctional labors. From published and unpublished data we construct mathematical models for fourteen ionic currents of USMCs: Ca2+ currents (L- and T-type, Na+ current, an hyperpolarization-activated current, three voltage-gated K+ currents, two Ca2+-activated K+ current, Ca2+-activated Cl current, non-specific cation current, Na+-Ca2+ exchanger, Na+-K+ pump and background current. The magnitudes and kinetics of each current system in a spindle shaped single cell with a specified surface area:volume ratio is described by differential equations, in terms of maximal conductances, electrochemical gradient, voltage-dependent activation/inactivation gating variables and temporal changes in intracellular Ca2+ computed from known Ca2+ fluxes. These quantifications are validated by the reconstruction of the individual experimental ionic currents obtained under voltage-clamp. Phasic contraction is modeled in relation to the time constant of changing [Ca2+]i. This integrated model is validated by its reconstruction of the different USMC AP configurations (spikes, plateau and bursts of spikes, the change from bursting to plateau type AP produced by estradiol and of simultaneous experimental recordings of spontaneous AP, [Ca2+]i and phasic force. In summary, our advanced mathematical model provides a powerful tool to

  18. Inward Rectifier K+ Currents Are Regulated by CaMKII in Endothelial Cells of Primarily Cultured Bovine Pulmonary Arteries.

    Science.gov (United States)

    Qu, Lihui; Yu, Lei; Wang, Yanli; Jin, Xin; Zhang, Qianlong; Lu, Ping; Yu, Xiufeng; Zhong, Weiwei; Zheng, Xiaodong; Cui, Ningren; Jiang, Chun; Zhu, Daling

    2015-01-01

    Endothelium lines the interior surface of vascular walls and regulates vascular tones. The endothelial cells sense and respond to chemical and mechanical stimuli in the circulation, and couple the stimulus signals to vascular smooth muscles, in which inward rectifier K+ currents (Kir) play an important role. Here we applied several complementary strategies to determine the Kir subunit in primarily cultured pulmonary arterial endothelial cells (PAECs) that was regulated by the Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII). In whole-cell voltage clamp, the Kir currents were sensitive to micromolar concentrations of extracellular Ba2+. In excised inside-out patches, an inward rectifier K+ current was observed with single-channel conductance 32.43 ± 0.45 pS and Popen 0.27 ± 0.04, which were consistent with known unitary conductance of Kir 2.1. RT-PCR and western blot results showed that expression of Kir 2.1 was significantly stronger than that of other subtypes in PAECs. Pharmacological analysis of the Kir currents demonstrated that insensitivity to intracellular ATP, pinacidil, glibenclamide, pH, GDP-β-S and choleratoxin suggested that currents weren't determined by KATP, Kir2.3, Kir2.4 and Kir3.x. The currents were strongly suppressed by exposure to CaMKII inhibitor W-7 and KN-62. The expression of Kir2.1 was inhibited by knocking down CaMKII. Consistently, vasodilation was suppressed by Ba2+, W-7 and KN-62 in isolated and perfused pulmonary arterial rings. These results suggest that the PAECs express an inward rectifier K+ current that is carried dominantly by Kir2.1, and this K+ channel appears to be targeted by CaMKII-dependent intracellular signaling systems.

  19. Inward Rectifier K+ Currents Are Regulated by CaMKII in Endothelial Cells of Primarily Cultured Bovine Pulmonary Arteries.

    Directory of Open Access Journals (Sweden)

    Lihui Qu

    Full Text Available Endothelium lines the interior surface of vascular walls and regulates vascular tones. The endothelial cells sense and respond to chemical and mechanical stimuli in the circulation, and couple the stimulus signals to vascular smooth muscles, in which inward rectifier K+ currents (Kir play an important role. Here we applied several complementary strategies to determine the Kir subunit in primarily cultured pulmonary arterial endothelial cells (PAECs that was regulated by the Ca2+/calmodulin (CaM-dependent protein kinase II (CaMKII. In whole-cell voltage clamp, the Kir currents were sensitive to micromolar concentrations of extracellular Ba2+. In excised inside-out patches, an inward rectifier K+ current was observed with single-channel conductance 32.43 ± 0.45 pS and Popen 0.27 ± 0.04, which were consistent with known unitary conductance of Kir 2.1. RT-PCR and western blot results showed that expression of Kir 2.1 was significantly stronger than that of other subtypes in PAECs. Pharmacological analysis of the Kir currents demonstrated that insensitivity to intracellular ATP, pinacidil, glibenclamide, pH, GDP-β-S and choleratoxin suggested that currents weren't determined by KATP, Kir2.3, Kir2.4 and Kir3.x. The currents were strongly suppressed by exposure to CaMKII inhibitor W-7 and KN-62. The expression of Kir2.1 was inhibited by knocking down CaMKII. Consistently, vasodilation was suppressed by Ba2+, W-7 and KN-62 in isolated and perfused pulmonary arterial rings. These results suggest that the PAECs express an inward rectifier K+ current that is carried dominantly by Kir2.1, and this K+ channel appears to be targeted by CaMKII-dependent intracellular signaling systems.

  20. Ca2+ cycling in heart cells from ground squirrels: adaptive strategies for intracellular Ca2+ homeostasis.

    Directory of Open Access Journals (Sweden)

    Xiao-Chen Li

    Full Text Available Heart tissues from hibernating mammals, such as ground squirrels, are able to endure hypothermia, hypoxia and other extreme insulting factors that are fatal for human and nonhibernating mammals. This study was designed to understand adaptive mechanisms involved in intracellular Ca(2+ homeostasis in cardiomyocytes from the mammalian hibernator, ground squirrel, compared to rat. Electrophysiological and confocal imaging experiments showed that the voltage-dependence of L-type Ca(2+ current (I(Ca was shifted to higher potentials in ventricular myocytes from ground squirrels vs. rats. The elevated threshold of I(Ca did not compromise the Ca(2+-induced Ca(2+ release, because a higher depolarization rate and a longer duration of action potential compensated the voltage shift of I(Ca. Both the caffeine-sensitive and caffeine-resistant components of cytosolic Ca(2+ removal were more rapid in ground squirrels. Ca(2+ sparks in ground squirrels exhibited larger amplitude/size and much lower frequency than in rats. Due to the high I(Ca threshold, low SR Ca(2+ leak and rapid cytosolic Ca(2+ clearance, heart cells from ground squirrels exhibited better capability in maintaining intracellular Ca(2+ homeostasis than those from rats and other nonhibernating mammals. These findings not only reveal adaptive mechanisms of hibernation, but also provide novel strategies against Ca(2+ overload-related heart diseases.

  1. Calcium influx through L-type channels attenuates skeletal muscle contraction via inhibition of adenylyl cyclases.

    Science.gov (United States)

    Menezes-Rodrigues, Francisco Sandro; Pires-Oliveira, Marcelo; Duarte, Thiago; Paredes-Gamero, Edgar Julian; Chiavegatti, Tiago; Godinho, Rosely Oliveira

    2013-11-15

    Skeletal muscle contraction is triggered by acetylcholine induced release of Ca(2+) from sarcoplasmic reticulum. Although this signaling pathway is independent of extracellular Ca(2+), L-type voltage-gated calcium channel (Cav) blockers have inotropic effects on frog skeletal muscles which occur by an unknown mechanism. Taking into account that skeletal muscle fiber expresses Ca(+2)-sensitive adenylyl cyclase (AC) isoforms and that cAMP is able to increase skeletal muscle contraction force, we investigated the role of Ca(2+) influx on mouse skeletal muscle contraction and the putative crosstalk between extracellular Ca(2+) and intracellular cAMP signaling pathways. The effects of Cav blockers (verapamil and nifedipine) and extracellular Ca(2+) chelator EGTA were evaluated on isometric contractility of mouse diaphragm muscle under direct electrical stimulus (supramaximal voltage, 2 ms, 0.1 Hz). Production of cAMP was evaluated by radiometric assay while Ca(2+) transients were assessed by confocal microscopy using L6 cells loaded with fluo-4/AM. Ca(2+) channel blockers verapamil and nifedipine had positive inotropic effect, which was mimicked by removal of extracellular Ca(+2) with EGTA or Ca(2+)-free Tyrode. While phosphodiesterase inhibitor IBMX potentiates verapamil positive inotropic effect, it was abolished by AC inhibitors SQ22536 and NYK80. Finally, the inotropic effect of verapamil was associated with increased intracellular cAMP content and mobilization of intracellular Ca(2+), indicating that positive inotropic effects of Ca(2+) blockers depend on cAMP formation. Together, our results show that extracellular Ca(2+) modulates skeletal muscle contraction, through inhibition of Ca(2+)-sensitive AC. The cross-talk between extracellular calcium and cAMP-dependent signaling pathways appears to regulate the extent of skeletal muscle contraction responses. © 2013 Published by Elsevier B.V.

  2. Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma

    International Nuclear Information System (INIS)

    Bevilacqua, M.; Vago, T.; Norbiato, G.

    1991-01-01

    Propionyl-L-carnitine (PC) protects perfused rat hearts against damage by ischemia-reperfusion. Activation of L-type calcium channel play a role on ischemia-reperfusion damage. Therefore, we studied the effect of PC on some properties of L-type calcium channels in an in vitro preparation from human myocardium sarcolemma (from patients with idiopathic dilated cardiomyopathy). Binding of the L-type calcium channel blockers isradipine [ 3 H]-PN 200-110 (PN) to plasma membrane preparations revealed a single population of binding sites (total number: Bmax = 213 +/- 34 fM/mg protein and affinity: Kd = 152 +/- 19 nM; n = 6). The characteristics of these binding sites were evaluated in the presence and in the absence of Ca 2+ and of calcium blockers (D-888, a verapamillike drug, and diltiazem). Incubation in a Ca 2+ -containing buffer increased the affinity of PN binding sites. Binding sites for PN were modulated by organic calcium channel blockers; in competition isotherms at 37 degree C, D-888 (desmethoxyverapamil) decreased the PN binding, whereas diltiazem increased it. These results strongly suggest that the site labelled by PN is the voltage-operated calcium channel of the human myocardium. The addition of PC (1 mM) to plasma membranes labelled with PN at 37 degree C decreased the affinity of the binding; this effect was counteracted by the addition of Ca 2+ to the medium. This result was consistent with a competition between Ca 2+ and PC. The effect of PC incubation at 4 degree C was the opposite; at this temperature PC increased the affinity of the binding sites and the effect was obscured by Ca 2+

  3. A novel dihydropyridine with 3-aryl meta-hydroxyl substitution blocks L-type calcium channels in rat cardiomyocytes

    International Nuclear Information System (INIS)

    Galvis-Pareja, David; Zapata-Torres, Gerald; Hidalgo, Jorge; Ayala, Pedro

    2014-01-01

    Rationale: Dihydropyridines are widely used for the treatment of several cardiac diseases due to their blocking activity on L-type Ca 2+ channels and their renowned antioxidant properties. Methods: We synthesized six novel dihydropyridine molecules and performed docking studies on the binding site of the L-type Ca 2+ channel. We used biochemical techniques on isolated adult rat cardiomyocytes to assess the efficacy of these molecules on their Ca 2+ channel-blocking activity and antioxidant properties. The Ca 2+ channel-blocking activity was evaluated by confocal microscopy on fluo-3AM loaded cardiomyocytes, as well as using patch clamp experiments. Antioxidant properties were evaluated by flow cytometry using the ROS sensitive dye 1,2,3 DHR. Results: Our docking studies show that a novel compound with 3-OH substitution inserts into the active binding site of the L-type Ca 2+ channel previously described for nitrendipine. In biochemical assays, the novel meta-OH group in the aryl in C4 showed a high blocking effect on L-type Ca 2+ channel as opposed to para-substituted compounds. In the tests we performed, none of the molecules showed antioxidant properties. Conclusions: Only substitutions in C2, C3 and C5 of the aryl ring render dihydropyridine compounds with the capacity of blocking LTCC. Based on our docking studies, we postulate that the antioxidant activity requires a larger group than the meta-OH substitution in C2, C3 or C5 of the dihydropyridine ring. - Highlights: • Dihydropyridine (DHP) molecules are widely used in cardiovascular disease. • DHPs block Ca 2+ entry through LTCC—some DHPs have antioxidant activity as well. • We synthesized 6 new DHPs and tested their Ca 2+ blocking and antioxidant activities. • 3-Aryl meta-hydroxyl substitution strongly increases their Ca 2+ blocking activity. • 3-Aryl meta-hydroxyl substitution did not affect the antioxidant properties

  4. The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses.

    Science.gov (United States)

    Shi, Liheng; Chang, Janet Ya-An; Yu, Fei; Ko, Michael L; Ko, Gladys Y-P

    2017-01-01

    L-type voltage-gated calcium channels (LTCCs) regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Ca v 1.2, Ca v 1.3, and Ca v 1.4) expressed in the retina. While Ca v 1.2 is expressed in all retinal cells including the Müller glia and neurons, Ca v 1.3 and Ca v 1.4 are expressed in the retinal neurons with Ca v 1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Ca v 1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Ca v 1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Ca v 1.3 are not associated with severe vision impairment in humans or in Ca v 1.3-null (Ca v 1.3 -/- ) mice. However, a failure to regulate Ca v 1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Ca v 1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Ca v 1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG) recordings and immunohistochemical staining, we found that Ca v 1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Ca v 1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Ca v 1.3 -/- mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT). Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Ca v 1.3 -/- mice retinas. Hence, Ca v 1.3 plays a more prominent role in retinal physiology and function than previously reported.

  5. Biophysical characterization of inwardly rectifying potassium currents (I(K1) I(K,ACh), I(K,Ca)) using sinus rhythm or atrial fibrillation action potential waveforms

    DEFF Research Database (Denmark)

    Tang, Chuyi; Skibsbye, Lasse; Yuan, Lei

    2015-01-01

    Although several physiological, pathophysiological and regulatory properties of classical inward rectifier K+ current I(K1), G-protein coupled inwardly-rectifying K+ current I(K,ACh) and the small-conductance Ca2+ activated K+ current I(K,Ca) have been identified, quantitative biophysical details...

  6. Charge effects controlling the current hysteresis and negative differential resistance in periodical nanosize Si/CaF sub 2 structures

    CERN Document Server

    Berashevich, Y A; Kholod, A N; Borisenko, V E

    2002-01-01

    A kinetic model of charge carrier transport in nanosize periodical Si/CaF sub 2 structures via localized states in dielectric is proposed. Computer simulation of the current-voltage characteristics of such structures has shown that the built-in field arises in a dielectric due to polarization of the trapped charge by localized centers. This results in current hysteresis and negative differential resistance region at the current-voltage characteristics when the bias polarity is changed. At temperature below 250 K, the portion of negative differential resistance vanishes

  7. Voltage clamp methods for the study of membrane currents and SR Ca2+ release in adult skeletal muscle fibres

    Science.gov (United States)

    Hernández-Ochoa, Erick O.; Schneider, Martin F.

    2012-01-01

    Skeletal muscle excitation-contraction (E-C)1 coupling is a process composed of multiple sequential stages, by which an action potential triggers sarcoplasmic reticulum (SR)2 Ca2+ release and subsequent contractile activation. The various steps in the E-C coupling process in skeletal muscle can be studied using different techniques. The simultaneous recordings of sarcolemmal electrical signals and the accompanying elevation in myoplasmic Ca2+, due to depolarization-initiated SR Ca2+ release in skeletal muscle fibres, have been useful to obtain a better understanding of muscle function. In studying the origin and mechanism of voltage dependency of E-C coupling a variety of different techniques have been used to control the voltage in adult skeletal fibres. Pioneering work in muscles isolated from amphibians or crustaceans used microelectrodes or ‘high resistance gap’ techniques to manipulate the voltage in the muscle fibres. The development of the patch clamp technique and its variant, the whole-cell clamp configuration that facilitates the manipulation of the intracellular environment, allowed the use of the voltage clamp techniques in different cell types, including skeletal muscle fibres. The aim of this article is to present an historical perspective of the voltage clamp methods used to study skeletal muscle E-C coupling as well as to describe the current status of using the whole-cell patch clamp technique in studies in which the electrical and Ca2+ signalling properties of mouse skeletal muscle membranes are being investigated. PMID:22306655

  8. Chronic Ca2+ influx through voltage-dependent Ca2+ channels enhance delayed rectifier K+ currents via activating Src family tyrosine kinase in rat hippocampal neurons.

    Science.gov (United States)

    Yang, Yoon-Sil; Jeon, Sang-Chan; Kim, Dong-Kwan; Eun, Su-Yong; Jung, Sung-Cherl

    2017-03-01

    Excessive influx and the subsequent rapid cytosolic elevation of Ca 2+ in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca 2+ level in normal as well as pathological conditions. Delayed rectifier K + channels (I DR channels) play a role to suppress membrane excitability by inducing K + outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca 2+ -mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of I DR channels to hyperexcitable conditions induced by high Ca 2+ pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca 2+ -treatment significantly increased the amplitude of I DR without changes of gating kinetics. Nimodipine but not APV blocked Ca 2+ -induced I DR enhancement, confirming that the change of I DR might be targeted by Ca 2+ influx through voltage-dependent Ca 2+ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I DR enhancement was not affected by either Ca 2+ -induced Ca 2+ release (CICR) or small conductance Ca 2+ -activated K + channels (SK channels). Furthermore, PP2 but not H89 completely abolished I DR enhancement under high Ca 2+ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca 2+ -mediated I DR enhancement. Thus, SFKs may be sensitive to excessive Ca 2+ influx through VDCCs and enhance I DR to activate a neuroprotective mechanism against Ca 2+ -mediated hyperexcitability in neurons.

  9. The CaV2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture.

    Science.gov (United States)

    Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco

    2014-05-01

    Voltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) influx into RTN neurons can trigger small-conductance Ca(2+)-activated K(+)-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV2.3 R-type Ca(2+) channels in rodent sleep. The role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and time-frequency analysis. CaV2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined. Low-voltage activated CaV2.3 R-type Ca(2+) channels in the thalamocortical loop and extra

  10. Serotonin-mediated modulation of Na+/K+ pump current in rat hippocampal CA1 pyramidal neurons.

    Science.gov (United States)

    Zhang, Li Nan; Su, Su Wen; Guo, Fang; Guo, Hui Cai; Shi, Xiao Lu; Li, Wen Ya; Liu, Xu; Wang, Yong Li

    2012-01-19

    The aim of this study was to investigate whether serotonin (5-hydroxytryptamine, 5-HT) can modulate Na+/K+ pump in rat hippocampal CA1 pyramidal neurons. 5-HT (0.1, 1 mM) showed Na+/K+ pump current (Ip) densities of 0.40 ± 0.04, 0.34 ± 0.03 pA/pF contrast to 0.63 ± 0.04 pA/pF of the control of 0.5 mM strophanthidin (Str), demonstrating 5-HT-induced inhibition of Ip in a dose-dependent manner in hippocampal CA1 pyramidal neurons. The effect was partly attenuated by ondasetron, a 5-HT3 receptor (5-HT3R) antagonist, not by WAY100635, a 5-HT1AR antagonist, while 1-(3-Chlorophenyl) biguanide hydrochloride (m-CPBG), a 5-HT3R specific agonist, mimicked the effect of 5-HT on Ip. 5-HT inhibits neuronal Na+/K+ pump activity via 5-HT3R in rat hippocampal CA1 pyramidal neurons. This discloses novel mechanisms for the function of 5-HT in learning and memory, which may be a useful target to benefit these patients with cognitive disorder.

  11. Inhibition of PaCaMKII-E isoform in the dorsal unpaired median neurosecretory cells of cockroach reduces nicotine- and clothianidin-induced currents.

    Science.gov (United States)

    List, Olivier; Calas-List, Delphine; Taillebois, Emiliane; Juchaux, Marjorie; Heuland, Emilie; Thany, Steeve H

    2014-08-01

    Cellular responses to Ca(2+) require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII), which transduces the signal into downstream effects. We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms, and only PaCaMKII-E isoform is specifically expressed in the dorsal unpaired median neurosecretory cells. In the present study, using antisense oligonucleotides, we demonstrated that PaCaMKII-E isoform inhibition reduced nicotine-induced currents through α-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptor subtypes. Specifically, PaCaMKII-E isoform is sufficient to repress nicotinic current amplitudes as a result of its depression by antisense oligonucleotides. Similar results were found using the neonicotinoid insecticide clothianidin, which acted as a full agonist of dorsal unpaired median neuron nicotinic acetylcholine receptors. Clothianidin current amplitudes are strongly reduced under bath application of PaCaMKII-E antisense oligonucleotides but no significant results are found with α-bungarotoxin co-applied, demonstrating that CaMKII-E isoform affects nicotine currents through α-bungarotoxin-sensitive and -insensitive receptor subtypes whereas clothianidin currents are reduced via α-bungarotoxin-insensitive receptors. In addition, we found that intracellular calcium increase induced by nicotine and clothianidin were reduced by PaCaMKII-E antisense oligonucleotides, demonstrating that intracellular calcium increase induced by nicotine and clothianidin are affected by PaCaMKII-E inhibition. Cellular responses to Ca(2+) require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII). We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms and only PaCaMKII-E isoform was specifically expressed in the dorsal unpaired median neurosecretory cells. Here we show that specific inhibition of PaCaMKII-E isoform is

  12. L-Type Calcium Channels Modulation by Estradiol.

    Science.gov (United States)

    Vega-Vela, Nelson E; Osorio, Daniel; Avila-Rodriguez, Marco; Gonzalez, Janneth; García-Segura, Luis Miguel; Echeverria, Valentina; Barreto, George E

    2017-09-01

    Voltage-gated calcium channels are key regulators of brain function, and their dysfunction has been associated with multiple conditions and neurodegenerative diseases because they couple membrane depolarization to the influx of calcium-and other processes such as gene expression-in excitable cells. L-type calcium channels, one of the three major classes and probably the best characterized of the voltage-gated calcium channels, act as an essential calcium binding proteins with a significant biological relevance. It is well known that estradiol can activate rapidly brain signaling pathways and modulatory/regulatory proteins through non-genomic (or non-transcriptional) mechanisms, which lead to an increase of intracellular calcium that activate multiple kinases and signaling cascades, in the same way as L-type calcium channels responses. In this context, estrogens-L-type calcium channels signaling raises intracellular calcium levels and activates the same signaling cascades in the brain probably through estrogen receptor-independent modulatory mechanisms. In this review, we discuss the available literature on this area, which seems to suggest that estradiol exerts dual effects/modulation on these channels in a concentration-dependent manner (as a potentiator of these channels in pM concentrations and as an inhibitor in nM concentrations). Indeed, estradiol may orchestrate multiple neurotrophic responses, which open a new avenue for the development of novel estrogen-based therapies to alleviate different neuropathologies. We also highlight that it is essential to determine through computational and/or experimental approaches the interaction between estradiol and L-type calcium channels to assist these developments, which is an interesting area of research that deserves a closer look in future biomedical research.

  13. Apo calmodulin binding to the L-type voltage-gated calcium channel Cav1.2 IQ peptide

    International Nuclear Information System (INIS)

    Lian Luyun; Myatt, Daniel; Kitmitto, Ashraf

    2007-01-01

    The influx of calcium through the L-type voltage-gated calcium channels (LTCCs) is the trigger for the process of calcium-induced calcium release (CICR) from the sarcoplasmic recticulum, an essential step for cardiac contraction. There are two feedback mechanisms that regulate LTCC activity: calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF), both of which are mediated by calmodulin (CaM) binding. The IQ domain (aa 1645-1668) housed within the cytoplasmic domain of the LTCC Ca v 1.2 subunit has been shown to bind both calcium-loaded (Ca 2+ CaM ) and calcium-free CaM (apoCaM). Here, we provide new data for the structural basis for the interaction of apoCaM with the IQ peptide using NMR, revealing that the apoCaM C-lobe residues are most significantly perturbed upon complex formation. In addition, we have employed transmission electron microscopy of purified LTCC complexes which shows that both apoCaM and Ca 2+ CaM can bind to the intact channel

  14. Voltage-dependent inward currents in smooth muscle cells of skeletal muscle arterioles

    Science.gov (United States)

    Shirokov, Roman E.

    2018-01-01

    Voltage-dependent inward currents responsible for the depolarizing phase of action potentials were characterized in smooth muscle cells of 4th order arterioles in mouse skeletal muscle. Currents through L-type Ca2+ channels were expected to be dominant; however, action potentials were not eliminated in nominally Ca2+-free bathing solution or by addition of L-type Ca2+ channel blocker nifedipine (10 μM). Instead, Na+ channel blocker tetrodotoxin (TTX, 1 μM) reduced the maximal velocity of the upstroke at low, but not at normal (2 mM), Ca2+ in the bath. The magnitude of TTX-sensitive currents recorded with 140 mM Na+ was about 20 pA/pF. TTX-sensitive currents decreased five-fold when Ca2+ increased from 2 to 10 mM. The currents reduced three-fold in the presence of 10 mM caffeine, but remained unaltered by 1 mM of isobutylmethylxanthine (IBMX). In addition to L-type Ca2+ currents (15 pA/pF in 20 mM Ca2+), we also found Ca2+ currents that are resistant to 10 μM nifedipine (5 pA/pF in 20 mM Ca2+). Based on their biophysical properties, these Ca2+ currents are likely to be through voltage-gated T-type Ca2+ channels. Our results suggest that Na+ and at least two types (T- and L-) of Ca2+ voltage-gated channels contribute to depolarization of smooth muscle cells in skeletal muscle arterioles. Voltage-gated Na+ channels appear to be under a tight control by Ca2+ signaling. PMID:29694371

  15. A novel dihydropyridine with 3-aryl meta-hydroxyl substitution blocks L-type calcium channels in rat cardiomyocytes

    Energy Technology Data Exchange (ETDEWEB)

    Galvis-Pareja, David [Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas and Facultad Medicina, Universidad de Chile, Santiago (Chile); Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas and Facultad Medicina, Universidad de Chile, Santiago (Chile); Zapata-Torres, Gerald [Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago (Chile); Hidalgo, Jorge [Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas and Facultad Medicina, Universidad de Chile, Santiago (Chile); Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago (Chile); Ayala, Pedro [Centro Estudios Moleculares de la Célula (CEMC), Facultad de Ciencias Químicas y Farmacéuticas and Facultad Medicina, Universidad de Chile, Santiago (Chile); and others

    2014-08-15

    Rationale: Dihydropyridines are widely used for the treatment of several cardiac diseases due to their blocking activity on L-type Ca{sup 2+} channels and their renowned antioxidant properties. Methods: We synthesized six novel dihydropyridine molecules and performed docking studies on the binding site of the L-type Ca{sup 2+} channel. We used biochemical techniques on isolated adult rat cardiomyocytes to assess the efficacy of these molecules on their Ca{sup 2+} channel-blocking activity and antioxidant properties. The Ca{sup 2+} channel-blocking activity was evaluated by confocal microscopy on fluo-3AM loaded cardiomyocytes, as well as using patch clamp experiments. Antioxidant properties were evaluated by flow cytometry using the ROS sensitive dye 1,2,3 DHR. Results: Our docking studies show that a novel compound with 3-OH substitution inserts into the active binding site of the L-type Ca{sup 2+} channel previously described for nitrendipine. In biochemical assays, the novel meta-OH group in the aryl in C4 showed a high blocking effect on L-type Ca{sup 2+} channel as opposed to para-substituted compounds. In the tests we performed, none of the molecules showed antioxidant properties. Conclusions: Only substitutions in C2, C3 and C5 of the aryl ring render dihydropyridine compounds with the capacity of blocking LTCC. Based on our docking studies, we postulate that the antioxidant activity requires a larger group than the meta-OH substitution in C2, C3 or C5 of the dihydropyridine ring. - Highlights: • Dihydropyridine (DHP) molecules are widely used in cardiovascular disease. • DHPs block Ca{sup 2+} entry through LTCC—some DHPs have antioxidant activity as well. • We synthesized 6 new DHPs and tested their Ca{sup 2+} blocking and antioxidant activities. • 3-Aryl meta-hydroxyl substitution strongly increases their Ca{sup 2+} blocking activity. • 3-Aryl meta-hydroxyl substitution did not affect the antioxidant properties.

  16. Muscarinic activation of Ca2+-activated Cl- current in interstitial cells of Cajal.

    Science.gov (United States)

    Zhu, Mei Hong; Sung, In Kyung; Zheng, Haifeng; Sung, Tae Sik; Britton, Fiona C; O'Driscoll, Kate; Koh, Sang Don; Sanders, Kenton M

    2011-09-15

    Interstitial cells of Cajal (ICC) provide pacemaker activity and functional bridges between enteric motor nerve terminals and gastrointestinal smooth muscle cells. The ionic conductance(s) in ICC that are activated by excitatory neural inputs are unknown. Transgenic mice (Kit(copGFP/+)) with constitutive expression of a bright green fluorescent protein were used to investigate cellular responses of ICC to cholinergic stimulation. ICC displayed spontaneous transient inward currents (STICs) under voltage clamp that corresponded to spontaneous transient depolarizations (STDs) under current clamp. STICs reversed at 0 mV when E(Cl) = 0 mV and at -40 mV when E(Cl) was -40 mV, suggesting the STICs were due to a chloride conductance. Carbachol (CCh, 100 nm and 1 μm) induced a sustained inward current (depolarization in current clamp) and increased the amplitude and frequency of STICs and STDs. CCh responses were blocked by atropine (10 μm) or 4-DAMP (100 nm), an M(3) receptor antagonist. STDs were blocked by niflumic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (both 100 μm), and CCh had no effect in the presence of these drugs. The responses of intact circular muscles to CCh and stimulation of intrinsic excitatory nerves by electrical field stimulation (EFS) were also compared. CCh (1 μm) caused atropine-sensitive depolarization and increased the maximum depolarization of slow waves. Similar atropine-sensitive responses were elicited by stimulation of intrinsic excitatory neurons. Niflumic acid (100 μm) blocked responses to EFS but had minor effect on responses to exogenous CCh. These data suggest that different ionic conductances are responsible for electrical responses elicited by bath-applied CCh and cholinergic nerve stimulation.

  17. Muscarinic activation of Ca2+-activated Cl− current in interstitial cells of Cajal

    Science.gov (United States)

    Zhu, Mei Hong; Sung, In Kyung; Zheng, Haifeng; Sung, Tae Sik; Britton, Fiona C; O'Driscoll, Kate; Koh, Sang Don; Sanders, Kenton M

    2011-01-01

    Abstract Interstitial cells of Cajal (ICC) provide pacemaker activity and functional bridges between enteric motor nerve terminals and gastrointestinal smooth muscle cells. The ionic conductance(s) in ICC that are activated by excitatory neural inputs are unknown. Transgenic mice (KitcopGFP/+) with constitutive expression of a bright green fluorescent protein were used to investigate cellular responses of ICC to cholinergic stimulation. ICC displayed spontaneous transient inward currents (STICs) under voltage clamp that corresponded to spontaneous transient depolarizations (STDs) under current clamp. STICs reversed at 0 mV when ECl = 0 mV and at –40 mV when ECl was –40 mV, suggesting the STICs were due to a chloride conductance. Carbachol (CCh, 100 nm and 1 μm) induced a sustained inward current (depolarization in current clamp) and increased the amplitude and frequency of STICs and STDs. CCh responses were blocked by atropine (10 μm) or 4-DAMP (100 nm), an M3 receptor antagonist. STDs were blocked by niflumic acid and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (both 100 μm), and CCh had no effect in the presence of these drugs. The responses of intact circular muscles to CCh and stimulation of intrinsic excitatory nerves by electrical field stimulation (EFS) were also compared. CCh (1 μm) caused atropine-sensitive depolarization and increased the maximum depolarization of slow waves. Similar atropine-sensitive responses were elicited by stimulation of intrinsic excitatory neurons. Niflumic acid (100 μm) blocked responses to EFS but had minor effect on responses to exogenous CCh. These data suggest that different ionic conductances are responsible for electrical responses elicited by bath-applied CCh and cholinergic nerve stimulation. PMID:21768263

  18. Quantitative analysis of the Ca2+‐dependent regulation of delayed rectifier K+ current I Ks in rabbit ventricular myocytes

    Science.gov (United States)

    Bartos, Daniel C.; Morotti, Stefano; Ginsburg, Kenneth S.; Grandi, Eleonora

    2017-01-01

    Key points [Ca2+]i enhanced rabbit ventricular slowly activating delayed rectifier K+ current (I Ks) by negatively shifting the voltage dependence of activation and slowing deactivation, similar to perfusion of isoproterenol.Rabbit ventricular rapidly activating delayed rectifier K+ current (I Kr) amplitude and voltage dependence were unaffected by high [Ca2+]i.When measuring or simulating I Ks during an action potential, I Ks was not different during a physiological Ca2+ transient or when [Ca2+]i was buffered to 500 nm. Abstract The slowly activating delayed rectifier K+ current (I Ks) contributes to repolarization of the cardiac action potential (AP). Intracellular Ca2+ ([Ca2+]i) and β‐adrenergic receptor (β‐AR) stimulation modulate I Ks amplitude and kinetics, but details of these important I Ks regulators and their interaction are limited. We assessed the [Ca2+]i dependence of I Ks in steady‐state conditions and with dynamically changing membrane potential and [Ca2+]i during an AP. I Ks was recorded from freshly isolated rabbit ventricular myocytes using whole‐cell patch clamp. With intracellular pipette solutions that controlled free [Ca2+]i, we found that raising [Ca2+]i from 100 to 600 nm produced similar increases in I Ks as did β‐AR activation, and the effects appeared additive. Both β‐AR activation and high [Ca2+]i increased maximally activated tail I Ks, negatively shifted the voltage dependence of activation, and slowed deactivation kinetics. These data informed changes in our well‐established mathematical model of the rabbit myocyte. In both AP‐clamp experiments and simulations, I Ks recorded during a normal physiological Ca2+ transient was similar to I Ks measured with [Ca2+]i clamped at 500–600 nm. Thus, our study provides novel quantitative data as to how physiological [Ca2+]i regulates I Ks amplitude and kinetics during the normal rabbit AP. Our results suggest that micromolar [Ca2+]i, in the submembrane or junctional cleft

  19. Elementary properties of CaV1.3 Ca(2+) channels expressed in mouse cochlear inner hair cells.

    Science.gov (United States)

    Zampini, Valeria; Johnson, Stuart L; Franz, Christoph; Lawrence, Neil D; Münkner, Stefan; Engel, Jutta; Knipper, Marlies; Magistretti, Jacopo; Masetto, Sergio; Marcotti, Walter

    2010-01-01

    Mammalian cochlear inner hair cells (IHCs) are specialized to process developmental signals during immature stages and sound stimuli in adult animals. These signals are conveyed onto auditory afferent nerve fibres. Neurotransmitter release at IHC ribbon synapses is controlled by L-type Ca(V)1.3 Ca(2+) channels, the biophysics of which are still unknown in native mammalian cells. We have investigated the localization and elementary properties of Ca(2+) channels in immature mouse IHCs under near-physiological recording conditions. Ca(V)1.3 Ca(2+) channels at the cell pre-synaptic site co-localize with about half of the total number of ribbons present in immature IHCs. These channels activated at about 70 mV, showed a relatively short first latency and weak inactivation, which would allow IHCs to generate and accurately encode spontaneous Ca(2+) action potential activity characteristic of these immature cells. The Ca(V)1.3 Ca(2+) channels showed a very low open probability (about 0.15 at 20 mV: near the peak of an action potential). Comparison of elementary and macroscopic Ca(2+) currents indicated that very few Ca(2+) channels are associated with each docked vesicle at IHC ribbon synapses. Finally, we found that the open probability of Ca(2+) channels, but not their opening time, was voltage dependent. This finding provides a possible correlation between presynaptic Ca(2+) channel properties and the characteristic frequency/amplitude of EPSCs in auditory afferent fibres.

  20. Wave Energy Converter (WEC) Array Effects on Wave Current and Sediment Circulation: Monterey Bay CA.

    Energy Technology Data Exchange (ETDEWEB)

    Roberts, Jesse D.; Jones, Craig; Magalen, Jason

    2014-09-01

    The goal s of this study were to develop tools to quantitatively characterize environments where wave energy converter ( WEC ) devices may be installed and to assess e ffects on hydrodynamics and lo cal sediment transport. A large hypothetical WEC array was investigated using wave, hydrodynamic, and sediment transport models and site - specific average and storm conditions as input. The results indicated that there were significant changes in sediment s izes adjacent to and in the lee of the WEC array due to reduced wave energy. The circulation in the lee of the array was also altered; more intense onshore currents were generated in the lee of the WECs . In general, the storm case and the average case show ed the same qualitative patterns suggesting that these trends would be maintained throughout the year. The framework developed here can be used to design more efficient arrays while minimizing impacts on nearshore environmen ts.

  1. Cell cycle-related fluctuations in transcellular ionic currents and plasma membrane Ca2+/Mg2+ ATPase activity during early cleavages of Lymnaea stagnalis embryos.

    Science.gov (United States)

    Zivkovic, Danica; Créton, Robbert; Dohmen, René

    1991-08-01

    During the first four mitotic division cycles of Lymnaea stagnalis embryos, we have detected cell cycle-dependent changes in the pattern of transcellular ionic currents and membrane-bound Ca 2+ -stimulated ATPase activity. Ionic currents ranging from 0.05 to 2.50 μA/cm 2 have been measured using the vibrating probe technique. Enzyme activity was detected using Ando's cytochemical method (Ando et al. 1981) which reveals Ca 2+ /Mg 2+ ATPase localization at the ultrastructural level, and under high-stringency conditions with respect to calcium availability, it reveals Ca 2+ -stimulated ATPase. The ionic currents and Ca 2+ -stimulated ATPase localization have in common that important changes occur during the M-phase of the cell cycles. Minimal outward current at the vegetal pole coincides with metaphase/anaphase. Maximal inward current at the animal pole coincides with the onset of cytokinesis at that pole. Ca 2+ -stimulated ATPase is absent from one half of the embryo at metaphase/anaphase of the two- and four-cell stage, whereas it is present in all cells during the remaining part of the cell cycle. Since fluctuations of cytosolic free calcium concentrations appear to correlate with both karyokinesis and cytokinesis, we speculate that part of the cyclic pattern of Ca 2+ -stimulated ATPase localization and of the transcellular ionic currents reflects the elevation of cytosolic free calcium concentration during the M-phase.

  2. Modified cytoplasmic Ca2+ sequestration contributes to spinal cord injury-induced augmentation of nerve-evoked contractions in the rat tail artery.

    Directory of Open Access Journals (Sweden)

    Hussain Al Dera

    Full Text Available In rat tail artery (RTA, spinal cord injury (SCI increases nerve-evoked contractions and the contribution of L-type Ca2+ channels to these responses. In RTAs from unoperated rats, these channels play a minor role in contractions and Bay K8644 (L-type channel agonist mimics the effects of SCI. Here we investigated the mechanisms underlying the facilitatory actions of SCI and Bay K8644 on nerve-evoked contractions of RTAs and the hypothesis that Ca2+ entering via L-type Ca2+ channels is rapidly sequestered by the sarcoplasmic reticulum (SR limiting its role in contraction. In situ electrochemical detection of noradrenaline was used to assess if Bay K8644 increased noradrenaline release. Perforated patch recordings were used to assess if SCI changed the Ca2+ current recorded in RTA myocytes. Wire myography was used to assess if SCI modified the effects of Bay K8644 and of interrupting SR Ca2+ uptake on nerve-evoked contractions. Bay K8644 did not change noradrenaline-induced oxidation currents. Neither the size nor gating of Ca2+ currents differed between myocytes from sham-operated (control and SCI rats. Bay K8644 increased nerve-evoked contractions in RTAs from both control and SCI rats, but the magnitude of this effect was reduced by SCI. By contrast, depleting SR Ca2+ stores with ryanodine or cyclopiazonic acid selectively increased nerve-evoked contractions in control RTAs. Cyclopiazonic acid also selectively increased the blockade of these responses by nifedipine (L-type channel blocker in control RTAs, whereas ryanodine increased the blockade produced by nifedipine in both groups of RTAs. These findings suggest that Ca2+ entering via L-type channels is normally rapidly sequestered limiting its access to the contractile mechanism. Furthermore, the findings suggest SCI reduces the role of this mechanism.

  3. Absolute emission current density of O- from 12CaO·7Al2O3 crystal

    International Nuclear Information System (INIS)

    Li, Q.X.; Hayashi, K.; Nishioka, M.; Kashiwagi, H.; Hirano, M.; Torimoto, Y.; Hosono, H.; Sadakata, M.

    2002-01-01

    Strong and high purity O - negative ion emission has been observed from a synthesized crystal 12CaO·7Al 2 O 3 surface. A μA/cm2-level O - emission from this material has been achieved at the surface temperature of 800 deg. C and the extraction field over 1000 V/cm, which is about three orders of magnitude higher than the current density emitted from the Y 2 O 3 -stabilized ZrO 2 electrolyte surface. The strong emissivity of this material, as well as easy and economical fabrication, may provide a useful tool to generate the O - negative ion, which is expected to be one of the most important radicals for chemical syntheses and material modifications

  4. [Atomic/ionic fluorescence in microwave plasma torch discharge with excitation of high current and microsecond pulsed hollow cathode lamp: Ca atomic/ionic fluorescence spectrometry].

    Science.gov (United States)

    Gong, Zhen-bin; Liang, Feng; Yang, Peng-yuan; Jin, Qin-han; Huang, Ben-li

    2002-02-01

    A system of atomic and ionic fluorescence spectrometry in microwave plasma torch (MPT) discharge excited by high current microsecond pulsed hollow cathode lamp (HCMP HCL) has been developed. The operation conditions for Ca atomic and ionic fluorescence spectrometry have been optimized. Compared with atomic fluorescence spectrometry (AFS) in argon microwave induced plasma (MIP) and MPT with the excitation of direct current and conventional pulsed HCL, the system with HCMP HCL excitation can improve AFS and ionic fluorescence spectrometry (IFS) detection limits in MPT atomizer and ionizer. Detection limits (3 sigma) with HCMP HCL-MPT-AFS/IFS are 10.1 ng.mL-1 for Ca I 422.7 nm, 14.6 ng.mL-1 for Ca II 393.4 nm, and 37.4 ng.mL-1 for Ca II 396.8 nm, respectively.

  5. Local membrane deformations activate Ca2+-dependent K+ and anionic currents in intact human red blood cells

    DEFF Research Database (Denmark)

    Dyrda, Agnieszka; Cytlak, Urszula; Ciuraszkiewicz, Anna

    2010-01-01

    -activated transient PCa observed here under local membrane deformation is a likely contributor to the Ca(2+)-mediated effects observed during the normal aging process of red blood cells, and to the increased Ca(2+) content of red cells in certain hereditary anemias such as thalassemia and sickle cell anemia....

  6. The Role of L-type Calcium Channels in Olfactory Learning and Its Modulation by Norepinephrine

    Directory of Open Access Journals (Sweden)

    Abhinaba Ghosh

    2017-12-01

    Full Text Available L type calcium channels (LTCCs are prevalent in different systems and hold immense importance for maintaining/performing selective functions. In the nervous system, CaV1.2 and CaV1.3 are emerging as critical modulators of neuronal functions. Although the general role of these calcium channels in modulating synaptic plasticity and memory has been explored, their role in olfactory learning is not well understood. In this review article we first discuss the role of LTCCs in olfactory learning especially focusing on early odor preference learning in neonate rodents, presenting evidence that while NMDARs initiate stimulus-specific learning, LTCCs promote protein-synthesis dependent long-term memory (LTM. Norepinephrine (NE release from the locus coeruleus (LC is essential for early olfactory learning, thus noradrenergic modulation of LTCC function and its implication in olfactory learning is discussed here. We then address the differential roles of LTCCs in adult learning and learning in aged animals.

  7. Currents of thermally stimulated depolarization in CaIn{sub 2}S{sub 4} single crystals; Toki termostimulirovannoj depolyarizatsii v monokristallakh CaIN{sub 2}S{sub 4}

    Energy Technology Data Exchange (ETDEWEB)

    Tagiev, B G; Tagiev, O B; Dzhabbarov, R B; Musaeva, N N [AN Azerbajdzhanskoj SSR, Baku (Azerbaijan). Inst. Fiziki

    1996-10-01

    The results of investigation into currents of thermally stimulated depolarization in CaIn{sub 2}S{sub 4} monocrystals are presented for the first time. Spectra of thermally stimulated depolarization for In-CaIn{sub S4}-In structures are measured under T=99 K at various rates of heat, times of polarization and times of expectation following switching off of electrical field up to beginning of measurements of shorting. The main parameters of capture cross section, partial factor, concentration of traps, are determined. It is determined that one may observed a biomolecular mechanism with a strong secondary capture in CaIn{sub 2}S{sub 4} monocrystals. 9 refs.; 4 figs.

  8. The activity of spontaneous action potentials in developing hair cells is regulated by Ca(2+-dependence of a transient K+ current.

    Directory of Open Access Journals (Sweden)

    Snezana Levic

    Full Text Available Spontaneous action potentials have been described in developing sensory systems. These rhythmic activities may have instructional roles for the functional development of synaptic connections. The importance of spontaneous action potentials in the developing auditory system is underpinned by the stark correlation between the time of auditory system functional maturity, and the cessation of spontaneous action potentials. A prominent K(+ current that regulates patterning of action potentials is I(A. This current undergoes marked changes in expression during chicken hair cell development. Although the properties of I(A are not normally classified as Ca(2+-dependent, we demonstrate that throughout the development of chicken hair cells, I(A is greatly reduced by acute alterations of intracellular Ca(2+. As determinants of spike timing and firing frequency, intracellular Ca(2+ buffers shift the activation and inactivation properties of the current to more positive potentials. Our findings provide evidence to demonstrate that the kinetics and functional expression of I(A are tightly regulated by intracellular Ca(2+. Such feedback mechanism between the functional expression of I(A and intracellular Ca(2+ may shape the activity of spontaneous action potentials, thus potentially sculpting synaptic connections in an activity-dependent manner in the developing cochlea.

  9. Glu¹⁰⁶ in the Orai1 pore contributes to fast Ca²⁺-dependent inactivation and pH dependence of Ca²⁺ release-activated Ca²⁺ (CRAC) current.

    Science.gov (United States)

    Scrimgeour, Nathan R; Wilson, David P; Rychkov, Grigori Y

    2012-01-15

    FCDI (fast Ca²⁺-dependent inactivation) is a mechanism that limits Ca²⁺ entry through Ca²⁺ channels, including CRAC (Ca²⁺ release-activated Ca²⁺) channels. This phenomenon occurs when the Ca²⁺ concentration rises beyond a certain level in the vicinity of the intracellular mouth of the channel pore. In CRAC channels, several regions of the pore-forming protein Orai1, and STIM1 (stromal interaction molecule 1), the sarcoplasmic/endoplasmic reticulum Ca²⁺ sensor that communicates the Ca²⁺ load of the intracellular stores to Orai1, have been shown to regulate fast Ca²⁺-dependent inactivation. Although significant advances in unravelling the mechanisms of CRAC channel gating have occurred, the mechanisms regulating fast Ca²⁺-dependent inactivation in this channel are not well understood. We have identified that a pore mutation, E106D Orai1, changes the kinetics and voltage dependence of the ICRAC (CRAC current), and the selectivity of the Ca²⁺-binding site that regulates fast Ca²⁺-dependent inactivation, whereas the V102I and E190Q mutants when expressed at appropriate ratios with STIM1 have fast Ca²⁺-dependent inactivation similar to that of WT (wild-type) Orai1. Unexpectedly, the E106D mutation also changes the pH dependence of ICRAC. Unlike WT ICRAC, E106D-mediated current is not inhibited at low pH, but instead the block of Na⁺ permeation through the E106D Orai1 pore by Ca²⁺ is diminished. These results suggest that Glu¹⁰⁶ inside the CRAC channel pore is involved in co-ordinating the Ca²⁺-binding site that mediates fast Ca²⁺-dependent inactivation.

  10. The calmodulin-binding, short linear motif, NSCaTE is conserved in L-type channel ancestors of vertebrate Cav1.2 and Cav1.3 channels.

    Directory of Open Access Journals (Sweden)

    Valentina Taiakina

    Full Text Available NSCaTE is a short linear motif of (xWxxx(I or Lxxxx, composed of residues with a high helix-forming propensity within a mostly disordered N-terminus that is conserved in L-type calcium channels from protostome invertebrates to humans. NSCaTE is an optional, lower affinity and calcium-sensitive binding site for calmodulin (CaM which competes for CaM binding with a more ancient, C-terminal IQ domain on L-type channels. CaM bound to N- and C- terminal tails serve as dual detectors to changing intracellular Ca(2+ concentrations, promoting calcium-dependent inactivation of L-type calcium channels. NSCaTE is absent in some arthropod species, and is also lacking in vertebrate L-type isoforms, Cav1.1 and Cav1.4 channels. The pervasiveness of a methionine just downstream from NSCaTE suggests that L-type channels could generate alternative N-termini lacking NSCaTE through the choice of translational start sites. Long N-terminus with an NSCaTE motif in L-type calcium channel homolog LCav1 from pond snail Lymnaea stagnalis has a faster calcium-dependent inactivation than a shortened N-termini lacking NSCaTE. NSCaTE effects are present in low concentrations of internal buffer (0.5 mM EGTA, but disappears in high buffer conditions (10 mM EGTA. Snail and mammalian NSCaTE have an alpha-helical propensity upon binding Ca(2+-CaM and can saturate both CaM N-terminal and C-terminal domains in the absence of a competing IQ motif. NSCaTE evolved in ancestors of the first animals with internal organs for promoting a more rapid, calcium-sensitive inactivation of L-type channels.

  11. Activation of the Ca2+-sensing receptors increases currents through inward rectifier K+ channels via activation of phosphatidylinositol 4-kinase

    OpenAIRE

    Liu, Chung-Hung; Chang, Hsueh-Kai; Lee, Sue-Ping; Shieh, Ru-Chi

    2016-01-01

    Inward rectifier K+ channels are important for maintaining normal electrical function in many cell types. The proper function of these channels requires the presence of membrane phosphoinositide 4,5-bisphosphate (PIP2). Stimulation of the Ca2+-sensing receptor CaR, a pleiotropic G protein-coupled receptor, activates both Gq/11, which decreases PIP2, and phosphatidylinositol 4-kinase (PI-4-K), which, conversely, increases PIP2. How membrane PIP2 levels are regulated by CaR activation and wheth...

  12. A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome

    Science.gov (United States)

    Wilson, Dan; Ermentrout, Bard; Němec, Jan; Salama, Guy

    2017-09-01

    Abnormal Ca2+ handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca2+ release from Ca2+-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca2+-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca2+ elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca2+ dynamics in bradycardia and LQT2. Abnormal systolic Ca2+-oscillations and EADs caused by SR Ca2+-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca2+ while a third gate senses luminal junctional SR Ca2+. The model predicts EADs in bradycardia and low extracellular [K+] and cessation of SR Ca2+-release terminate salvos of EADs. Ca2+-waves, systolic cell-synchronous Ca2+-release, and multifocal diastolic Ca2+ release seen in subcellular Ca2+-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca2+-overload, abnormal SR Ca2+-release, and the subsequent activation of the electrogenic Na+/Ca2+-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.

  13. Different Densities of Na-Ca Exchange Current in T-Tubular and Surface Membranes and Their Impact on Cellular Activity in a Model of Rat Ventricular Cardiomyocyte

    Czech Academy of Sciences Publication Activity Database

    Pásek, Michal; Šimurda, J.; Christé, G.

    2017-01-01

    Roč. 2017, č. 2017 (2017), č. článku 6343821. ISSN 2314-6133 Institutional support: RVO:61388998 Keywords : rat ventricular cell * mathematical model * Na-Ca current * t-tubules Subject RIV: BO - Biophysics OBOR OECD: Biophysics Impact factor: 2.476, year: 2016

  14. Critical current density, irreversibility line, and flux creep activation energy in silver-sheathed Bi2Sr2Ca2Cu3Ox superconducting tapes

    International Nuclear Information System (INIS)

    Shi, D.; Wang, Z.; Sengupta, S.; Smith, M.; Goodrich, L.F.; Dou, S.X.; Liu, H.K.; Guo, Y.C.

    1992-08-01

    Transport data, magnetic hysteresis and flux creep activation energy experimental results are presented for silver-sheathed high-T c Bi 2 Sr 2 Ca 2 Cu 3 O x superconducting tapes. The 110 K superconducting phase was formed by lead doping in a Bi-Sr-Ca-Cu-0 system. The transport critical current density was measured at 4.0 K to be 0.7 x 10 5 A/cm 2 (the corresponding critical current is 74 A) at zero field and 1.6 x 10 4 A/cm 2 at 12 T for H parallel ab. Excellent grain alignment in the a-b plane was achieved by a short-melting method, which considerably improved the critical current density and irreversibility line. Flux creep activation energy as a function of current is obtained based on the magnetic relaxation measurements

  15. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

    Directory of Open Access Journals (Sweden)

    Sergiy V Korol

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM, an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM plus diazepam (1 μM, only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

  16. Vitamin E isomer δ-tocopherol enhances the efficiency of neural stem cell differentiation via L-type calcium channel.

    Science.gov (United States)

    Deng, Sihao; Hou, Guoqiang; Xue, Zhiqin; Zhang, Longmei; Zhou, Yuye; Liu, Chao; Liu, Yanqing; Li, Zhiyuan

    2015-01-12

    The effects of the vitamin E isomer δ-tocopherol on neural stem cell (NSC) differentiation have not been investigated until now. Here we investigated the effects of δ-tocopherol on NSC neural differentiation, maturation and its possible mechanisms. Neonatal rat NSCs were grown in suspended neurosphere cultures, and were identified by their expression of nestin protein and their capacity for self-renewal. Treatment with a low concentration of δ-tocopherol induced a significant increase in the percentage of β-III-tubulin-positive cells. δ-Tocopherol also stimulated morphological maturation of neurons in culture. We further observed that δ-tocopherol stimulation increased the expression of voltage-dependent Ca(2+) channels. Moreover, a L-type specific Ca(2+) channel blocker verapamil reduced the percentage of differentiated neurons after δ-tocopherol treatment, and blocked the effects of δ-tocopherol on NSC differentiation into neurons. Together, our study demonstrates that δ-tocopherol may act through elevation of L-type calcium channel activity to increase neuronal differentiation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. BAG3 regulates contractility and Ca(2+) homeostasis in adult mouse ventricular myocytes.

    Science.gov (United States)

    Feldman, Arthur M; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D; Tilley, Douglas G; Gao, Erhe; Hoffman, Nicholas E; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y

    2016-03-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na(+)-K(+)-ATPase and L-type Ca(2+) channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca(2+) channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca(2+)]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca(2+) current (ICa) and sarcoplasmic reticulum (SR) Ca(2+) content but not Na(+)/Ca(2+) exchange current (INaCa) or SR Ca(2+) uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyryl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca(2+) entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca(2+) channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. Copyright © 2016 Elsevier Ltd. All rights

  18. BAG3 regulates contractility and Ca2+ homeostasis in adult mouse ventricular myocytes

    Science.gov (United States)

    Feldman, Arthur M.; Gordon, Jennifer; Wang, JuFang; Song, Jianliang; Zhang, Xue-Qian; Myers, Valerie D.; Tilley, Douglas G.; Gao, Erhe; Hoffman, Nicholas E.; Tomar, Dhanendra; Madesh, Muniswamy; Rabinowitz, Joseph; Koch, Walter J.; Su, Feifei; Khalili, Kamel; Cheung, Joseph Y.

    2016-01-01

    Bcl2-associated athanogene 3 (BAG3) is a 575 amino acid anti-apoptotic protein that is constitutively expressed in the heart. BAG3 mutations, including mutations leading to loss of protein, are associated with familial cardiomyopathy. Furthermore, BAG3 levels have been found to be reduced in end-stage non-familial failing myocardium. In contrast to neonatal myocytes in which BAG3 is found in the cytoplasm and involved in protein quality control and apoptosis, in adult mouse left ventricular (LV) myocytes BAG3 co-localized with Na+-K+-ATPase and L-type Ca2+ channels in the sarcolemma and t-tubules. BAG3 co-immunoprecipitated with β1-adrenergic receptor, L-type Ca2+ channels and phospholemman. To simulate decreased BAG3 protein levels observed in human heart failure, we targeted BAG3 by shRNA (shBAG3) in adult LV myocytes. Reducing BAG3 by 55% resulted in reduced contraction and [Ca2+]i transient amplitudes in LV myocytes stimulated with isoproterenol. L-type Ca2+ current (ICa) and sarcoplasmic reticulum (SR) Ca2+ content but not Na+/Ca2+ exchange current (INaCa) or SR Ca2+ uptake were reduced in isoproterenol-treated shBAG3 myocytes. Forskolin or dibutyrl cAMP restored ICa amplitude in shBAG3 myocytes to that observed in WT myocytes, consistent with BAG3 having effects upstream and at the level of the receptor. Resting membrane potential and action potential amplitude were unaffected but APD50 and APD90 were prolonged in shBAG3 myocytes. Protein levels of Ca2+ entry molecules and other important excitation-contraction proteins were unchanged in myocytes with lower BAG3. Our findings that BAG3 is localized at the sarcolemma and t-tubules while modulating myocyte contraction and action potential duration through specific interaction with the β1-adrenergic receptor and L-type Ca2+ channel provide novel insight into the role of BAG3 in cardiomyopathies and increased arrhythmia risks in heart failure. PMID:26796036

  19. Elementary properties of CaV1.3 Ca2+ channels expressed in mouse cochlear inner hair cells

    Science.gov (United States)

    Zampini, Valeria; Johnson, Stuart L; Franz, Christoph; Lawrence, Neil D; Münkner, Stefan; Engel, Jutta; Knipper, Marlies; Magistretti, Jacopo; Masetto, Sergio; Marcotti, Walter

    2010-01-01

    Mammalian cochlear inner hair cells (IHCs) are specialized to process developmental signals during immature stages and sound stimuli in adult animals. These signals are conveyed onto auditory afferent nerve fibres. Neurotransmitter release at IHC ribbon synapses is controlled by L-type CaV1.3 Ca2+ channels, the biophysics of which are still unknown in native mammalian cells. We have investigated the localization and elementary properties of Ca2+ channels in immature mouse IHCs under near-physiological recording conditions. CaV1.3 Ca2+ channels at the cell pre-synaptic site co-localize with about half of the total number of ribbons present in immature IHCs. These channels activated at about −70 mV, showed a relatively short first latency and weak inactivation, which would allow IHCs to generate and accurately encode spontaneous Ca2+ action potential activity characteristic of these immature cells. The CaV1.3 Ca2+ channels showed a very low open probability (about 0.15 at −20 mV: near the peak of an action potential). Comparison of elementary and macroscopic Ca2+ currents indicated that very few Ca2+ channels are associated with each docked vesicle at IHC ribbon synapses. Finally, we found that the open probability of Ca2+ channels, but not their opening time, was voltage dependent. This finding provides a possible correlation between presynaptic Ca2+ channel properties and the characteristic frequency/amplitude of EPSCs in auditory afferent fibres. PMID:19917569

  20. Magnetization and critical currents of Bi-Sr-Ca-Cu-O and Ba2YCu3O7 superconductors

    International Nuclear Information System (INIS)

    Gyorgy, E.M.; van Dover, R.B.; Jin, S.; Sherwood, R.C.; Schneemeyer, L.F.; Tiefel, T.H.; Waszczak, J.V.

    1988-01-01

    We have measured the critical currrent density J/sub c/ as a function of temperature for a Bi-Sr-Ca-Cu-O sample containing a substantial fraction of a phase with T/sub c/≅110 K and for a Ba 2 YCu 3 O 7 sample (TT/sub c/≅92 K). The behavior of J/sub c/ was deduced from magnetization measurements. For both samples the magnetization at fixed temperature and field decayed logarithmically with time. The values of J/sub c/ so derived, allowing for the decay to occur, went to zero for temperatures above 35 K for the Bi-Sr-Ca-Cu-O ceramic and to zero above 70 K for the Ba 2 YCu 3 O 7 sample. These values are substantially lower than those deduced from dynamic M-H loops

  1. Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation

    Science.gov (United States)

    He, Fengping; Xu, Xin; Yuan, Shuguo; Tan, Liangqiu; Gao, Lingjun; Ma, Shaochun; Zhang, Shebin; Ma, Zhanzhong; Jiang, Wei; Liu, Fenglian; Chen, Baofeng; Zhang, Beibei; Pang, Jungang; Huang, Xiuyan; Weng, Jiaqiang

    2016-08-01

    Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.

  2. PLC-dependent intracellular Ca2+ release was associated with C6-ceramide-induced inhibition of Na+ current in rat granule cells.

    Science.gov (United States)

    Liu, Zheng; Fei, Xiao-Wei; Fang, Yan-Jia; Shi, Wen-Jie; Zhang, Yu-Qiu; Mei, Yan-Ai

    2008-09-01

    In this report, the effects of C(6)-ceramide on the voltage-gated inward Na(+) currents (I(Na)), two types of main K(+) current [outward rectifier delayed K(+) current (I(K)) and outward transient K(+) current (I(A))], and cell death in cultured rat cerebellar granule cells were investigated. At concentrations of 0.01-100 microM, ceramide produced a dose-dependent and reversible inhibition of I(Na) without alteration of the steady-state activation and inactivation properties. Treatment with C(2)-ceramide caused a similar inhibitory effect on I(Na). However, dihydro-C(6)-ceramide failed to modulate I(Na). The effect of C(6)-ceramide on I(Na) was abolished by intracellular infusion of the Ca(2+)-chelating agent, 1,2-bis (2-aminophenoxy) ethane-N, N, N9, N9-tetraacetic acid, but was mimicked by application of caffeine. Blocking the release of Ca(2+) from the sarcoplasmic reticulum with ryanodine receptor blocker induced a gradual increase in I(Na) amplitude and eliminated the effect of ceramide on I(Na). In contrast, the blocker of the inositol 1,4,5-trisphosphate-sensitive Ca(2+) receptor did not affect the action of C(6)-ceramide. Intracellular application of GTPgammaS also induced a gradual decrease in I(Na) amplitude, while GDPbetaS eliminated the effect of C(6)-ceramide on I(Na). Furthermore, the C(6)-ceramide effect on I(Na) was abolished after application of the phospholipase C (PLC) blockers and was greatly reduced by the calmodulin inhibitors. Fluorescence staining showed that C(6)-ceramide decreased cell viability and blocking I(Na) by tetrodotoxin did not mimic the effect of C(6)-ceramide, and inhibiting intracellular Ca(2+) release by dantrolene could not decrease the C(6)-ceramide-induced cell death. We therefore suggest that increased PLC-dependent Ca(2+) release through the ryanodine-sensitive Ca(2+) receptor may be responsible for the C(6)-ceramide-induced inhibition of I(Na), which does not seem to be associated with C(6)-ceramide-induced granule

  3. Lowering glucose level elevates [Ca2+]i in hypothalamic arcuate nucleus NPY neurons through P/Q-type Ca2+ channel activation and GSK3β inhibition

    Science.gov (United States)

    Chen, Yu; Zhou, Jun; Xie, Na; Huang, Chao; Zhang, Jun-qi; Hu, Zhuang-li; Ni, Lan; Jin, You; Wang, Fang; Chen, Jian-guo; Long, Li-hong

    2012-01-01

    Aim: To identify the mechanisms underlying the elevation of intracellular Ca2+ level ([Ca2+]i) induced by lowering extracellular glucose in rat hypothalamic arcuate nucleus NPY neurons. Methods: Primary cultures of hypothalamic arcuate nucleus (ARC) neurons were prepared from Sprague-Dawley rats. NPY neurons were identified with immunocytochemical method. [Ca2+]i was measured using fura-2 AM. Ca2+ current was recorded using whole-cell patch clamp recording. AMPK and GSK3β levels were measured using Western blot assay. Results: Lowering glucose level in the medium (from 10 to 1 mmol/L) induced a transient elevation of [Ca2+]i in ARC neurons, but not in hippocampal and cortical neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons depended on extracellular Ca2+, and was blocked by P/Q-type Ca2+channel blocker ω-agatoxin TK (100 nmol/L), but not by L-type Ca2+ channel blocker nifedipine (10 μmol/L) or N-type Ca2+channel blocker ω-conotoxin GVIA (300 nmol/L). Lowering glucose level increased the peak amplitude of high voltage-activated Ca2+ current in ARC neurons. The low-glucose induced elevation of [Ca2+]i in ARC neurons was blocked by the AMPK inhibitor compound C (20 μmol/L), and enhanced by the GSK3β inhibitor LiCl (10 mmol/L). Moreover, lowering glucose level induced the phosphorylation of AMPK and GSK3β, which was inhibited by compound C (20 μmol/L). Conclusion: Lowering glucose level enhances the activity of P/Q type Ca2+channels and elevates [Ca2+]i level in hypothalamic arcuate nucleus neurons via inhibition of GSK3β. PMID:22504905

  4. Two distinct voltage-sensing domains control voltage sensitivity and kinetics of current activation in CaV1.1 calcium channels.

    Science.gov (United States)

    Tuluc, Petronel; Benedetti, Bruno; Coste de Bagneaux, Pierre; Grabner, Manfred; Flucher, Bernhard E

    2016-06-01

    Alternative splicing of the skeletal muscle CaV1.1 voltage-gated calcium channel gives rise to two channel variants with very different gating properties. The currents of both channels activate slowly; however, insertion of exon 29 in the adult splice variant CaV1.1a causes an ∼30-mV right shift in the voltage dependence of activation. Existing evidence suggests that the S3-S4 linker in repeat IV (containing exon 29) regulates voltage sensitivity in this voltage-sensing domain (VSD) by modulating interactions between the adjacent transmembrane segments IVS3 and IVS4. However, activation kinetics are thought to be determined by corresponding structures in repeat I. Here, we use patch-clamp analysis of dysgenic (CaV1.1 null) myotubes reconstituted with CaV1.1 mutants and chimeras to identify the specific roles of these regions in regulating channel gating properties. Using site-directed mutagenesis, we demonstrate that the structure and/or hydrophobicity of the IVS3-S4 linker is critical for regulating voltage sensitivity in the IV VSD, but by itself cannot modulate voltage sensitivity in the I VSD. Swapping sequence domains between the I and the IV VSDs reveals that IVS4 plus the IVS3-S4 linker is sufficient to confer CaV1.1a-like voltage dependence to the I VSD and that the IS3-S4 linker plus IS4 is sufficient to transfer CaV1.1e-like voltage dependence to the IV VSD. Any mismatch of transmembrane helices S3 and S4 from the I and IV VSDs causes a right shift of voltage sensitivity, indicating that regulation of voltage sensitivity by the IVS3-S4 linker requires specific interaction of IVS4 with its corresponding IVS3 segment. In contrast, slow current kinetics are perturbed by any heterologous sequences inserted into the I VSD and cannot be transferred by moving VSD I sequences to VSD IV. Thus, CaV1.1 calcium channels are organized in a modular manner, and control of voltage sensitivity and activation kinetics is accomplished by specific molecular mechanisms

  5. L-type calcium channels play a crucial role in the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Wen, Li [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Wang, Yu [Department of Oncology, Xijing Hospital, Fourth Military Medical University, Xi' an 710032 (China); Wang, Huan [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Kong, Lingmin [Department of Fundamental Medicine, Cell Engineering Research Centre, Fourth Military Medical University, Xi' an 710032 (China); Zhang, Liang [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China); Chen, Xin [Department of General Dentistry, The 174th Hospital of Chinese PLA, Xiamen 361003 (China); Ding, Yin, E-mail: dingyin@fmmu.edu.cn [Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi' an 710032 (China)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We detect the functional Ca{sup 2+} currents and mRNA expression of VDCC{sub L} in rMSCs. Black-Right-Pointing-Pointer Blockage of VDCC{sub L} exert antiproliferative and apoptosis-inducing effects on rMSCs. Black-Right-Pointing-Pointer Inhibiting VDCC{sub L} can suppress the ability of rMSCs to differentiate into osteoblasts. Black-Right-Pointing-Pointer {alpha}1C of VDCC{sub L} may be a primary functional subunit in VDCC{sub L}-regulating rMSCs. -- Abstract: L-type voltage-dependent Ca{sup 2+} channels (VDCC{sub L}) play an important role in the maintenance of intracellular calcium homeostasis, and influence multiple cellular processes. They have been confirmed to contribute to the functional activities of osteoblasts. Recently, VDCC{sub L} expression was reported in mesenchymal stem cells (MSCs), but the role of VDCC{sub L} in MSCs is still undetermined. The aim of this study was to determine whether VDCC{sub L} may be regarded as a new regulator in the proliferation and osteogenic differentiation of rat MSC (rMSCs). In this study, we examined functional Ca{sup 2+} currents (I{sub Ca}) and mRNA expression of VDCC{sub L} in rMSCs, and then suppressed VDCC{sub L} using nifedipine (Nif), a VDCC{sub L} blocker, to investigate its role in rMSCs. The proliferation and osteogenic differentiation of MSCs were analyzed by MTT, flow cytometry, alkaline phosphatase (ALP), Alizarin Red S staining, RT-PCR, and real-time PCR assays. We found that Nif exerts antiproliferative and apoptosis-inducing effects on rMSCs. ALP activity and mineralized nodules were significantly decreased after Nif treatment. Moreover, the mRNA levels of the osteogenic markers, osteocalcin (OCN), bone sialoprotein (BSP), and runt-related transcription factor 2 (Runx2), were also down-regulated. In addition, we transfected {alpha}1C-siRNA into the cells to further confirm the role of VDCC{sub L} in rMSCs, and a similar effect on osteogenesis was found. These

  6. Critical current density of four-CuO2-layer T1Ba2Ca3Cu4O11-δ

    International Nuclear Information System (INIS)

    Zhang, L.; Liu, J.Z.; Shelton, R.N.

    1998-01-01

    Full text: A key requirement for technological application is to have superconductors with high critical current density at practical operating temperatures and magnetic fields. The critical current density is strongly related to underlying properties of high T c superconductors, such as layering, anisotropy and other intrinsic material structures. The thallium-based superconductors attracted much attention at early stage mainly due to their high superconducting transitions. Recent studies show that these materials appear to be a better choice for achieving higher critical current density because of a stronger interlayer coupling between superconducting layers. Single crystals of TlBa 2 Ca 3 Cu 4 O 11-δ were grown by a self-flux method. This material is a strong-layered superconductor with four-CuO 2 -planes in a unit cell and a superconducting transition temperature of 128K. Our experimental results show that TlBa 2 Ca 3 Cu 4 O 11-δ crystals have high irreversibility line, large critical current density and high upper critical field. The impact of layering and the number of Cu-O layers on flux pinning, critical current density and other magnetic properties will also be discussed

  7. Experimental studies of effect of high current pulse electron and carbon ion beams on high temperature Y-Ba-Cu-O, Bi-Ca-Sr-Cu-O superconductors

    International Nuclear Information System (INIS)

    Korenev, S.A.; Sikolenko, V.V.; Chernakova, A.

    1989-01-01

    This work shows the results of the experiment on the effect of high current electron and carbon ion pulse beams irradiation on High-T c superconductors Y-Ba-Cu-O and Bi-Ca-Cu-O in vacuum (P∼5x10 -5 torr). The parameters of electron beam used in the experiment were: E∼100-300 keV, j e ∼10-1000 A/cm 2 , τ) p ∼300ns. The parameters of carbon ions used in the experiment were: E∼100-300keV j i ∼1-60A/cm, τ p ∼300ns. Experiments had shown the threshold electron beam power density for surface melting in adiabatic heat condition for Y-Ba-Cu-O ceramics up to P 0 >or approx. 10 7 W/cm 2 , and for Bi-Ca-Sr-Cu-O ceramics up to P 0 ∼4x10 6 W/cm 2 . Increasing of critical current in ∼2 times was observed in samples with a melting surface layer. The integral resistance of Y-Ba-Cu-O and Bi-Ca-Sr-Cu-O decreased in ∼2-2.5 times for electron beam irradiated samples and in ∼1.25-1.8 times for ion irradiated samples. Amorphization did not take place and stoichiometry remained after such irradiation. 6 refs.; 2 figs.; 1 tab

  8. CNTF-ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through upregulating L-type calcium channel activity.

    Science.gov (United States)

    Sun, Meiqun; Liu, Hongli; Xu, Huanbai; Wang, Hongtao; Wang, Xiaojing

    2016-09-01

    A specialized culture medium termed ciliary neurotrophic factor-treated astrocyte-conditioned medium (CNTF-ACM) allows investigators to assess the peripheral effects of CNTF-induced activated astrocytes upon cultured neurons. CNTF-ACM has been shown to upregulate neuronal L-type calcium channel current activity, which has been previously linked to changes in mitochondrial respiration and oxidative stress. Therefore, the aim of this study was to evaluate CNTF-ACM's effects upon mitochondrial respiration and oxidative stress in rat cortical neurons. Cortical neurons, CNTF-ACM, and untreated control astrocyte-conditioned medium (UC-ACM) were prepared from neonatal Sprague-Dawley rat cortical tissue. Neurons were cultured in either CNTF-ACM or UC-ACM for a 48-h period. Changes in the following parameters before and after treatment with the L-type calcium channel blocker isradipine were assessed: (i) intracellular calcium levels, (ii) mitochondrial membrane potential (ΔΨm), (iii) oxygen consumption rate (OCR) and adenosine triphosphate (ATP) formation, (iv) intracellular nitric oxide (NO) levels, (v) mitochondrial reactive oxygen species (ROS) production, and (vi) susceptibility to the mitochondrial complex I toxin rotenone. CNTF-ACM neurons displayed the following significant changes relative to UC-ACM neurons: (i) increased intracellular calcium levels (p ACM (p ACM promotes mitochondrial respiration and oxidative stress in cortical neurons through elevating L-type calcium channel activity.

  9. A EUropean study on effectiveness and sustainability of current Cardiac Rehabilitation programmes in the Elderly: Design of the EU-CaRE randomised controlled trial.

    Science.gov (United States)

    Prescott, Eva; Meindersma, Esther P; van der Velde, Astrid E; Gonzalez-Juanatey, Jose R; Iliou, Marie Christine; Ardissino, Diego; Zoccai, Giuseppe Biondi; Zeymer, Uwe; Prins, Leonie F; Van't Hof, Arnoud Wj; Wilhelm, Matthias; de Kluiver, Ed P

    2016-10-01

    Cardiac rehabilitation (CR) is an evidence-based intervention to increase survival and quality of life. Yet studies consistently show that elderly patients are less frequently referred to CR, show less uptake and more often drop out of CR programmes. The European study on effectiveness and sustainability of current cardiac rehabilitation programmes in the elderly (EU-CaRE) project consists of an observational study and an open prospective, investigator-initiated multicentre randomised controlled trial (RCT) involving mobile telemonitoring guided CR (mCR). The aim of EU-CaRE is to map the efficiency of current CR of the elderly in Europe, and to investigate whether mCR is an effective alternative in terms of efficacy, adherence and sustainability. The EU-CaRE study includes patients aged 65 years or older with ischaemic heart disease or who have undergone heart valve surgery. A total of 1760 patients participating in existing CR programmes in eight regions of Europe will be included. Of patients declining regular CR, 238 will be included in the RCT and randomised in two study arms. The experimental group (mCR) will receive a personalised home-based programme while the control group will receive no advice or coaching throughout the study period. Outcomes will be assessed after the end of CR and at 12 months follow-up. The primary outcome is VO 2peak and secondary outcomes include variables describing CR uptake, adherence, efficacy and sustainability. The study will provide important information to improve CR in the elderly. The EU-CaRE RCT is the first European multicentre study of mCR as an alternative for elderly patients not attending usual CR. © The European Society of Cardiology 2016.

  10. Leftward shift in the voltage-dependence for Ca2+ currents activation induced by a new toxin from Phoneutria reidyi (Aranae, Ctenidae) venom.

    Science.gov (United States)

    Vieira, L B; Pimenta, A M C; Richardson, M; Bemquerer, M P; Reis, H J; Cruz, J S; Gomez, M V; Santoro, M M; Ferreira-de-Oliveira, R; Figueiredo, S G; Snutch, T P; Cordeiro, M N

    2007-02-01

    Various neurotoxins have been described from the venom of the Brazilian spider Phoneutria nigriventer, but little is known about the venoms of the other species of this genus. In the present work, we describe the purification and some structural and pharmacological features of a new toxin (PRTx3-7) from Phoneutria reidyi that causes flaccid paralysis in mice. The observed molecular mass (4627.26 Da) was in accordance with the calculated mass for the amidated form of the amino acid sequence (4627.08 Da). The presence of an alpha-amidated C-terminus was confirmed by MS/MS analysis of the C-terminal peptide, isolated after enzymatic digestion of the native protein with Glu-C endoproteinase. The purified protein was injected (intracerebro-ventricular) into mice at dose levels of 5 microg/mouse causing immediate agitation and clockwise gyration, followed by the gradual development of general flaccid paralysis. PRTx3-7 at 1 microM inhibited by 20% the KCl-induced increase on [Ca2+]i in rat brain synaptosomes. The HEK cells permanently expressing L, N, P/Q and R HVA Ca2+ channels were also used to better characterize the pharmacological features of PRTx3-7. To our surprise, PRTx3-7 shifted the voltage-dependence for activation towards hyperpolarized membrane potentials for L (-4 mV), P/Q (-8 mV) and R (-5 mV) type Ca2+ currents. In addition, the new toxin also affected the steady state of inactivation of L-, N- and P/Q-type Ca2+ currents.

  11. Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

    Science.gov (United States)

    Tharp, Darla L.; Ivey, Jan R.; Ganjam, Venkataseshu K.; Bowles, Douglas K.

    2011-01-01

    Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K+ currents (IK+) in coronary smooth muscle cells. Raising internal Ca2+ from 200 to 500 nM increased Ca2+-sensitive K+ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca2+-sensitive IK+ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca2+-sensitive IK+, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy. PMID:21841018

  12. Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca²⁺-sensitive K⁺ current in miniature swine with LV hypertrophy.

    Science.gov (United States)

    Emter, Craig A; Tharp, Darla L; Ivey, Jan R; Ganjam, Venkataseshu K; Bowles, Douglas K

    2011-10-01

    Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ET(A)) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K(+) currents (I(K(+))) in coronary smooth muscle cells. Raising internal Ca(2+) from 200 to 500 nM increased Ca(2+)-sensitive K(+) current in HF-TR and control, but not HF animals. In conclusion, an ET(A)-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca(2+)-sensitive I(K(+)) was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca(2+)-sensitive I(K(+)), illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

  13. Biological evaluation of [18F]-nifedipine as a novel PET tracer for L-type calcium channel imaging

    International Nuclear Information System (INIS)

    Sadeghpour, H.; Jalilian, A.R.; Akhlaghi, M.; Mirzaii, M.; Saddadi, F.; Shafiee, A.; Miri, R.

    2008-01-01

    Due to interesting role of dihydropyridines in cardiovascular diseases and drug resistance studies and lack of a fluorine-18 labeled imaging agent for L-type calcium channel studies, this study was designed. [ 18 F] Dimethyl 2 - (fluoromethyl) - 6 - methyl - 4 - (2 - nitrophenyl) - 1,4 - dihydropyridine - 3,5 - dicarboxylate 2 was prepared in no-carrier-added (n.c.a.) form from a starting brominated compound in one step at 80 o C in Kryptofix2.2.2/[ 18 F]. Compound 2 was administered to normal rats via their tail veins for preliminary biodistribution studies and the ID/g % of the labeled compound was determined up to 3 h post injections. Coincidence images were obtained in rats 5 to 120 min. Radiofluorination on bromo precursor gave a fluorinated compound in 95 % radiochemical purity and a 8% yield shown by RTLC and HPLC. Biodistribution studies showed that the tracer is accumulated in the heart in the first few minutes, followed by metabolism resulting in very soluble 18 F-containing metabolites eliminated through the urinary tract. In coincidence images, the target organ was shown to be the heart. Lung had high accumulation possibly due to the presence of Ca 2+ channels and/or hydrolyzing enzymes showing a significant myocardial uptake at 120 min. The data demonstrates a significant agreement with the reported L-type calcium channels throughout the animal body. To our knowledge, this is the first example of 18 F-DHPs in the literature. (authors)

  14. Electroconvulsive stimulations prevent chronic stress-induced increases in L-type calcium channel mRNAs in the hippocampus and basolateral amygdala

    DEFF Research Database (Denmark)

    Maigaard, Katrine; Pedersen, Ida Hageman; Jørgensen, Anders

    2012-01-01

    Although affective disorders have high prevalence, morbidity and mortality, we do not fully understand disease etiopathology, nor have we determined the exact mechanisms by which treatment works. Recent research indicates that intracellular calcium ion dysfunction might be involved. Here we use...... the chronic restraint stress model of affective disorder (6 h restraint per day for 21 days) in combination with electroconvulsive stimulations to examine the effects of stress and an effective antidepressive treatment modality on L-type voltage gated calcium channel subunit mRNA expression patterns...... in the brain. We find that stress tended to upregulate Ca(v)1.2 and Ca(v)1.3 channels in a brain region specific manner, while ECS tended to normalise this effect. This was more pronounced for Ca(v)1.2 channels, where stress clearly increased expression in both the basolateral amygdala, dentate gyrus and CA3...

  15. Pacific ciguatoxin-1b effect over Na+ and K+ currents, inositol 1,4,5-triphosphate content and intracellular Ca2+ signals in cultured rat myotubes

    Science.gov (United States)

    Hidalgo, Jorge; Liberona, José Luis; Molgó, Jordi; Jaimovich, Enrique

    2002-01-01

    The action of the main ciguatoxin involved in ciguatera fish poisoning in the Pacific region (P-CTX-1b) was studied in myotubes originated from rat skeletal muscle cells kept in primary culture. The effect of P-CTX-1b on sodium currents at short times of exposure (up to 1 min) showed a moderate increase in peak Na+ current. During prolonged exposures, P-CTX-1b decreased the peak Na+ current. This action was always accompanied by an increase of leakage currents, tail currents and outward Na+ currents, resulting in an intracellular Na+ accumulation. This effect is blocked by prior exposure to tetrodotoxin (TTX) and becomes evident only after washout of TTX. Low to moderate concentrations of P-CTX-1b (2–5 nM) partially blocked potassium currents in a manner that was dependent on the membrane potential. P-CTX-1b (2–12 nM) caused a small membrane depolarization (3–5 mV) and an increase in the frequency of spontaneous action potential discharges that reached in general low frequencies (0.1–0.5 Hz). P-CTX-1b (10 nM) caused a transient increase of intracellular inositol 1,4,5-trisphosphate (IP3) mass levels, which was blocked by TTX. In the presence of P-CTX-1b (10 nM) and in the absence of external Ca2+, the intracellular Ca2+ levels show a transient increase in the cytoplasm as well as in the nuclei. The time course of this effect may reflect the action of IP3 over internal stores activated by P-CTX-1b-induced membrane depolarization. PMID:12429578

  16. Characterisation of an optimised high current MgO/Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub 8.21} composite conductor using pulsed transport currents with pulsed magnetic fields

    Energy Technology Data Exchange (ETDEWEB)

    Glowacki, B A; Gilewski, A; Rogacki, K; Kursumovic, A; Evetts, J E; Jones, H; Henson, R; Tsukamoto, O

    2003-01-15

    High temperature superconducting conductors are already used in hybrid magnets to produce fields that enhance the performance of conventional magnets made from A-15 type low temperature superconducting wires. For such applications it is vital that the interdependence of the critical parameters such as critical current versus magnetic field can be mapped under high field and high current conditions. However these superconductors have high critical currents even at fields over 20 T, making accurate measurements difficult due to the thermal and mechanical problems. In this paper, we compare measurements on the fully optimised Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub 8.21} flat rigid conductors using an innovative pulsed high transport current and pulsed high field technique. We show how analysis of the voltage signal from Bi{sub 2}Sr{sub 2}CaCu{sub 2}O{sub 8.21} tape in pulsed conditions may be used to extract the critical current under quasi-stationary conditions.

  17. Atrial natriuretic peptide regulates Ca channel in early developmental cardiomyocytes.

    Directory of Open Access Journals (Sweden)

    Lin Miao

    Full Text Available BACKGROUND: Cardiomyocytes derived from murine embryonic stem (ES cells possess various membrane currents and signaling cascades link to that of embryonic hearts. The role of atrial natriuretic peptide (ANP in regulation of membrane potentials and Ca(2+ currents has not been investigated in developmental cardiomyocytes. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of ANP in regulating L-type Ca(2+ channel current (I(CaL in different developmental stages of cardiomyocytes derived from ES cells. ANP decreased the frequency of action potentials (APs in early developmental stage (EDS cardiomyocytes, embryonic bodies (EB as well as whole embryo hearts. ANP exerted an inhibitory effect on basal I(CaL in about 70% EDS cardiomyocytes tested but only in about 30% late developmental stage (LDS cells. However, after stimulation of I(CaL by isoproterenol (ISO in LDS cells, ANP inhibited the response in about 70% cells. The depression of I(CaL induced by ANP was not affected by either Nomega, Nitro-L-Arginine methyl ester (L-NAME, a nitric oxide synthetase (NOS inhibitor, or KT5823, a cGMP-dependent protein kinase (PKG selective inhibitor, in either EDS and LDS cells; whereas depression of I(CaL by ANP was entirely abolished by erythro-9-(2-Hydroxy-3-nonyl adenine (EHNA, a selective inhibitor of type 2 phosphodiesterase(PDE2 in most cells tested. CONCLUSION/SIGNIFICANCES: Taken together, these results indicate that ANP induced depression of action potentials and I(CaL is due to activation of particulate guanylyl cyclase (GC, cGMP production and cGMP-activation of PDE2 mediated depression of adenosine 3', 5'-cyclic monophophate (cAMP-cAMP-dependent protein kinase (PKA in early cardiomyogenesis.

  18. A combination of genistein and magnesium enhances the vasodilatory effect via an eNOS pathway and BK(Ca) current amplification.

    Science.gov (United States)

    Sun, Lina; Hou, Yunlong; Zhao, Tingting; Zhou, Shanshan; Wang, Xiaoran; Zhang, Liming; Yu, Guichun

    2015-04-01

    The phytoestrogen genistein (GST) and magnesium have been independently shown to regulate vascular tone; however, their individual vasodilatory effects are limited. The aim of this study was to examine the combined effects of GST plus magnesium on vascular tone in mesenteric arteries. The effects of pretreatment with GST (0-200 μmol/L), MgCl2 (0-4.8 mmol/L) and GST plus MgCl2 on 10 μmol/L phenylephrine (PE) precontracted mesenteric arteries in rats were assessed by measuring isometric force. BK(Ca) currents were detected by the patch clamp method. GST caused concentration- and partial endothelium-dependent relaxation. Magnesium resulted in dual adjustment of vascular tone. Magnesium-free solution eliminated the vasodilatation of GST in both endothelium-intact and denuded rings. GST (50 μmol/L) plus magnesium (4.8 mmol/L) caused stronger relaxation in both endothelium-intact and denuded rings. Pretreatment with the nitric oxide synthase (NOS) inhibitor L-N-nitroarginine methyl ester (L-NAME, 100 μmol/L) significantly inhibited the effects of GST, high magnesium, and the combination of GST and magnesium. BK(Ca) currents were amplified to a greater extent when GST (50 μmol/L) was combined with 4.8 versus 1.2 mmol/L Mg(2+). Our data suggest that GST plus magnesium provides enhanced vasodilatory effects in rat mesenteric arteries compared with that observed when either is used separately, which was related to an eNOS pathway and BK(Ca) current amplification.

  19. Current-carrying capacity dependence of composite Bi2Sr2CaCu2O8 superconductors on the liquid coolant conditions

    International Nuclear Information System (INIS)

    Romanovskii, V R; Watanabe, K; Awaji, S; Nishijima, G

    2006-01-01

    The thermal runaway conditions of the composite Bi 2 Sr 2 CaCu 2 O 8 superconductor cooled by liquid helium or liquid hydrogen are compared. The study based on the static analysis of thermoelectric modes was made when the volume fraction of the superconductor in a composite was varied. Some specific trends underlying the onset of thermal runaway in superconducting composites cooled by liquid coolants are discussed. It is stated that the operating modes of superconducting composites may be characterized by stable states during which the current-carrying capacity of a superconductor is not effectively used even with a high amount of superconductor in the composite. These states are possible due to the corresponding temperature variation of the resistivities of the matrix and the superconductor in the high operating temperature range. They have to be considered in experiments when the critical current of a superconductor is determined or when the optimal stable operating modes of the current-carrying elements based on the Bi 2 Sr 2 CaCu 2 O 8 superconductor, which is cooled by liquid coolant, are defined

  20. Study of critical current density from ac susceptibility measurements in (La1-xYx)2Ba2CaCu5O2 superconductors

    International Nuclear Information System (INIS)

    Nayak, P.K.; Ravi, S. . sravi@iitg.ernet.in

    2008-01-01

    We have prepared a series of compounds (La 1-x Y x ) 2 Ba 2 CaCu 5 O 2 for x = 0 to 0.5 by adding a CaCuO 2 layer to the parent compound La 2 Ba 2 Cu 4 O 2 and by doping Y in place of La. These materials are also prepared by adding 5 wt% of Ag to enhance the intergranular coupling and critical current density. X-ray diffraction measurements show that all the samples are essentially in single phase form and the patterns could be refined using P4/mmm space group in tetragonal cell. The typical lattice parameters are found to be a = b 3.856 A, c = 11.576 A for x = 0.5 sample. Temperature variations of dc electrical resistivity measured on the above samples show that they exhibit superconductivity with T c ranging from 60 to 75 K. Temperature and ac field amplitude variation of ac susceptibility have been measured on the above samples. The field variation of ac susceptibility data has been analyzed by using Bean critical state model. Using both temperature and field variations of ac susceptibility data, the material dependent parameters, such as critical current density as a function of temperature and effective volume fraction grains have been estimated. The Ag doped samples show relatively large critical current density compared to pure samples due to improved intergranular coupling. (author)

  1. Release from the cone ribbon synapse under bright light conditions can be controlled by the opening of only a few Ca(2+) channels.

    Science.gov (United States)

    Bartoletti, Theodore M; Jackman, Skyler L; Babai, Norbert; Mercer, Aaron J; Kramer, Richard H; Thoreson, Wallace B

    2011-12-01

    Light hyperpolarizes cone photoreceptors, causing synaptic voltage-gated Ca(2+) channels to open infrequently. To understand neurotransmission under these conditions, we determined the number of L-type Ca(2+) channel openings necessary for vesicle fusion at the cone ribbon synapse. Ca(2+) currents (I(Ca)) were activated in voltage-clamped cones, and excitatory postsynaptic currents (EPSCs) were recorded from horizontal cells in the salamander retina slice preparation. Ca(2+) channel number and single-channel current amplitude were calculated by mean-variance analysis of I(Ca). Two different comparisons-one comparing average numbers of release events to average I(Ca) amplitude and the other involving deconvolution of both EPSCs and simultaneously recorded cone I(Ca)-suggested that fewer than three Ca(2+) channel openings accompanied fusion of each vesicle at the peak of release during the first few milliseconds of stimulation. Opening fewer Ca(2+) channels did not enhance fusion efficiency, suggesting that few unnecessary channel openings occurred during strong depolarization. We simulated release at the cone synapse, using empirically determined synaptic dimensions, vesicle pool size, Ca(2+) dependence of release, Ca(2+) channel number, and Ca(2+) channel properties. The model replicated observations when a barrier was added to slow Ca(2+) diffusion. Consistent with the presence of a diffusion barrier, dialyzing cones with diffusible Ca(2+) buffers did not affect release efficiency. The tight clustering of Ca(2+) channels, along with a high-Ca(2+) affinity release mechanism and diffusion barrier, promotes a linear coupling between Ca(2+) influx and vesicle fusion. This may improve detection of small light decrements when cones are hyperpolarized by bright light.

  2. Serotonin Regulates the Firing of Principal Cells of the Subiculum by Inhibiting a T-type Ca(2+) Current

    DEFF Research Database (Denmark)

    Petersen, Anders V; Jensen, Camilla S; Crépel, Valérie

    2017-01-01

    The subiculum is the main output of the hippocampal formation. A high proportion of its principal neurons fire action potentials in bursts triggered by the activation of low threshold calcium currents. This firing pattern promotes synaptic release and regulates spike-timing-dependent plasticity. ...... of epileptiform discharges induced in in vitro models for temporal lobe epilepsy (TLE)....

  3. Current developments in optical engineering and commercial optics; Proceedings of the Meeting, San Diego, CA, Aug. 7-11, 1989

    Science.gov (United States)

    Fischer, Robert E. (Editor); Pollicove, Harvey M. (Editor); Smith, Warren J. (Editor)

    1989-01-01

    Various papers on current developments in optical engineering and commercial optics are presented. Individual topics addressed include: large optics fabrication technology drivers and new manufacturing techniques, new technology for beryllium mirror production, design examples of hybrid refractive-diffractive lenses, optical sensor designs for detecting cracks in optical materials, retroreflector field-of-view properties for open and solid cube corners, correction of misalignment-dependent aberrations of the HST via phase retrieval, basic radiometry review for seeker test set, radiation effects on visible optical elements, and nonlinear simulation of efficiency for large-orbit nonwiggler FELs.

  4. Contrasting Impact of Future CO2 Emission Scenarios on the Extent of CaCO3 Mineral Undersaturation in the Humboldt Current System

    Science.gov (United States)

    Franco, A. C.; Gruber, N.; Frölicher, T. L.; Kropuenske Artman, L.

    2018-03-01

    The eastern boundary upwelling systems are among those regions that are most vulnerable to an ocean acidification-induced transition toward undersaturated conditions with respect to mineral CaCO3, but no assessment exists yet for the Humboldt Current System. Here we use a high-resolution (˜7.5 km) regional ocean model to investigate past and future changes in ocean pH and CaCO3 saturation state in this system. We find that within the next few decades, the nearshore waters off Peru are projected to become corrosive year round with regard to aragonite, the more soluble form of CaCO3. The volume of aragonite undersaturated water off Peru will continue to increase in the future irrespective of the amount of CO2 emitted to the atmosphere. In contrast, the development of the saturation state with regard to calcite, a less soluble form of carbonate, depends strongly on the scenario followed. By 2050, calcite undersaturation appears in the nearshore waters off Peru occasionally, but by 2090 in a high-emission scenario (RCP8.5), ˜60% of the water in the euphotic zone will become permanently calcite undersaturated. Most of this calcite undersaturation off Peru can likely be avoided if a low emission scenario (RCP2.6) consistent with the Paris Agreement is followed. The progression of ocean acidification off Chile follows a similar pattern, except that the saturation states are overall higher. But also here, calcite undersaturated waters will become common in the subsurface waters under the RCP8.5 scenario by the end of this century, while this can be avoided under the RCP2.6 scenario.

  5. Dynamics of receptor-operated Ca(2+) currents through TRPC channels controlled via the PI(4,5)P2-PLC signaling pathway.

    Science.gov (United States)

    Mori, Masayuki X; Itsuki, Kyohei; Hase, Hideharu; Sawamura, Seishiro; Kurokawa, Tatsuki; Mori, Yasuo; Inoue, Ryuji

    2015-01-01

    Transient receptor potential canonical (TRPC) channels are Ca(2+)-permeable, nonselective cation channels that carry receptor-operated Ca(2+) currents (ROCs) triggered by receptor-induced, phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction, and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5)P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5)P2 and the possible role of PI(4,5)P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5)P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5)P2 using a model simulation that could explain the complicated effects of PI(4,5)P2 on different ROCs.

  6. Short-term plasticity in turtle dorsal horn neurons mediated by L-type Ca2+ channels

    DEFF Research Database (Denmark)

    Russo, R E; Hounsgaard, J

    1994-01-01

    Windup--the gradual increase of the response--of dorsal horn neurons to repeated activation of primary afferents is an elementary form of short-term plasticity that may mediate central sensitization to pain. In deep dorsal horn neurons of the turtle spinal cord in vitro we report windup of the re......Windup--the gradual increase of the response--of dorsal horn neurons to repeated activation of primary afferents is an elementary form of short-term plasticity that may mediate central sensitization to pain. In deep dorsal horn neurons of the turtle spinal cord in vitro we report windup...

  7. Bursting response to current-evoked depolarization in rat CA1 pyramidal neurons is correlated with lucifer yellow dye coupling but not with the presence of calbindin-D28k

    International Nuclear Information System (INIS)

    Baimbridge, K.G.; Peet, M.J.; McLennan, H.; Church, J.

    1991-01-01

    Calbindin-D28k (CaBP) immunohistochemistry has been combined with electrophysiological recording and Lucifer Yellow (LY) cell identification in the CA1 region of the rat hippocampal formation. CaBP is shown to be contained within a distinct sub-population of CA1 pyramidal cells which is equivalent to the superficial layer described by Lorente de No (1934). The neurogenesis of these CaBP-positive neurons occurs 1-2 days later than the CaBP-negative neurons in the deep pyramidal cell layer, as shown by 3H-thymidine autoradiography. No correlation could be found between the presence or absence of CaBP and the type of electrophysiological response to current-evoked depolarizing pulses. The latter could be separated into bursting or non-bursting types, and the bursting-type response was nearly always found to be associated with the presence of LY dye coupling. Furthermore, when dye coupling involved three neurons, a characteristic pattern was observed which may represent the coupling of phenotypically identical neurons into distinct functional units within the CA1 pyramidal cell layer. In this particular case the three neurons were all likely to be CaBP-positive

  8. Improvement of critical current density in thallium-based (Tl, Bi)Sr1.6Ba0.4Ca2Cu3O9-δ superconductors

    International Nuclear Information System (INIS)

    Ren, Z.F.; Wang, C.A.; Wang, J.H.

    1994-07-01

    Epitaxial (Tl,Bi)Sr 1.6 Ba 0.4 Ca 2 Cu 3 O x ((Tl, Bi)-1223) thin films on (100) single crystal LaAlO 3 substrates were synthesized by a two-step procedure. Phase development, microstructure, and relationships between film and substrate were studied by x-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Resistance versus temperature, zero-field-cooled and field-cooled magnetization, and transport critical current density (J c ) were measured. The zero-resistance temperature was 105--111 K. J c at 77 K and zero field was >2 x 10 6 A/cm 2 . The films exhibited good flux pinning properties

  9. Improvement of critical current density in thallium-based (Tl,Bi)Sr1.6Ba0.4Ca2Cu3Ox superconductors

    International Nuclear Information System (INIS)

    Ren, Z.F.; Wang, C.A.; Wang, J.H.

    1994-01-01

    Epitaxial (Tl,Bi)Sr 1.6 Ba 0.4 Ca 2 Cu 3 O x (Tl,Bi)-1223 thin films on (100) single crystal LaAlO 3 substrates were synthesized by a two-step procedure. Phase development, microstructure, and relationships between film and substrate were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Resistance versus temperature, zero-field-cooled and field-cooled magnetization, and transport critical current density (J c ) were measured. The zero-resistance temperature was 105-111 K. J c at 77 K and zero field was > 2 x 10 6 A/cm 2 . The films exhibited good flux pinning properties

  10. Activation of H2O2-induced VSOR Cl- currents in HTC cells require phospholipase Cgamma1 phosphorylation and Ca2+ mobilisation

    DEFF Research Database (Denmark)

    Varela, Diego; Simon, Felipe; Olivero, Pablo

    2007-01-01

    )R) blocker 2-APB. In line with these results, manoeuvres that prevented PLCgamma1 activation and/or [Ca(2+)](i) rise, abolished H(2)O(2)-induced VSOR Cl(-) currents. Furthermore, in cells that overexpress a phosphorylation-defective dominant mutant of PLCgamma1, H(2)O(2) did not induce activation......Volume-sensitive outwardly rectifying (VSOR) Cl(-) channels participate in several physiological processes such as regulatory volume decrease, cell cycle regulation, proliferation and apoptosis. Recent evidence points to a significant role of hydrogen peroxide (H(2)O(2)) in VSOR Cl(-) channel...... activation. The aim of this study was to determine the signalling pathways responsible for H(2)O(2)-induced VSOR Cl(-) channel activation. In rat hepatoma (HTC) cells, H(2)O(2) elicited a transient increase in tyrosine phosphorylation of phospholipase Cgamma1 (PLCgamma1) that was blocked by PP2, a Src...

  11. Critical current density and flux pinning in superconducting wires and coils of silver-clad Bi-Pb-Sr-Ca-Cu-O

    International Nuclear Information System (INIS)

    Dou, S.X.; Liu, H.K.; Apperley, M.H.; Song, K.H.; Sorrell, C.C.; Guo, S.J.; Loberg, B.; Easterling, K.E.

    1991-01-01

    The critical current density (J c ) of Ag-clad of Bi-Pb-Sr-Ca-Cu-O has been measured to be about 12,000 A/cm 2 at 77 K in zero field. This wire was rolled into a tape of thickness 0.1 mm and width of 2 to 3 mm, and a coil of 35 mm diameter was formed. The J c of this coil was measured to be about 2,000 A/cm 2 at 77 K over the full length (1.00 meter) of the coil. In this paper compositions, heat treatment parameters, and cold-deformation for enhancement of J c are presented. The microstructure is characterized and pinning interactions as well as possible weak links are emphasised. (orig.)

  12. Thermally stimulated depolarization currents and dielectric properties of Mg0.95Ca0.05TiO3 filled HDPE composites

    Science.gov (United States)

    Shi, Yunzhou; Zhang, Li; Zhang, Jie; Yue, Zhenxing

    2017-12-01

    Mg0.95Ca0.05TiO3 (MCT) filled high density polyethylene (HDPE) composites were prepared by twin-screw extrusion followed by hot pressing technique. The thermally stimulated depolarization current (TSDC) measurement was performed to analyze the contribution of charge distribution and interfacial characteristics to the dielectric loss. TSDC spectra under different polarization conditions show that the introduction of ceramic fillers engenders shallow traps in the vicinity of ceramic-polymer interface, which hinders the injection of space charge from the electrode into the polymer matrix. In the composite materials applied to an external field, charges tend to be captured by these traps. The temperature dependence of relative permittivity and dielectric loss of the composites was measured, and a strong reliance of dielectric loss on temperature was observed. In the heating process, the release of charges accumulating at interfacial region is considered to contribute to the rise in dielectric loss with the increase of temperature.

  13. [The effect of enzymatic treatment using proteases on properties of persistent sodium current in CA1 pyramidal neurons of rat hippocampus].

    Science.gov (United States)

    Lun'ko, O O; Isaiev, D S; Maxymiuk, O P; Kryshtal', O O; Isaieva, O V

    2014-01-01

    We investigated the effect of proteases, widely used for neuron isolation in electrophysiological studies, on the amplitude and kinetic characteristics of persistent sodium current (I(NaP)) in hippocampal CA1 pyramidal neurons. Properties of I(NaP) were studied on neurons isolated by mechanical treatment (control group) and by mechanical and enzymatic treatment using pronase E (from Streptomyces griseus) or protease type XXIII (from Aspergillus oryzae). We show that in neurons isolated with pronase E kinetic of activation and density of I(NaP) was unaltered. Enzymatic treatment with protease type XXIII did not alter I(NaP) activation but result in significant decrease in I(NaP) density. Our data indicates that enzymatic treatment using pronase E for neuron isolation is preferable for investigation of I(NaP).

  14. Filament to filament bridging and its influence on developing high critical current density in multifilamentary Bi2Sr2CaCu2Ox round wires

    International Nuclear Information System (INIS)

    Shen, T; Jiang, J; Kametani, F; Trociewitz, U P; Larbalestier, D C; Schwartz, J; Hellstrom, E E

    2010-01-01

    Increasing the critical current density (J c ) of the multifilamentary round wire Ag/Bi 2 Sr 2 CaCu 2 O x (2212) requires understanding its complicated microstructure, in which extensive bridges between filaments are prominent. In this first through-process quench study of 2212 round wire, we determined how its microstructure develops during a standard partial-melt process and how filament bridging occurs. We found that filaments can bond together in the melt state. As 2212 starts to grow on subsequent cooling, we observed that two types of 2212 bridges form. One type, which we call Type-A bridges, forms within filaments that bonded in the melt; Type-A bridges are single grains that span multiple bonded filaments. The other type, called Type-B bridges, form between discrete filaments through 2212 outgrowths that penetrate into the Ag matrix and intersect with other 2212 outgrowths from adjacent filaments. We believe the ability of these two types of bridges to carry inter-filament current is intrinsically different: Type-A bridges are high- J c inter-filament paths whereas Type-B bridges contain high-angle grain boundaries and are typically weak linked. Slow cooling leads to more filament bonding, more Type-A bridges and a doubling of J c without changing the flux pinning. We suggest that Type-A bridges create a 3D current flow that is vital to developing high J c in multifilamentary 2212 round wire.

  15. Martensitic transformation in 304L and 316L types stainless steels cathodically hydrogen charged

    International Nuclear Information System (INIS)

    Minkovitz, E.; Eliezer, D.

    1984-01-01

    This paper reports a TEM study on the role of phase transitions at the crack tip in 304L and 316L types stainless steels cathodically hydrogen charged in the absence of any eternally applied forces. The possible role of α prime and epsilon martensite phases in the fracture mechanism is discussed

  16. The potent activation of Ca(2+)-activated K(+) current by NVP-AUY922 in the human pancreatic duct cell line (PANC-1) possibly independent of heat shock protein 90 inhibition.

    Science.gov (United States)

    Chiang, Nai-Jung; Wu, Sheng-Nan; Chen, Li-Tzong

    2015-04-01

    NVP-AUY922 (AUY) is a potent inhibitor of heat shock protein 90 (HSP90). Whether this compound can exert additional effects on membrane ion channels remains elusive. We investigated the effect of AUY on ion currents in human pancreatic duct epithelial cells (PDECs), including PANC-1 and MIA PaCa-2. AUY increased the amplitude of the K(+) current (IK) in PANC-1 cells shown by whole-cell configuration. Single-channel recordings revealed a large-conductance Ca(2+)-activated K(+) (BKCa) channel in PANC-1, but not in MIA PaCa-2. In cell-attached mode, AUY increased the probability of BKCa channel opening and also potentiated the activity of stretch-induced channels. However, other HSP inhibitors, 17-AAG or BIIB021 only slightly increased the activity of BKCa channels. In inside-out recordings, sodium hydrosulphide or caffeic acid phenethyl ester increased the activity of BKCa channels, but AUY did not. We further evaluated whether conductance of Ca(2+)-activated K(+) channels (IK(Ca)) influenced secretion of HCO3(-) and fluid in PDECs by using a modified Whitcomb-Ermentrout model. Simulation studies showed that an increase in IK(Ca) resulted in additional secretion of HCO3(-) and fluid by mimicking the effect of AUY in PDECs. Collectively, AUY can interact with the BKCa channel to largely increase IK(Ca) in PDECs. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Dynamics of receptor-operated Ca2+ Currents Through TRPC Channels Controlled via the PI(4,5P2-PLC Signaling Pathway

    Directory of Open Access Journals (Sweden)

    Masayuki X Mori

    2015-02-01

    Full Text Available Transient receptor potential canonical (TRPC channels are Ca2+-permeable, nonselective cation channels that carry receptor-operated Ca2+ currents (ROCs triggered by receptor-induced, phospholipase C (PLC-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5P2. Within the vasculature, TRPC channel ROCs contribute to smooth muscle cell depolarization, vasoconstriction and vascular remodeling. However, TRPC channel ROCs exhibit a variable response to receptor-stimulation, and the regulatory mechanisms governing TRPC channel activity remain obscure. The variability of ROCs may be explained by their complex regulation by PI(4,5P2 and its metabolites, which differentially affect TRPC channel activity. To resolve the complex regulation of ROCs, the use of voltage-sensing phosphoinositide phosphatases and model simulation have helped to reveal the time-dependent contribution of PI(4,5P2 and the possible role of PI(4,5P2 in the regulation of ROCs. These approaches may provide unprecedented insight into the dynamics of PI(4,5P2 regulation of TRPC channels and the fundamental mechanisms underlying transmembrane ion flow. Within that context, we summarize the regulation of TRPC channels and their coupling to receptor-mediated signaling, as well as the application of voltage-sensing phosphoinositide phosphatases to this research. We also discuss the controversial bidirectional effects of PI(4,5P2 using a model simulation that could explain the complicated effects of PI(4,5P2 on different ROCs.

  18. Fine Tuning of CaV1.3 Ca2+ channel properties in adult inner hair cells positioned in the most sensitive region of the Gerbil Cochlea.

    Directory of Open Access Journals (Sweden)

    Valeria Zampini

    Full Text Available Hearing relies on faithful signal transmission by cochlear inner hair cells (IHCs onto auditory fibres over a wide frequency and intensity range. Exocytosis at IHC ribbon synapses is triggered by Ca(2+ inflow through Ca(V1.3 (L-type Ca(2+ channels. We investigated the macroscopic (whole-cell and elementary (cell-attached properties of Ca(2+ currents in IHCs positioned at the middle turn (frequency ∼ 2 kHz of the adult gerbil cochlea, which is their most sensitive hearing region. Using near physiological recordings conditions (body temperature and a Na(+ based extracellular solution, we found that the macroscopic Ca(2+ current activates and deactivates very rapidly (time constant below 1 ms and inactivates slowly and only partially. Single-channel recordings showed an elementary conductance of 15 pS, a sub-ms latency to first opening, and a very low steady-state open probability (Po: 0.024 in response to 500-ms depolarizing steps at ∼-18 mV. The value of Po was significantly larger (0.06 in the first 40 ms of membrane depolarization, which corresponds to the time when most Ca(2+ channel openings occurred clustered in bursts (mean burst duration: 19 ms. Both the Po and the mean burst duration were smaller than those previously reported in high-frequency basal IHCs. Finally, we found that middle turn IHCs are likely to express about 4 times more Ca(2+ channels per ribbon than basal cells. We propose that middle-turn IHCs finely-tune Ca(V1.3 Ca(2+ channel gating in order to provide reliable information upon timing and intensity of lower-frequency sounds.

  19. Fine Tuning of CaV1.3 Ca2+ channel properties in adult inner hair cells positioned in the most sensitive region of the Gerbil Cochlea.

    Science.gov (United States)

    Zampini, Valeria; Johnson, Stuart L; Franz, Christoph; Knipper, Marlies; Holley, Matthew C; Magistretti, Jacopo; Russo, Giancarlo; Marcotti, Walter; Masetto, Sergio

    2014-01-01

    Hearing relies on faithful signal transmission by cochlear inner hair cells (IHCs) onto auditory fibres over a wide frequency and intensity range. Exocytosis at IHC ribbon synapses is triggered by Ca(2+) inflow through Ca(V)1.3 (L-type) Ca(2+) channels. We investigated the macroscopic (whole-cell) and elementary (cell-attached) properties of Ca(2+) currents in IHCs positioned at the middle turn (frequency ∼ 2 kHz) of the adult gerbil cochlea, which is their most sensitive hearing region. Using near physiological recordings conditions (body temperature and a Na(+) based extracellular solution), we found that the macroscopic Ca(2+) current activates and deactivates very rapidly (time constant below 1 ms) and inactivates slowly and only partially. Single-channel recordings showed an elementary conductance of 15 pS, a sub-ms latency to first opening, and a very low steady-state open probability (Po: 0.024 in response to 500-ms depolarizing steps at ∼-18 mV). The value of Po was significantly larger (0.06) in the first 40 ms of membrane depolarization, which corresponds to the time when most Ca(2+) channel openings occurred clustered in bursts (mean burst duration: 19 ms). Both the Po and the mean burst duration were smaller than those previously reported in high-frequency basal IHCs. Finally, we found that middle turn IHCs are likely to express about 4 times more Ca(2+) channels per ribbon than basal cells. We propose that middle-turn IHCs finely-tune Ca(V)1.3 Ca(2+) channel gating in order to provide reliable information upon timing and intensity of lower-frequency sounds.

  20. Activation of L-type calcium channels is required for gap junction-mediated intercellular calcium signaling in osteoblastic cells

    DEFF Research Database (Denmark)

    Jørgensen, Niklas Rye; Teilmann, Stefan Cuoni; Henriksen, Zanne

    2003-01-01

    The propagation of mechanically induced intercellular calcium waves (ICW) among osteoblastic cells occurs both by activation of P2Y (purinergic) receptors by extracellular nucleotides, resulting in "fast" ICW, and by gap junctional communication in cells that express connexin43 (Cx43), resulting...... in "slow" ICW. Human osteoblastic cells transmit intercellular calcium signals by both of these mechanisms. In the current studies we have examined the mechanism of slow gap junction-dependent ICW in osteoblastic cells. In ROS rat osteoblastic cells, gap junction-dependent ICW were inhibited by removal...... of extracellular calcium, plasma membrane depolarization by high extracellular potassium, and the L-type voltage-operated calcium channel inhibitor, nifedipine. In contrast, all these treatments enhanced the spread of P2 receptor-mediated ICW in UMR rat osteoblastic cells. Using UMR cells transfected to express Cx...

  1. Patient-specific mutations impair BESTROPHIN1’s essential role in mediating Ca2+-dependent Cl- currents in human RPE

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yao [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Zhang, Yu [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Xu, Yu [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Department of Ophthalmology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Kittredge, Alec [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Ward, Nancy [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States; Chen, Shoudeng [Molecular Imaging Center, Department of Experimental Medicine, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China; Tsang, Stephen H. [Jonas Children’s Vision Care, and Bernard and Shirlee Brown Glaucoma Laboratory, Department of Ophthalmology and Pathology & Cell Biology, Edward S. Harkness Eye Institute, New York Presbyterian Hospital/Columbia University, New York, United States; Yang, Tingting [Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, United States

    2017-10-24

    Mutations in the human BEST1 gene lead to retinal degenerative diseases displaying progressive vision loss and even blindness. BESTROPHIN1, encoded by BEST1, is predominantly expressed in retinal pigment epithelium (RPE), but its physiological role has been a mystery for the last two decades. Using a patient-specific iPSC-based disease model and interdisciplinary approaches, we comprehensively analyzed two distinct BEST1 patient mutations, and discovered mechanistic correlations between patient clinical phenotypes, electrophysiology in their RPEs, and the structure and function of BESTROPHIN1 mutant channels. Our results revealed that the disease-causing mechanism of BEST1 mutations is centered on the indispensable role of BESTROPHIN1 in mediating the long speculated Ca2+-dependent Cl- current in RPE, and demonstrate that the pathological potential of BEST1 mutations can be evaluated and predicted with our iPSC-based ‘disease-in-a-dish’ approach. Moreover, we demonstrated that patient RPE is rescuable with viral gene supplementation, providing a proof-of-concept for curing BEST1-associated diseases.

  2. The AKAP Cypher/Zasp contributes to β-adrenergic/PKA stimulation of cardiac CaV1.2 calcium channels.

    Science.gov (United States)

    Yu, Haijie; Yuan, Can; Westenbroek, Ruth E; Catterall, William A

    2018-06-04

    Stimulation of the L-type Ca 2+ current conducted by Ca V 1.2 channels in cardiac myocytes by the β-adrenergic/protein kinase A (PKA) signaling pathway requires anchoring of PKA to the Ca V 1.2 channel by an A-kinase anchoring protein (AKAP). However, the AKAP(s) responsible for regulation in vivo remain unknown. Here, we test the role of the AKAP Cypher/Zasp in β-adrenergic regulation of Ca V 1.2 channels using physiological studies of cardiac ventricular myocytes from young-adult mice lacking the long form of Cypher/Zasp (LCyphKO mice). These myocytes have increased protein levels of Ca V 1.2, PKA, and calcineurin. In contrast, the cell surface density of Ca V 1.2 channels and the basal Ca 2+ current conducted by Ca V 1.2 channels are significantly reduced without substantial changes to kinetics or voltage dependence. β-adrenergic regulation of these L-type Ca 2+ currents is also significantly reduced in myocytes from LCyphKO mice, whether calculated as a stimulation ratio or as net-stimulated Ca 2+ current. At 100 nM isoproterenol, the net β-adrenergic-Ca 2+ current conducted by Ca V 1.2 channels was reduced to 39 ± 12% of wild type. However, concentration-response curves for β-adrenergic stimulation of myocytes from LCyphKO mice have concentrations that give a half-maximal response similar to those for wild-type mice. These results identify Cypher/Zasp as an important AKAP for β-adrenergic regulation of cardiac Ca V 1.2 channels. Other AKAPs may work cooperatively with Cypher/Zasp to give the full magnitude of β-adrenergic regulation of Ca V 1.2 channels observed in vivo. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.

  3. Modulation of contraction by intracellular Na+ via Na(+)-Ca2+ exchange in single shark (Squalus acanthias) ventricular myocytes.

    Science.gov (United States)

    Näbauer, M; Morad, M

    1992-01-01

    1. The effect of direct alteration of intracellular Na+ concentration on contractile properties of whole-cell clamped shark ventricular myocytes was studied using an array of 256 photodiodes to monitor the length of the isolated myocytes. 2. In myocytes dialysed with Na(+)-free solution, the voltage dependence of Ca2+ current (ICa) and contraction were similar and bell shaped. Contractions activated at all voltages were completely suppressed by nifedipine (5 microM), and failed to show significant tonic components, suggesting dependence of the contraction on Ca2+ influx through the L-type Ca2+ channel. 3. In myocytes dialysed with 60 mM Na+, a ICa-dependent and a ICa-independent component of contraction could be identified. The Ca2+ current-dependent component was prominent in voltages between -30 to +10 mV. The ICa-independent contractions were maintained for the duration of depolarization, increased with increasing depolarization between +10 to +100 mV, and were insensitive to nifedipine. 4. In such myocytes, repolarization produced slowly decaying inward tail currents closely related to the time course of relaxation and the degree of shortening prior to repolarization. 5. With 60 mM Na+ in the pipette solution, positive clamp potentials activated decaying outward currents which correlated to the size of contraction. These outward currents appeared to be generated by the Na(+)-Ca(2+)-exchanger since they depended on the presence of intracellular Na+, and were neither suppressed by nifedipine nor by K+ channel blockers. 6. The results suggest that in shark (Squalus acanthias) ventricular myocytes, which lack functionally relevant Ca2+ release pools, both Ca2+ channel and the Na(+)-Ca2+ exchanger deliver sufficient Ca2+ to activate contraction, though the effectiveness of the latter mechanism was highly dependent on the [Na+]i. PMID:1338467

  4. Gestational hypothyroidism-induced changes in L-type calcium channels of rat aorta smooth muscle and their impact on the responses to vasoconstrictors.

    Science.gov (United States)

    Sedaghat, Katayoun; Zahediasl, Saleh; Ghasemi, Asghar

    2015-02-01

    Thyroid hormones play an essential role in fetal growth and maternal hypo-thyroidism which leads to cardiovascular deficiency in their offspring. Considering this, we intended to investigate the impact of gestational hypothyroidism on offspring vascular contractibility and possible underlying mechanisms. Hypothyroidism was induced in female rats by administration of 6-n-propyl-2-thiouracil in drinking water (0.02%) till delivery. The offspring aorta smooth muscle (without endothelium) contractile response to KCl (10-100 mM), KCl in the presence of nifedipine (10(-4)-10(-1) µM), phenylephrine (10(-9)-10(-6) M) and finally, phenylephrine and caffeine 100 mM in Ca(2+)-free Krebs were measured. KCl and phenylephrine-induced contractions were considerably lower in gestational hypothyroid (GH) than euthyroid offspring. GH responded to nifedipine with less sensitivity than control. The GH and control groups produced almost equal contraction in respond to phenylephrine and caffeine in Ca(2+)-free Krebs. This study suggests that in hypothyroid offspring L-type Ca(2+) channels are less functional, while intracellular Ca(2+) handling systems are less modified by low levels of maternal thyroid hormones.

  5. Computer modeling of siRNA knockdown effects indicates an essential role of the Ca2+ channel alpha2delta-1 subunit in cardiac excitation-contraction coupling.

    Science.gov (United States)

    Tuluc, Petronel; Kern, Georg; Obermair, Gerald J; Flucher, Bernhard E

    2007-06-26

    L-type Ca(2+) currents determine the shape of cardiac action potentials (AP) and the magnitude of the myoplasmic Ca(2+) signal, which regulates the contraction force. The auxiliary Ca(2+) channel subunits alpha(2)delta-1 and beta(2) are important regulators of membrane expression and current properties of the cardiac Ca(2+) channel (Ca(V)1.2). However, their role in cardiac excitation-contraction coupling is still elusive. Here we addressed this question by combining siRNA knockdown of the alpha(2)delta-1 subunit in a muscle expression system with simulation of APs and Ca(2+) transients by using a quantitative computer model of ventricular myocytes. Reconstitution of dysgenic muscle cells with Ca(V)1.2 (GFP-alpha(1C)) recapitulates key properties of cardiac excitation-contraction coupling. Concomitant depletion of the alpha(2)delta-1 subunit did not perturb membrane expression or targeting of the pore-forming GFP-alpha(1C) subunit into junctions between the outer membrane and the sarcoplasmic reticulum. However, alpha(2)delta-1 depletion shifted the voltage dependence of Ca(2+) current activation by 9 mV to more positive potentials, and it slowed down activation and inactivation kinetics approximately 2-fold. Computer modeling revealed that the altered voltage dependence and current kinetics exert opposing effects on the function of ventricular myocytes that in total cause a 60% prolongation of the AP and a 2-fold increase of the myoplasmic Ca(2+) concentration during each contraction. Thus, the Ca(2+) channel alpha(2)delta-1 subunit is not essential for normal Ca(2+) channel targeting in muscle but is a key determinant of normal excitation and contraction of cardiac muscle cells, and a reduction of alpha(2)delta-1 function is predicted to severely perturb normal heart function.

  6. Effect of epoxy resin on bending momentum in L type corner joins

    Directory of Open Access Journals (Sweden)

    Mehmet Nuri Yıldırım

    2017-11-01

    Full Text Available In the furniture industry, the joining points of frame and box construction furniture according to the loads to be affected by the use place is important for the security of the user and service life of the furniture element. In this direction, it is aimed to determine the diagonal compression and diagonal tensile moment values of "L" type corner joints of box framed construction furniture prepared from solid wood materials. The Pinus Nigra, Fagus Orientalis L and Populus Nigra were used as solid wood materials. Wood-based biscuit joining elements were used in corner joints of the test construction and epoxy resin was used as glue for materials. The static loads were applied to construction according to ASTM-D1037. The results show that, the highest tensile and compression values were obtained from Fagus Orientalis L and the lowest values were obtained from Populus Nigra specimens. In the statistical study, the difference between the tensile and compressive bending moment values of the biscuit connection element was found to be statistically significant. This study indicates that, it is suggested to use of L type joints prepared from Fagus Orientalis L by using epoxy resin and wood based biscuit joining element in frame constructions.

  7. Polar localization of plasma membrane Ca2+/Mg2+ ATPase correlates with the pattern of steady ionic currents in eggs of Lymnaea stagnalis and Bithynia tentaculata (Mollusca)

    NARCIS (Netherlands)

    D. Zivkovic (Dana); R. Créton (Robbert); G. Zwaan (Gideon); W.C. de Bruijn (Wim); M.R. Dohmen (M.René)

    1990-01-01

    textabstractDuring extrusion of the first polar body in eggs of Lymnaea stagnalis and Bithynia tentaculata a localized Ca2+ /Mg2+ ATPase activity was detected, using Ando's enzyme-cytochemical method for electron microscopy [Ando et al. (1981) Acta Histochem Cytochem 14:705-726]. The enzyme activity

  8. Divergent biophysical properties, gating mechanisms, and possible functions of the two skeletal muscle Ca(V)1.1 calcium channel splice variants.

    Science.gov (United States)

    Tuluc, Petronel; Flucher, Bernhard E

    2011-12-01

    Voltage-gated calcium channels are multi-subunit protein complexes that specifically allow calcium ions to enter the cell in response to membrane depolarization. But, for many years it seemed that the skeletal muscle calcium channel Ca(V)1.1 is the exception. The classical splice variant Ca(V)1.1a activates slowly, has a very small current amplitude and poor voltage sensitivity. In fact adult muscle fibers work perfectly well even in the absence of calcium influx. Recently a new splice variant of the skeletal muscle calcium channel Ca(V)1.1e has been characterized. The lack of the 19 amino acid exon 29 in this splice variant results in a rapidly activating calcium channel with high current amplitude and good voltage sensitivity. Ca(V)1.1e is the dominant channel in embryonic muscle, where the expression of this high calcium-conducting Ca(V)1.1 isoform readily explains developmental processes depending on L-type calcium currents. Moreover, the availability of these two structurally similar but functionally distinct channel variants facilitates the analysis of the molecular mechanisms underlying the unique current properties of the classical Ca(V)1.1a channel.

  9. Limits to the critical transport current in superconducting (Bi,Pb)2Sr2Ca2Cu3O10 silver-sheathed tapes: The railway-switch model

    International Nuclear Information System (INIS)

    Hensel, B.; Grasso, G.; Fluekiger, R.

    1995-01-01

    We have proposed the ''railway-switch'' model to describe the superconducting transport current in (Bi,Pb) 2 Sr 2 Ca 2 Cu 3 O 10 silver-sheathed tapes. The model assumes that in the textured polycrystalline filament the frequent small-angle c-axis tilt grain boundaries (''railway switches'') constitute strong links for the supercurrent. With the objective to identify the mechanisms that limit the critical-current density in the tapes we present measurements of the transport critical current normal to the tape plane and of the current-transfer length along the tape axis. From I-V curves we obtain the longitudinal critical-current distribution and compare it to the thickness variation of the filament. The experiments have been performed on monofilamentary powder-in-tube samples prepared in long lengths by rolling as the only tape-forming process. For all investigated samples the critical-current density at T=77 K in self-field was in the range j c =20--30 kA/cm 2 . We conclude that the dominant limitation for the transport critical current in the tapes is imposed by the low intragrain critical-current density j c c along the c axis (as compared to the in-plane critical-current density j c ab ) and by the even lower critical-current density j c t across twist boundaries or intergrowths. Possibilities for an improvement of the performance of the (Bi,Pb) 2 Sr 2 Ca 2 Cu 3 O 10 silver-sheathed tapes are discussed

  10. Electrophysiological heterogeneity of pacemaker cells in the rabbit intercaval region, including the SA node: insights from recording multiple ion currents in each cell.

    Science.gov (United States)

    Monfredi, Oliver; Tsutsui, Kenta; Ziman, Bruce; Stern, Michael D; Lakatta, Edward G; Maltsev, Victor A

    2018-03-01

    Cardiac pacemaker cells, including cells of the sinoatrial node, are heterogeneous in size, morphology, and electrophysiological characteristics. The exact extent to which these cells differ electrophysiologically is unclear yet is critical to understanding their functioning. We examined major ionic currents in individual intercaval pacemaker cells (IPCs) sampled from the paracristal, intercaval region (including the sinoatrial node) that were spontaneously beating after enzymatic isolation from rabbit hearts. The beating rate was measured at baseline and after inhibition of the Ca 2+ pump with cyclopiazonic acid. Thereafter, in each cell, we consecutively measured the density of funny current ( I f ), delayed rectifier K + current ( I K ) (a surrogate of repolarization capacity), and L-type Ca 2+ current ( I Ca,L ) using whole cell patch clamp . The ionic current densities varied to a greater extent than previously appreciated, with some IPCs demonstrating very small or zero I f . The density of none of the currents was correlated with cell size, while I Ca,L and I f densities were related to baseline beating rates. I f density was correlated with I K density but not with that of I Ca,L . Inhibition of Ca 2+ cycling had a greater beating rate slowing effect in IPCs with lower I f densities. Our numerical model simulation indicated that 1) IPCs with small (or zero) I f or small I Ca,L can operate via a major contribution of Ca 2+ clock, 2) I f -Ca 2+ -clock interplay could be important for robust pacemaking function, and 3) coupled I f - I K function could regulate maximum diastolic potential. Thus, we have demonstrated marked electrophysiological heterogeneity of IPCs. This heterogeneity is manifested in basal beating rate and response to interference of Ca 2+ cycling, which is linked to I f . NEW & NOTEWORTHY In the present study, a hitherto unrecognized range of heterogeneity of ion currents in pacemaker cells from the intercaval region is demonstrated

  11. Polar localization of plasma membrane Ca2+/Mg2+ ATPase correlates with the pattern of steady ionic currents in eggs of Lymnaea stagnalis and Bithynia tentaculata (Mollusca)

    OpenAIRE

    Zivkovic, Dana; Créton, Robbert; Zwaan, Gideon; Bruijn, Wim; Dohmen, M.René

    1990-01-01

    textabstractDuring extrusion of the first polar body in eggs of Lymnaea stagnalis and Bithynia tentaculata a localized Ca2+ /Mg2+ ATPase activity was detected, using Ando's enzyme-cytochemical method for electron microscopy [Ando et al. (1981) Acta Histochem Cytochem 14:705-726]. The enzyme activity was distributed in a polar fashion, along the cytoplasmic face of the plasma membrane. In the eggs of Lymnaea it was found only in the vegetal hemisphere, whereas in Bithynia eggs it was localized...

  12. Critical current anisotropy in Ag/(Pb,Bi){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub 10+x} multifilamentary tapes: influence of self-magnetic field

    Energy Technology Data Exchange (ETDEWEB)

    Majoros, M [IRC in Superconductivity, University of Cambridge, Cambridge (United Kingdom); Institute of Electrical Engineering, Slovak Academy of Sciences, Bratislava (Slovakia); Glowacki, B A [IRC in Superconductivity, University of Cambridge, Cambridge (United Kingdom); Department of Materials Science and Metallurgy, University of Cambridge, Cambridge (United Kingdom); Campbell, A M [IRC in Superconductivity, University of Cambridge, Cambridge (United Kingdom)

    2001-06-01

    Two factors affect critical current anisotropy in multifilamentary Ag/(Pb,Bi){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub 10+x} tapes - the intrinsic material anisotropy and the geometry. Experimental results on the magnetic field dependence and anisotropy of the critical current in a multifilamentary Ag/(Pb,Bi){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub 10+x} tape after correction for self-magnetic field effects were found to fit the anisotropic Kim relation. Based on this relation a finite-element-method numerical code for solving the nonlinear Poisson equation for vector magnetic potential was adopted. It allowed the experimental data to be reproduced by back calculation and made possible the study of the interplay of self and external magnetic fields in different cases with well defined physical parameters of the material. The model was used to analyse the distribution of the critical current in individual filaments as well as to evaluate the influence of their geometrical arrangements on the critical current of the tape. The self-field critical current of an individual filament 'extracted' from the tape was compared with the critical current of the overall tape. The effect of the self-magnetic field on critical current distribution obtained by the cutting method was determined. The critical currents of the tapes with different cross sections were calculated and compared with experiments and the influence of the self-field was analysed. The anisotropic properties of a low anisotropy architecture of a multifilamentary Ag/(Pb,Bi){sub 2}Sr{sub 2}Ca{sub 2}Cu{sub 3}O{sub 10+x} conductor were studied. The dependence of critical currents (normalized to self-field critical currents) on external magnetic field corrected for the self-field was found to follow nearly the same curves as those for tapes with different critical current densities (in the range 20-70 kA cm{sup -2} in a self-field), which makes the numerical model applicable to different tapes. (author)

  13. T-type Ca(2+) channels and Autoregulation of Local Blood Flow

    DEFF Research Database (Denmark)

    Jensen, Lars Jørn; Nielsen, Morten Schak; Salomonsson, Max

    2017-01-01

    L-type voltage gated Ca(2+) channels are considered to be the primary source of calcium influx during the myogenic response. However, many vascular beds also express T-type voltage gated Ca(2+) channels. Recent studies suggest that these channels may also play a role in autoregulation. At low pre...

  14. Ca2+ handling abnormalities in early-onset muscle diseases: Novel concepts and perspectives.

    NARCIS (Netherlands)

    Treves, S.; Jungbluth, H.; Voermans, N.C.; Muntoni, F.; Zorzato, F.

    2017-01-01

    The physiological process by which Ca2+ is released from the sarcoplasmic reticulum is called excitation-contraction coupling; it is initiated by an action potential which travels deep into the muscle fiber where it is sensed by the dihydropyridine receptor, a voltage sensing L-type Ca2+channel

  15. Activation of sodium channels by α-scorpion toxin, BmK NT1, produced neurotoxicity in cerebellar granule cells: an association with intracellular Ca2+ overloading.

    Science.gov (United States)

    He, Yuwei; Zou, Xiaohan; Li, Xichun; Chen, Juan; Jin, Liang; Zhang, Fan; Yu, Boyang; Cao, Zhengyu

    2017-02-01

    Voltage-gated sodium channels (VGSCs) are responsible for the action potential generation in excitable cells including neurons and involved in many physiological and pathological processes. Scorpion toxins are invaluable tools to explore the structure and function of ion channels. BmK NT1, a scorpion toxin from Buthus martensii Karsch, stimulates sodium influx in cerebellar granule cells (CGCs). In this study, we characterized the mode of action of BmK NT1 on the VGSCs and explored the cellular response in CGC cultures. BmK NT1 delayed the fast inactivation of VGSCs, increased the Na + currents, and shifted the steady-state activation and inactivation to more hyperpolarized membrane potential, which was similar to the mode of action of α-scorpion toxins. BmK NT1 stimulated neuron death (EC 50  = 0.68 µM) and produced massive intracellular Ca 2+ overloading (EC 50  = 0.98 µM). TTX abrogated these responses, suggesting that both responses were subsequent to the activation of VGSCs. The Ca 2+ response of BmK NT1 was primary through extracellular Ca 2+ influx since reducing the extracellular Ca 2+ concentration suppressed the Ca 2+ response. Further pharmacological evaluation demonstrated that BmK NT1-induced Ca 2+ influx and neurotoxicity were partially blocked either by MK-801, an NMDA receptor blocker, or by KB-R7943, an inhibitor of Na + /Ca 2+ exchangers. Nifedipine, an L-type Ca 2+ channel inhibitor, slightly suppressed both Ca 2+ response and neurotoxicity. A combination of these three inhibitors abrogated both responses. Considered together, these data ambiguously demonstrated that activation of VGSCs by an α-scorpion toxin was sufficient to produce neurotoxicity which was associated with intracellular Ca 2+ overloading through both NMDA receptor- and Na + /Ca 2+ exchanger-mediated Ca 2+ influx.

  16. CO, Pb++ and SO2 effects on L-type calcium channel and action potential in human atrial myocytes. In silico study

    Directory of Open Access Journals (Sweden)

    Diana C. Pachajoa

    2017-09-01

    Full Text Available Exposure to air pollutants like carbon monoxide (CO, lead (Pb++ and sulfur dioxide (SO2 promotes the occurrence of cardiovascular diseases. Experimental studies have shown that CO, Pb++ and SO2 block L-type calcium channels, reducing the calcium current (ICaL and the action potential duration (APD, which favors the initiation of atrial arrhythmias. The goal is to study the effects of CO, Pb++ and SO2 at different concentrations on ICaL and action potential using computational simulation. For this purpose, models of the effects of the air pollutants on the atrial L-type calcium channel were developed and were incorporated into a mathematical model of a human atrial cell. The results suggest that CO, Pb++ and SO2 block the ICaL current in a fraction that increases along with the concentration, generating an APD shortening. These results are consistent with experimental studies. The combined effect of the three air pollutants produced an APD shortening, which is considered to be a pro-arrhythmic effect.

  17. The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Ca(v)3.2 channels

    Czech Academy of Sciences Publication Activity Database

    Proft, Juliane; Rzhepetskyy, Yuriy; Lazniewska, Joanna; Zhang, F. X.; Cain, S. M.; Snutch, T. P.; Zamponi, G. W.; Weiss, Norbert

    2017-01-01

    Roč. 7, Sep 14 (2017), č. článku 11513. ISSN 2045-2322 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : asparagine-linked glycosylation * idiopathic generalized epilepsies * voltage-activated currents Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) Impact factor: 4.259, year: 2016 https://www.nature.com/articles/s41598-017-11591-5

  18. The role of solvation in the binding selectivity of the L-type calcium channel.

    Science.gov (United States)

    Boda, Dezső; Henderson, Douglas; Gillespie, Dirk

    2013-08-07

    We present grand canonical Monte Carlo simulation results for a reduced model of the L-type calcium channel. While charged residues of the protein amino acids in the selectivity filter are treated explicitly, most of the degrees of freedom (including the rest of the protein and the solvent) are represented by their dielectric response, i.e., dielectric continua. The new aspect of this paper is that the dielectric coefficient in the channel is different from that in the baths. The ions entering the channel, thus, cross a dielectric boundary at the entrance of the channel. Simulating this case has been made possible by our recent methodological development [D. Boda, D. Henderson, B. Eisenberg, and D. Gillespie, J. Chem. Phys. 135, 064105 (2011)]. Our main focus is on the effect of solvation energy (represented by the Born energy) on monovalent vs. divalent ion selectivity in the channel. We find no significant change in selectivity by changing the dielectric coefficient in the channel because the larger solvation penalty is counterbalanced by the enhanced Coulomb attraction inside the channel as soon as we use the Born radii (fitted to experimental hydration energies) to compute the solvation penalty from the Born equation.

  19. Temporal and spatial differences in intracellular Ca++ changes elicited by K+ and glutamate in single cultured neocortical neurons

    DEFF Research Database (Denmark)

    Belhage, B; Frandsen, A; Schousboe, A

    1996-01-01

    characteristics of voltage gated Ca++ channels are dramatically different in cell bodies and neurites. Moreover, the distribution of L-type channels activated by glutamate differs in cell bodies and neurites. Such differences in the spatial distribution of Ca++ channels are likely to be of major importance...... after exposure to K+. The Ca++ channel blockers verapamil and nifedipine affecting N- and L-type channels, respectively had differential effects on K+ stimulated increases in [Ca++]i. Nifedipine only affected the increase marginally whereas verapamil inhibited the response by 50-60% both in cell bodies...

  20. The BK(Ca) channels deficiency as a possible reason for radiation-induced vascular hypercontractility.

    Science.gov (United States)

    Kyrychenko, Sergii; Tishkin, Sergey; Dosenko, Victor; Ivanova, Irina; Novokhatska, Tatiana; Soloviev, Anatoly

    2012-01-01

    It is likely that large-conductance Ca²⁺-activated K⁺ (BK(Ca)) channels channelopathy tightly involved in vascular malfunctions and arterial hypertension development. In the present study, we compared the results of siRNAs-induced α-BK(Ca) gene silencing and vascular abnormalities produced by whole-body ionized irradiation in rats. The experimental design comprised RT-PCR and patch clamp technique, thoracic aorta smooth muscle (SM) contractile recordings and arterial blood pressure (BP) measurements on the 30th day after whole body irradiation (6Gy) and following siRNAs KCNMA1 gene silencing in vivo. The expression profile of BK(Ca) mRNA transcripts in SM was significantly decreased in siRNAs-treated rats in a manner similar to irradiated SM. In contrast, the mRNA levels of K(v) and K(ATP) were significantly increased while L-type calcium channels mRNA transcripts demonstrated tendency to increment. The SMCs obtained from irradiated animals and after KCNMA1 gene silencing showed a significant decrease in total K⁺ current density amplitude. Paxilline (500 nM)-sensitive components of outward current were significantly decreased in both irradiated and gene silencing SMCs. KCNMA1 gene silencing increased SM sensitivity to norepinephrine while Ach-induced relaxation had decreased. The silencing of KCNMA1 had no significant effect on BP while radiation produced sustained arterial hypertension. Therefore, radiation alters the form and function of the BK(Ca) channel and this type of channelopathy may contribute to related vascular abnormalities. Nevertheless, it is unlikely that BK(Ca) can operate as a crucial factor for radiation-induced arterial hypertension. Copyright © 2012 Elsevier Inc. All rights reserved.

  1. Effect of pelletization pressure on structural properties and critical current hysteresis of ceramic superconducting Bi sub 1 sub . sub 7 Pb sub 0 sub . sub 3 Sr sub 2 Ca sub 2 Cu sub 3 O sub y

    CERN Document Server

    Tepe, M; Abukay, D

    2003-01-01

    The effect of pelletization pressures on structural properties and critical current hysteresis of Bi sub 1 sub . sub 7 Pb sub 0 sub . sub 3 Sr sub 2 Ca sub 2 Cu sub 3 O sub y samples was investigated. The samples used in this study were prepared by classical solid-state reaction at the pressures from 100 up to 500 MPa. The obtained samples were characterized by resistance vs. temperature, (R-T), critical current density vs. applied magnetic field, (J sub c -H), material density vs. pressure, (rho-P), XRD, SEM, and EDAX. The results of this study showed that the quality of electrical and structural properties of Bi-2223 bulk superconductors strongly depends on the pelletization pressure. Pressing of bulk samples at 400 MPa produces textured grain alignment and associates microstructural modifications in order to enhance flux pinning and thus increases current carrying capacities. (Abstract Copyright [2003], Wiley Periodicals, Inc.)

  2. Potential Biomarker of L type Amino Acid Transporter 1 in Breast Cancer Progression

    International Nuclear Information System (INIS)

    Liang, Zhongxing; Cho, Heidi T.; Williams, Larry; Zhu, Aizhi; Liang, Ke; Huang, Ke; Wu, Hui; Jiang, Chunsu; Hong, Samuel; Crowe, Ronald; Goodman, Mark M.; Shim, Hyunsuk

    2011-01-01

    L type amino acid transporter 1 (LAT1) is essential for the transport of large neutral amino acids. However, its role in breast cancer growth remains largely unknown. The purpose of the study is to investigate whether LAT1 is a potential biomarker for the diagnosis and treatment of breast cancer. LAT1 mRNA and protein levels in breast cancer cell lines and tissues were analyzed. In addition, the effects of targeting LAT1 for the inhibition of breast cancer cell tumorigenesis were assessed with soft agar assay. The imaging of xenograft with 1 amino 3 [ 18F ]fluorocyclo butane 1 carboxylic acid ([ 18F ]FACBC) PET was assessed for its diagnostic biomarker potential. Normal breast tissue or low malignant cell lines expressed low levels of LAT1 mRNA and protein, while highly malignant cancer cell lines and high grade breast cancer tissue expressed high levels of LAT1. In addition, higher expression levels of LAT1 in breast cancer tissues were consistent with advanced stage breast cancer. Furtermore, the blockade of LAT1 with its inhibitor, 2 amino bicyclo[2.2.1]heptane 2 carboxylic acid (BCH), or the knockdown of LAT1 with siRNA, inhibited proliferation and tumorigenesis of breast cancer cells. A leucine analog, [ 18F ]FACBC, has been demonstrated to be an excellent PET tracer for the non invasive imaging og malignant breast cancer using an orthotopic animal model. The overexpression of LAT1 is required for the progression of breast cancer. LAT1 represents a potential biomarker for therapy and diagnosis of breast cancer. [ 18F ]FACBC that correlates with LAT1 function is a potential PET tracer for malignant breast tumor imaging

  3. CaMKII in sinoatrial node physiology and dysfunction

    Directory of Open Access Journals (Sweden)

    Yuejin eWu

    2014-03-01

    Full Text Available The calcium and calmodulin dependent protein kinase II (CaMKII is present in sinoatrial node (SAN pacemaker cells and is required for physiological fight or flight SAN beating rate responses. Inhibition of CaMKII in SAN does not affect baseline heart rate, but reduces heart rate increases in response to physiological stress. CaMKII senses intracellular calcium (Ca2+ changes, oxidation status and hyperglycemia to phosphorylate substrates that regulate Ca2+-sensitive proteins, such as L-type Ca2+ channels, phospholamban (PLN, and cardiac ryanodine receptors (RyR2. All of these substrates are involved in the SAN pacemaking mechanism. Excessive CaMKII activity, as occurs under pathological conditions such as heart failure, ischemia and diabetes, can promote intracellular Ca2+ overload and reactive oxygen species (ROS production. Oxidation of CaMKII (ox-CaMKII locks CaMKII into a constitutively active configuration that contributes to SAN cell apoptosis and fibrosis. This ox-CaMKII-mediated loss of functional SAN cells contributes to sinoatrial node dysfunction (SND and sudden death. Thus, CaMKII has emerged as a central regulator of physiological SAN responses and a key determinant of SND.

  4. Polar localization of plasma membrane Ca2+/Mg2+ ATPase correlates with the pattern of steady ionic currents in eggs ofLymnaea stagnalis andBithynia tentaculata (Mollusca).

    Science.gov (United States)

    Zivkovic, Danica; Créton, Robbert; Zwaan, Gideon; de Bruijn, Willem C; Dohmen, M René

    1990-11-01

    During extrusion of the first polar body in eggs ofLymnaea stagnalis andBithynia tentaculata a localized Ca 2+ /Mg 2+ ATPase activity was detected, using Ando's enzyme-cytochemical method for electron microscopy [Ando et al. (1981) Acta Histochem Cytochem 14:705-726]. The enzyme activity was distributed in a polar fashion, along the cytoplasmic face of the plasma membrane. In the eggs ofLymnaea it was found only in the vegetal hemisphere, whereas inBithynia eggs it was localized both in the vegetal hemisphere and at the animal pole. This pattern of enzyme activity corresponds to the polar pattern of transcellular ionic currents measured with the vibrating probe, which we showed to be partially carried or regulated by calcium [Zivkovic and Dohmen (1989) Biol Bull (Woods Hole) 176 (Suppl):103-109]. The characteristics of the ATPase were studied using a variety of approaches such as ion and substrate depletions and substitutions, addition of specific inhibitors of ATPase activity, treatment with EDTA/EGTA and electron energy-loss spectrometry. The results indicate that, inLymnaea, there are at least two enzymatic entities. The first one is a Ca 2+ /Mg 2+ ATPase localized along the membrane and in the cortex of the vegetal hemisphere. The second one is a Ca 2+ -stimulated ATPase (calcium pump of the plasma membrane) localized in a small region of the membrane at the vegetal pole. We speculate that in the eggs ofLymnaea andBithynia a functional relationship exists between the plasma-membrane-associated ATPase activity and the transcellular ionic currents measured in the same region.

  5. Control of ciliary motility by Ca2+: Integration of Ca2+-dependent functions and targets for Ca2+ action

    International Nuclear Information System (INIS)

    Evans, T.C.

    1988-01-01

    To identify functions that regulate Ca 2+ -induced ciliary reversal in Paramecium, mutants defective in terminating depolarization-induced backward swimming were selected. Six independent recessive mutations (k-shy) comprising two complementation groups, k-shyA and k-shyB, were identified. All mutants exhibited prolonged backward swimming in depolarizing solutions. Voltage clamp studies revealed that mutant Ca 2+ current amplitudes were reduced, but could be restored to wild type levels by EGTA injection. The recovery of the mutant Ca 2+ current from Ca 2+ -dependent inactivation, and the decay of the Ca 2+ -dependent K + and Ca 2+ -dependent Na + currents after depolarization were slow in k-shy compared to wild type. To identify protein targets of Ca 2+ action, ciliary proteins that interact with calmodulin (CaM) were characterized. With a 125 I-CaM blot assay, several CaM-binding proteins were identified including axonemal, soluble, and membrane-bound polypeptides. Competitive displacement studies with unlabeled Paramecium CaM, bovine CaM, and troponinC suggested that both protein types bind CaM with high affinity and specificity. To examine the presence of CaM-binding sites in intact axonemes, a filtration binding assay was developed

  6. The Contribution of L-Type Cav1.3 Channels to Retinal Light Responses

    Directory of Open Access Journals (Sweden)

    Liheng Shi

    2017-12-01

    Full Text Available L-type voltage-gated calcium channels (LTCCs regulate tonic neurotransmitter release from sensory neurons including retinal photoreceptors. There are three types of LTCCs (Cav1.2, Cav1.3, and Cav1.4 expressed in the retina. While Cav1.2 is expressed in all retinal cells including the Müller glia and neurons, Cav1.3 and Cav1.4 are expressed in the retinal neurons with Cav1.4 exclusively expressed in the photoreceptor synaptic terminals. Mutations in the gene encoding Cav1.4 cause incomplete X-linked congenital stationary night blindness in humans. Even though Cav1.3 is present in the photoreceptor inner segments and the synaptic terminals in various vertebrate species, its role in vision is unclear, since genetic alterations in Cav1.3 are not associated with severe vision impairment in humans or in Cav1.3-null (Cav1.3−/− mice. However, a failure to regulate Cav1.3 was found in a mouse model of Usher syndrome, the most common cause of combined deafness and blindness in humans, indicating that Cav1.3 may contribute to retinal function. In this report, we combined physiological and morphological data to demonstrate the role of Cav1.3 in retinal physiology and function that has been undervalued thus far. Through ex vivo and in vivo electroretinogram (ERG recordings and immunohistochemical staining, we found that Cav1.3 plays a role in retinal light responses and synaptic plasticity. Pharmacological inhibition of Cav1.3 decreased ex vivo ERG a- and b-wave amplitudes. In Cav1.3−/− mice, their dark-adapted ERG a-, b-wave, and oscillatory potential amplitudes were significantly dampened, and implicit times were delayed compared to the wild type (WT. Furthermore, the density of ribbon synapses was reduced in the outer plexiform layer of Cav1.3−/− mice retinas. Hence, Cav1.3 plays a more prominent role in retinal physiology and function than previously reported.

  7. Effect of a continuum current in Raman spectra of two magnons in Bi2Sr2Ca1Cu1Cu2O8+Δ

    International Nuclear Information System (INIS)

    Massa, N.E.; Etchegoin, P.G.; Fainstein, C.

    1990-01-01

    It is a known fact, that high temperature superconducting oxides show antiferromagnetic order of the CuO 2 plains as their main characteristic. This allows the use of techniques, which are common to Raman spectroscopy, for the detection of inelastic scattering of magnon pairs represented by a wide band centered around 2500 cm -1 . This communication presents the results of preliminary measurements of such excitations in Bi-2212 tablets which are nominally pure, semiconducting, and doped with Fe under a DC current at temperatures lower than T c . Under these circumstances we find an increase in the full width half maximum of the approximately symmetrical band of two magnons in the tablet and a significantly higher intensity on the high frequency side. These measurements suggest that the carriers involved in the direct current might affect the exchange interaction by means of an electro-magnon interaction. (Author). 5 refs., 2 figs

  8. Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges

    Directory of Open Access Journals (Sweden)

    Konold Timm

    2012-03-01

    Full Text Available Abstract Background The majority of atypical bovine spongiform encephalopathy (BSE cases so far identified worldwide have been detected by active surveillance. Consequently the volume and quality of material available for detailed characterisation is very limiting. Here we report on a small transmission study of both atypical forms, H- and L-type BSE, in cattle to provide tissue for test evaluation and research, and to generate clinical, molecular and pathological data in a standardised way to enable more robust comparison of the two variants with particular reference to those aspects most relevant to case ascertainment and confirmatory diagnosis within existing regulated surveillance programmes. Results Two groups of four cattle, intracerebrally inoculated with L-type or H-type BSE, all presented with a nervous disease form with some similarities to classical BSE, which progressed to a more dull form in one animal from each group. Difficulty rising was a consistent feature of both disease forms and not seen in two BSE-free, non-inoculated cattle that served as controls. The pathology and molecular characteristics were distinct from classical BSE, and broadly consistent with published data, but with some variation in the pathological characteristics. Both atypical BSE types were readily detectable as BSE by current confirmatory methods using the medulla brain region at the obex, but making a clear diagnostic distinction between the forms was not consistently straightforward in this brain region. Cerebellum proved a more reliable sample for discrimination when using immunohistochemistry. Conclusions The prominent feature of difficulty rising in atypical BSE cases may explain the detection of naturally occurring cases in emergency slaughter cattle and fallen stock. Current confirmatory diagnostic methods are effective for the detection of such atypical cases, but consistently and correctly identifying the variant forms may require modifications to

  9. Co-expression of mCysLT1 receptors and IK channels in Xenopus laevis oocytes elicits LTD4-stimulated IK current, independent of an increase in [Ca2+]i

    DEFF Research Database (Denmark)

    Wulff, Tune; Hougaard, Charlotte; Klaerke, Dan A

    2004-01-01

    did not result in any increase in [Ca2+]i. Even though activation of hIK by low concentrations of LTD4 was independent of an increase in [Ca2+]i, a certain "permissive" level of [Ca2+]i was required for its activation, since buffering of intracellular Ca2+ by EGTA completely abolished the response...

  10. Regulation of Blood Pressure by Targeting CaV1.2-Galectin-1 Protein Interaction.

    Science.gov (United States)

    Hu, Zhenyu; Li, Guang; Wang, Jiong-Wei; Chong, Suet Yen; Yu, Dejie; Wang, Xiaoyuan; Soon, Jia Lin; Liang, Mui Cheng; Wong, Yuk Peng; Huang, Na; Colecraft, Henry M; Liao, Ping; Soong, Tuck Wah

    2018-04-12

    Background -L-type Ca V 1.2 channels play crucial roles in regulation of blood pressure. Galectin-1 (Gal-1), has been reported to bind to the I-II loop of Ca V 1.2 channels to reduce their current density. However, the mechanistic understanding for the down-regulation of Ca V 1.2 channels by Gal-1, and whether Gal-1 plays a direct role in blood pressure regulation remain unclear. Methods - In vitro experiments involving co-IP, western blot, patch-clamp recordings, immunohistochemistry and pressure myography were used to evaluate the molecular mechanisms by which Gal-1 down-regulates Ca V 1.2 channel in transfected HEK 293 cells, smooth muscle cells, arteries from Lgasl1 -/- mice, rat and human patients. In vivo experiments involving delivery of Tat-e9c peptide and AAV5-Gal-1 into rats were performed to investigate the effect of targeting Ca V 1.2-Gal-1 interaction on blood pressure monitored by tail cuff or telemetry methods. Results -Our study reveals that Gal-1 is a key regulator for proteasomal degradation of Ca V 1.2 channels. Gal-1 competed allosterically with Ca V β subunit for binding to the I-II loop of Ca V 1.2 channel. This competitive disruption of Ca V β binding led to Ca V 1.2 degradation by exposing the channels to poly-ubiquitination. Notably, we demonstrated that the inverse relationship of reduced Gal-1 and increased Ca V 1.2 protein levels in arteries was associated with hypertension in hypertensive rats and patients, and Gal-1 deficiency induces higher blood pressure in mice due to up-regulated Ca V 1.2 protein level in arteries. To directly regulate blood pressure by targeting the Ca V 1.2-Gal-1 interaction, we administered Tat-e9c, a peptide that competed for binding of Gal-1, by a mini-osmotic pump and this specific disruption of Ca V 1.2-Gal-1 coupling increased smooth muscle Ca V 1.2 currents, induced larger arterial contraction and caused hypertension in rats. In contrasting experiments, over-expression of Gal-1 in smooth muscle by a

  11. Development of Bulk Bi2+xSr3-yCa yCu 2O8+delta Superconductors by Partial-Melting Route for Fault Current Limiters Application

    Directory of Open Access Journals (Sweden)

    Bojan A. Marinkovic

    2002-06-01

    Full Text Available The production of bulk Bi2+xSr3-yCa yCu 2O8+delta (Bi-2212 superconductors for fault current limiter application was developed via a partial-melting route. Aiming high Ic (critical current, which is the essential superconducting characteristic for application of this material in the construction of Fault Current Limiters (FCL, the produced blocks have predominance of Bi-2212 phase (83 wt%, which characterizes with high values of zero and onset transport critical temperature of 92K and 97.5K, respectively. A relatively low transition width, deltaT, from the superconducting to the normal state of 5.5K, revealed a good intergrain connectivity. Consequently, current measurements on the blocks of Bi-2212 show promising Ic values of 230A and 850A for direct and alternate current, respectively. It is expected that further increases in the Ic values will depend on the elimination of an observed amorphous phase and further reduction of amount and grain sizes of secondary phases, still present in the blocks obtained by the proposed partial-melting route. This may be achieved by a further optimization of the partial-melting processing parameters.

  12. Effects of low-dose ionising radiation on pituitary adenoma: is there a role for L-type calcium channel?

    Energy Technology Data Exchange (ETDEWEB)

    Soares, Marcella Araugio; Santos, Raquel Gouvea dos [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN), Belo Horizonte, MG (Brazil). Lab. de Radiobiologia]. E-mail: santosr@cdtn.br

    2005-10-15

    Pituitary adenomas constitute about 6-18% of brain tumours in adults. Activation of voltage gated calcium currents can account for growth hormone over secretion in some GH-secreting pituitary adenomas that produce an acromegaly appearance and increase mortality. Ca{sup 2+} ions, as mediators of intracellular signalling, are crucial for the development of apoptosis. However, the role of [Ca{sup 2+}] in the development of apoptosis is ambiguous. In this study, the effects of low-dose ionising gamma radiation ({sup 60} Co) on rat pituitary adenoma cells survival and proliferation and the role of calcium channels on the apoptosis radio-induced were evaluated. Doses as low as 3 Gy were found to inhibit GH3 cell proliferation. Even though there was a significant number of live cells,168 hours following irradiation, they were not able to proliferate. The results indicate that the blockade of extracellular calcium influx through these channels does not interfere in the radiation-induced apoptosis in GH3 cells. (author)

  13. Long-term habituation of the gill-withdrawal reflex in Aplysia requires gene transcription, calcineurin and L-type voltage-gated calcium channels

    Directory of Open Access Journals (Sweden)

    Joseph eEsdin

    2010-11-01

    Full Text Available Although habituation is possibly the simplest form of learning, we still do not fully understand the neurobiological basis of habituation in any organism. To advance the goal of a comprehensive understanding of habituation, we have studied long-term habituation (LTH of the gill-withdrawal reflex (GWR in the marine snail Aplysia californica. Previously, we showed that habituation of the GWR in a reduced preparation lasts for up to 12 hr, and depends on protein synthesis, as well as activation of protein phosphatases 1 and 2A and postsynaptic glutamate receptors. Here, we have used the reduced preparation to further analyze the mechanisms of LTH in Aplysia. We found that LTH of the GWR depends on RNA synthesis because it was blocked by both the irreversible transcriptional inhibitor actinomycin-D and the reversible transcriptional inhibitor, 5,6-dichlorobenzimidazole riboside (DRB. In addition, LTH requires activation of protein phosphatase 2B (calcineurin, because it was disrupted by ascomycin. Finally, LTH was blocked by nitrendipine, which indicates that activation of L-type voltage-gated Ca2+ channels is required for this form of learning. Together with our previous results, the present results indicate that exclusively presynaptic mechanisms, although possibly sufficient for short-term habituation, are insufficient for LTH. Rather, LTH must involve postsynaptic, as well as presynaptic, mechanisms.

  14. LaNiO3 buffer layers for high critical current density YBa2Cu3O7-δ and Tl2Ba2CaCu2O8-δ films

    International Nuclear Information System (INIS)

    Carlson, C.M.; Parilla, P.A.; Siegal, M.P.; Ginley, D.S.; Wang, Y.; Blaugher, R.D.; Price, J.C.; Overmyer, D.L.; Venturini, E.L.

    1999-01-01

    We demonstrate high critical current density superconducting films of YBa 2 Cu 3 O 7-δ (YBCO) and Tl 2 Ba 2 CaCu 2 O 8-δ (Tl-2212) using LaNiO 3 (LNO) buffer layers. YBCO films grown on an LNO buffer layer have only a slightly lower J c (5 K, H=0) than films grown directly on a bare LaAlO 3 substrate. YBCO films grown on LNO buffer layers exhibit minor microstructural disorder and enhanced flux pinning. LNO-buffered Tl-2212 samples show large reductions in J c at all temperatures and fields compared to those grown on bare LaAlO 3 , correlating to both a-axis grain and nonsuperconducting phase formation. LNO could be a promising buffer layer for both YBCO and Tl-based superconducting films in coated conductor applications. copyright 1999 American Institute of Physics

  15. LaNiO3 Buffer Layers for High Critical Current Density YBa2Cu3O7δ and Tl2Ba2CaCu2O8δ Films

    International Nuclear Information System (INIS)

    Carlson, C.M.; Parilla, P.A.; Siegal, M.P.; Ginley, D.S.; Wang, Y.-T.; Blaugher, R.D.; Price, J.C.; Overmyer, D.L.; Venturini, E.L.

    1999-01-01

    We demonstrate high critical current density superconducting films of YBa 2 Cu 3 O 7-δ (YBCO) and Tl 2 Ba 2 CaCu 2 O 8-δ (Tl-2212) using LaNiO 3 (LNO) buffer layers. YBCO films grown on an LNO buffer layer have only a slightly lower J c (5K, H=0) than films grown directly on a bare LaAlO 3 substrate. It is noteworthy that YBCO films grown on LNO buffer layers exhibit minor microstructural disorder and enhanced flux pinning. LNO-buffered Tl-2212 samples show large reductions in J c at all temperatures and fields compared to those grown on bare LaAlO 3 , correlating to both a-axis grain and nonsuperconducting phase formation. With additional optimization, LNO could be a promising buffer layer for both YBCO and Tl-based superconducting films, perhaps ideally suited for coated conductor applications

  16. Improvement of critical current density in thallium-based (Tl,Bi)Sr{sub 1.6}Ba{sub 0.4}Ca{sub 2}Cu{sub 3}O{sub x} superconductors

    Energy Technology Data Exchange (ETDEWEB)

    Ren, Z.F.; Wang, C.A.; Wang, J.H. [State Univ. of New York at Buffalo, Amherst, NY (United States)] [and others

    1994-12-31

    Epitaxial (Tl,Bi)Sr{sub 1.6}Ba{sub 0.4}Ca{sub 2}Cu{sub 3}O{sub x} (Tl,Bi)-1223 thin films on (100) single crystal LaAlO{sub 3} substrates were synthesized by a two-step procedure. Phase development, microstructure, and relationships between film and substrate were studied by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Resistance versus temperature, zero-field-cooled and field-cooled magnetization, and transport critical current density (J{sub c}) were measured. The zero-resistance temperature was 105-111 K. J{sub c} at 77 K and zero field was > 2 x 10{sup 6} A/cm{sup 2}. The films exhibited good flux pinning properties.

  17. Cerebellar ataxia by enhanced Cav2.1 currents is alleviated by Ca2+-dependent K-channel activators in Cacna1aS218l mutant mice

    NARCIS (Netherlands)

    Z. Gao (Zhenyu); B. Todorov (Boyan); C.F. Barrett (Curtis); S. van Dorp (Stijn); M.D. Ferrari (Michel); M. Dichgans (Martin); C.I. de Zeeuw (Chris); F.E. Hoebeek (Freek)

    2012-01-01

    textabstractMutations in the CACNA1A gene are associated with neurological disorders, such as ataxia, hemiplegic migraine, and epilepsy. These mutations affect the pore-forming α1A-subunit of CaV2.1 channels and thereby either decrease or increase neuronal Ca2+ influx. A decreased CaV2.1-mediated

  18. Investigation of inter-grain critical current density in Bi2Sr2CaCu2O8+δ superconducting wires and its relationship with the heat treatment protocol

    Science.gov (United States)

    Pallecchi, I.; Leveratto, A.; Braccini, V.; Zunino, V.; Malagoli, A.

    2017-09-01

    In this work we investigate the effect of each different heat treatment stage in the fabrication of Bi2Sr2CaCu2O8+δ superconducting wires on intra-grain and inter-grain superconducting properties. We measure magnetic critical temperature T c values and transport critical current density J c at temperatures from 4 K to 40 K and in fields up to 7 T. From an analysis of the temperature dependence of the self-field critical current density J c(T) that takes into account weak link behavior and the proximity effect, we study grain boundary (GB) transparency to supercurrents; we also establish a relationship between GB oxygenation in the different steps of the fabrication process and GB transparency to supercurrents. We find that GB oxygenation starts in the first crystallization stage, but it becomes complete in the plateau at 836 °C and in slow cooling stages and is further enhanced in the prolonged post-annealing step. Such oxygenation makes GBs more conductive, thus improving the inter-grain J c value and temperature dependence. On the other hand, from inspection of the T c values in the framework of the phase diagram dome, we find that grains are already oxygenated in the crystallization step up to the optimal doping, while successive slow cooling and post-annealing treatments further enhance the degree of overdoping, especially if carried out in oxygen atmosphere rather than in air.

  19. L-type calcium channels play a critical role in maintaining lens transparency by regulating phosphorylation of aquaporin-0 and myosin light chain and expression of connexins.

    Science.gov (United States)

    Maddala, Rupalatha; Nagendran, Tharkika; de Ridder, Gustaaf G; Schey, Kevin L; Rao, Ponugoti Vasantha

    2013-01-01

    Homeostasis of intracellular calcium is crucial for lens cytoarchitecture and transparency, however, the identity of specific channel proteins regulating calcium influx within the lens is not completely understood. Here we examined the expression and distribution profiles of L-type calcium channels (LTCCs) and explored their role in morphological integrity and transparency of the mouse lens, using cDNA microarray, RT-PCR, immunoblot, pharmacological inhibitors and immunofluorescence analyses. The results revealed that Ca (V) 1.2 and 1.3 channels are expressed and distributed in both the epithelium and cortical fiber cells in mouse lens. Inhibition of LTCCs with felodipine or nifedipine induces progressive cortical cataract formation with time, in association with decreased lens weight in ex-vivo mouse lenses. Histological analyses of felodipine treated lenses revealed extensive disorganization and swelling of cortical fiber cells resembling the phenotype reported for altered aquaporin-0 activity without detectable cytotoxic effects. Analysis of both soluble and membrane rich fractions from felodipine treated lenses by SDS-PAGE in conjunction with mass spectrometry and immunoblot analyses revealed decreases in β-B1-crystallin, Hsp-90, spectrin and filensin. Significantly, loss of transparency in the felodipine treated lenses was preceded by an increase in aquaporin-0 serine-235 phosphorylation and levels of connexin-50, together with decreases in myosin light chain phosphorylation and the levels of 14-3-3ε, a phosphoprotein-binding regulatory protein. Felodipine treatment led to a significant increase in gene expression of connexin-50 and 46 in the mouse lens. Additionally, felodipine inhibition of LTCCs in primary cultures of mouse lens epithelial cells resulted in decreased intracellular calcium, and decreased actin stress fibers and myosin light chain phosphorylation, without detectable cytotoxic response. Taken together, these observations reveal a crucial

  20. Preparation and preclinical evaluation of 68Ga-DOTA-amlodipine for L-type calcium channel imaging

    Science.gov (United States)

    Firuzyar, Tahereh; Jalilian, Amir Reza; Aboudzadeh, Mohammad Reza; Sadeghpour, Hossein; Shafiee-Ardestani, Mahdi; Khalaj, Ali

    2016-01-01

    Aim: In order to develop a possible tracer for L-type calcium channel imaging, we here report the development of a Ga-68 amlodipine derivative for possible PET imaging. Materials and Methods: Amlodipine DOTA conjugate was synthesized, characterized and went through calcium channel blockade, toxicity, apoptosis/necrosis tests. [68Ga] DOTA AMLO was prepared at optimized conditions followed by stability tests, partition coefficient determination and biodistribution studies using tissue counting and co incidence imaging up to 2 h. Results: [68Ga] DOTA AMLO was prepared at pH 4–5 in 7–10 min at 95°C in high radiochemical purity (>99%, radio thin layer chromatography; specific activity: 1.9–2.1 GBq/mmol) and was stable up to 4 h with a log P of −0.94. Calcium channel rich tissues including myocardium, and tissues with smooth muscle cells such as colon, intestine, and lungs demonstrated significant uptake. Co incidence images supported the biodistribution data up to 2 h. Conclusions: The complex can be a candidate for further positron emission tomography imaging for L type calcium channels. PMID:27833311

  1. LaNiO(3) Buffer Layers for High Critical Current Density YBa(2)Cu(3)O(7-delta) and Tl(2)Ba(2)CaCu(2)O(8-delta) Films

    Energy Technology Data Exchange (ETDEWEB)

    Carlson, C.M.; Parilla, P.A.; Siegal, M.P.; Ginley, D.S.; Wang, Y.-T.; Blaugher, R.D.; Price, J.C.; Overmyer, D.L.; Venturini, E.L.

    1999-08-24

    We demonstrate high critical current density superconducting films of YBa{sub 2}Cu{sub 3}O{sub 7{minus}{delta}} (YBCO) and Tl{sub 2}Ba{sub 2}CaCu{sub 2}O{sub 8{minus}{delta}} (Tl-2212) using LaNiO{sub 3} (LNO) buffer layers. YBCO films grown on an LNO buffer layer have only a slightly lower J{sub c} (5K, H=0) than films grown directly on a bare LaAlO{sub 3} substrate. It is noteworthy that YBCO films grown on LNO buffer layers exhibit minor microstructural disorder and enhanced flux pinning. LNO-buffered Tl-2212 samples show large reductions in J{sub c} at all temperatures and fields compared to those grown on bare LaAlO{sub 3}, correlating to both a-axis grain and nonsuperconducting phase formation. With additional optimization, LNO could be a promising buffer layer for both YBCO and Tl-based superconducting films, perhaps ideally suited for coated conductor applications.

  2. Cyclic ADP ribose-dependent Ca2+ release by group I metabotropic glutamate receptors in acutely dissociated rat hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Jong-Woo Sohn

    Full Text Available Group I metabotropic glutamate receptors (group I mGluRs; mGluR1 and mGluR5 exert diverse effects on neuronal and synaptic functions, many of which are regulated by intracellular Ca(2+. In this study, we characterized the cellular mechanisms underlying Ca(2+ mobilization induced by (RS-3,5-dihydroxyphenylglycine (DHPG; a specific group I mGluR agonist in the somata of acutely dissociated rat hippocampal neurons using microfluorometry. We found that DHPG activates mGluR5 to mobilize intracellular Ca(2+ from ryanodine-sensitive stores via cyclic adenosine diphosphate ribose (cADPR, while the PLC/IP(3 signaling pathway was not involved in Ca(2+ mobilization. The application of glutamate, which depolarized the membrane potential by 28.5±4.9 mV (n = 4, led to transient Ca(2+ mobilization by mGluR5 and Ca(2+ influx through L-type Ca(2+ channels. We found no evidence that mGluR5-mediated Ca(2+ release and Ca(2+ influx through L-type Ca(2+ channels interact to generate supralinear Ca(2+ transients. Our study provides novel insights into the mechanisms of intracellular Ca(2+ mobilization by mGluR5 in the somata of hippocampal neurons.

  3. Effects of Thermocapillary Forces during Welding of 316L-Type Wrought, Cast and Powder Metallurgy Austenitic Stainless Steels

    CERN Document Server

    Sgobba, Stefano

    2003-01-01

    The Large Hadron Collider (LHC) is now under construction at the European Organization for Nuclear Research (CERN). This 27 km long accelerator requires 1248 superconducting dipole magnets operating at 1.9 K. The cold mass of the dipole magnets is closed by a shrinking cylinder with two longitudinal welds and two end covers at both extremities of the cylinder. The end covers, for which fabrication by welding, casting or Powder Metallurgy (PM) was considered, are dished-heads equipped with a number of protruding nozzles for the passage of the different cryogenic lines. Structural materials and welds must retain high strength and toughness at cryogenic temperature. AISI 316L-type austenitic stainless steel grades have been selected because of their mechanical properties, ductility, weldability and stability of the austenitic phase against low-temperature spontaneous martensitic transformation. 316LN is chosen for the fabrication of the end covers, while the interconnection components to be welded on the protrud...

  4. Cellular tropism, population dynamics, host range and taxonomic status of an aphid secondary symbiont, SMLS (Sitobion miscanthi L type symbiont.

    Directory of Open Access Journals (Sweden)

    Tong Li

    Full Text Available SMLS (Sitobion miscanthi L type symbiont is a newly reported aphid secondary symbiont. Phylogenetic evidence from molecular markers indicates that SMLS belongs to the Rickettsiaceae and has a sibling relationship with Orientia tsutsugamushi. A comparative analysis of coxA nucleotide sequences further supports recognition of SMLS as a new genus in the Rickettsiaceae. In situ hybridization reveals that SMLS is housed in both sheath cells and secondary bacteriocytes and it is also detected in aphid hemolymph. The population dynamics of SMLS differ from those of Buchnera aphidicola and titer levels of SMLS increase in older aphids. A survey of 13 other aphids reveals that SMLS only occurs in wheat-associated species.

  5. Antiapolipoprotein A-1 IgG chronotropic effects require nongenomic action of aldosterone on L-type calcium channels.

    Science.gov (United States)

    Rossier, Michel F; Pagano, Sabrina; Python, Magaly; Maturana, Andres D; James, Richard W; Mach, François; Roux-Lombard, Pascale; Vuilleumier, Nicolas

    2012-03-01

    Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L-type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3-kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels.

  6. The direct l-type resonance spectrum of CF3CCH in the vibrational state ν 10 = 2

    International Nuclear Information System (INIS)

    Woetzel, Ulf; Maeder, Heinrich; Harder, Hauke; Pracna, Petr; Sarka, Kamil

    2005-01-01

    The direct l-type resonance spectrum of CF 3 CCH in the vibrational state ν 10 = 2 has been measured by means of waveguide microwave Fourier transform spectroscopy in the range 8-26 GHz. Two types of direct l-type resonance transitions induced by the (Δk = ±2, Δl = ±2) interaction could be observed: 262 transitions following the ΔJ = 0, Δk = Δl = 2 selection rule covering values of J = 17-64 and G vertical bar k - l vertical bar from 2 to 15, and 75 transitions following the ΔJ = 0, Δk = Δl = 4 selection rule covering values of J = 44-70 and G up to 3. The strong (2, 2) resonance furthermore allowed the observation of A 1 -A 2 splittings of the k = l = ±2 states from J = 63-70. The transitions with G = 3 showed splittings due to the (4, -2) and (0, 6) interactions. The corresponding energy level systems and part of the Hamiltonian matrix are discussed. Strong perturbations due to Δ(k - l) = 3 interactions coupling the states k = ±1, l = ±2 and k = ±4, l ±2 made possible the observation of perturbation-allowed transitions with selection rule k = ±1, l =± 2 ↔ k = 0, l = ±2. Additionally, the J = 2-1 and 3-2 rotational transitions have been measured. A multiple fitting analysis has been performed in which the experimental data have been fitted using five reduced forms of the effective Hamiltonian as proposed by Sarka and Harder [J. Mol. Spectrosc. 197 (1999) 254]. Parameters up to sixth order have been determined including the axial rotational constant A for both values of vertical bar l vertical bar and the unitary equivalence of the determined parameter sets has been demonstrated

  7. Microscopic fracture of filaments and its relation to the critical current under bending deformation in (Bi,Pb)2Sr2Ca2Cu3O10 composite superconducting tapes

    International Nuclear Information System (INIS)

    Hojo, Masaki; Nakamura, Mitsuhiro; Matsuoka, Tomoe; Tanaka, Mototsugu; Ochiai, Shojiro; Sugano, Michinaka; Osamura, Kozo

    2003-01-01

    The strain dependence of the critical current, I c , of (Bi,Pb) 2 Sr 2 Ca 2 Cu 3 O 10 (Bi2223)/Ag/Ag-Mg composite superconducting tapes has been studied both experimentally and analytically under bending deformation. Tests have been carried out for one type of tape used in the VAMAS bending round-robin programme. The complex stress-strain behaviour of each component was first analysed in tension. This was done by comparing the stress-strain curves of composite tapes with those of Ag and Ag-Mg alloy tapes. Here, the plastic deformation (work hardening) of Ag and Ag-Mg alloy, and the thermal residual strain due to the manufacturing process were taken into account. The fracture strain of Bi2223 filaments was inversely determined as 0.08% to meet the global tensile stress-strain curve of the composite tape. The calculated stress-strain curves finally agreed well with the experimental results when the as-supplied bending strain was taken into account. Then, the analysis was modified to fit the bending deformation. Here, the movement of the neutral axis due to the non-symmetric and elastic-plastic stress-strain curves of the components and their Bauschinger effect were taken into account. The relative decrease of I c with the increase in the Bi2223 tape curvature was calculated from the volume fraction of the broken filaments. The calculated I c agreed well with the experimental results when the movement of the neutral axis and the Bauschinger effect were taken into account. Microscopic observation of the spatial distribution of the filament fracture indicated that the damage occurred at the outermost layer on the tensile side when the curvature was small, and then the damage front shifted to the inside layers. The observed fracture behaviour of the Bi2223 filament agreed well with the estimated location based on the above analysis

  8. Currents, temperature, conductivity, attenuation, and sigma-theta data from moorings deployed off the coast of Orange County, CA from platforms ROBERT GORDON SPROUL and YELLOWFIN from June 13, 2001 to January 22, 2003 (NODC Accession 0067572)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — A large number of moorings were deployed in the summer of 2001 off Huntington Beach CA to monitor coastal ocean process that transport suspended material across the...

  9. Currents, temperature, conductivity, attenuation, and sigma-theta data from moorings deployed off the coast of Palos Verdes, CA from platforms VICKERS and ROBERT GORDON SPROUL from May 21, 1992 and March 30, 1993 (NODC Accession 0067573)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The sediments on the shelf off Palos Verdes CA are contaminated with large amounts of DDT. Moorings were deployed on the shelf in the winter of 1993 in part to...

  10. Apo-states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain

    Science.gov (United States)

    Findeisen, Felix; Rumpf, Christine; Minor, Daniel L.

    2013-01-01

    In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation (CDI) and limits calcium entry, whereas CaBP1 blocks CDI and allows sustained calcium influx. Here, we combine isothermal titration calorimetry (ITC) with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca2+/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium binding properties. The observation that the apo-forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. PMID:23811053

  11. Apo states of calmodulin and CaBP1 control CaV1 voltage-gated calcium channel function through direct competition for the IQ domain.

    Science.gov (United States)

    Findeisen, Felix; Rumpf, Christine H; Minor, Daniel L

    2013-09-09

    In neurons, binding of calmodulin (CaM) or calcium-binding protein 1 (CaBP1) to the CaV1 (L-type) voltage-gated calcium channel IQ domain endows the channel with diametrically opposed properties. CaM causes calcium-dependent inactivation and limits calcium entry, whereas CaBP1 blocks calcium-dependent inactivation (CDI) and allows sustained calcium influx. Here, we combine isothermal titration calorimetry with cell-based functional measurements and mathematical modeling to show that these calcium sensors behave in a competitive manner that is explained quantitatively by their apo-state binding affinities for the IQ domain. This competition can be completely blocked by covalent tethering of CaM to the channel. Further, we show that Ca(2+)/CaM has a sub-picomolar affinity for the IQ domain that is achieved without drastic alteration of calcium-binding properties. The observation that the apo forms of CaM and CaBP1 compete with each other demonstrates a simple mechanism for direct modulation of CaV1 function and suggests a means by which excitable cells may dynamically tune CaV activity. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Functional role of voltage gated Ca2+ channels in heart automaticity

    Directory of Open Access Journals (Sweden)

    Pietro eMesirca

    2015-02-01

    Full Text Available Pacemaker activity of automatic cardiac myocytes controls the heartbeat in everyday life. Cardiac automaticity is under the control of several neurotransmitters and hormones and is constantly regulated by the autonomic nervous system to match the physiological needs of the organism. Several classes of ion channels and proteins involved in intracellular Ca2+ dynamics contribute to pacemaker activity. The functional role of voltage-gated calcium channels (VGCCs in heart automaticity and impulse conduction has been matter of debate for 30 years. However, growing evidence shows that VGCCs are important regulators of the pacemaker mechanisms and play also a major role in atrio-ventricular impulse conduction. Incidentally, studies performed in genetically modified mice lacking L-type Cav1.3 (Cav1.3-/- or T-type Cav3.1 (Cav3.1-/- channels show that genetic inactivation of these channels strongly impacts pacemaking. In cardiac pacemaker cells, VGCCs activate at negative voltages at the beginning of the diastolic depolarization and importantly contribute to this phase by supplying inward current. Loss-of-function of these channels also impairs atrio-ventricular conduction. Furthermore, inactivation of Cav1.3 channels promotes also atrial fibrillation and flutter in knockout mice suggesting that these channels can play a role in stabilizing atrial rhythm. Genomic analysis demonstrated that Cav1.3 and Cav3.1 channels are widely expressed in pacemaker tissue of mice, rabbits and humans. Importantly, human diseases of pacemaker activity such as congenital bradycardia and heart block have been attributed to loss-of-function of Cav1.3 and Cav3.1 channels. In this article, we will review the current knowledge on the role of VGCCs in the generation and regulation of heart rate and rhythm. We will discuss also how loss of Ca2+ entry through VGCCs could influence intracellular Ca2+ handling and promote atrial arrhythmias.

  13. Impact of seawater [Ca

    NARCIS (Netherlands)

    Mewes, A.; Langer, G.; Thoms, S.; Nehrke, G.; Reichart, G.J.; de Nooijer, L.J.; Bijma, J.

    2015-01-01

    Mg / Ca ratios in foraminiferal tests are routinely used as paleotemperature proxies, but on long timescales, they also hold the potential to reconstruct past seawater Mg / Ca. The impact of both temperature and seawater Mg / Ca on Mg incorporation in Foraminifera has been quantified by a number of

  14. High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas

    International Nuclear Information System (INIS)

    Yanagisawa, Nobuyuki; Hana, Kiyomi; Nakada, Norihiro; Ichinoe, Masaaki; Koizumi, Wasaburo; Endou, Hitoshi; Okayasu, Isao; Murakumo, Yoshiki

    2014-01-01

    Oncocytic L-type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki-67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki-67 labeling index (LI). Kaplan–Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1-high and -low scores, whereas LAT2 and CD98 expression and Ki-67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1-high/LAT2-low than LAT1-low/LAT2-high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy

  15. Characterisation of L-Type Amino Acid Transporter 1 (LAT1 Expression in Human Skeletal Muscle by Immunofluorescent Microscopy

    Directory of Open Access Journals (Sweden)

    Nathan Hodson

    2017-12-01

    Full Text Available The branch chain amino acid leucine is a potent stimulator of protein synthesis in skeletal muscle. Leucine rapidly enters the cell via the L-Type Amino Acid Transporter 1 (LAT1; however, little is known regarding the localisation and distribution of this transporter in human skeletal muscle. Therefore, we applied immunofluorescence staining approaches to visualise LAT1 in wild type (WT and LAT1 muscle-specific knockout (mKO mice, in addition to basal human skeletal muscle samples. LAT1 positive staining was visually greater in WT muscles compared to mKO muscle. In human skeletal muscle, positive LAT1 staining was noted close to the sarcolemmal membrane (dystrophin positive staining, with a greater staining intensity for LAT1 observed in the sarcoplasmic regions of type II fibres (those not stained positively for myosin heavy-chain 1, Type II—25.07 ± 5.93, Type I—13.71 ± 1.98, p < 0.01, suggesting a greater abundance of this protein in these fibres. Finally, we observed association with LAT1 and endothelial nitric oxide synthase (eNOS, suggesting LAT1 association close to the microvasculature. This is the first study to visualise the distribution and localisation of LAT1 in human skeletal muscle. As such, this approach provides a validated experimental platform to study the role and regulation of LAT1 in human skeletal muscle in response to various physiological and pathophysiological models.

  16. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

    Directory of Open Access Journals (Sweden)

    Paula Patricia Perissinotti

    2015-01-01

    Full Text Available Kelch-like 1 (KLHL1 is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type and CaV3.2 (α1H T-type calcium channels; KLHL1 knockdown experiments (KD cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014. Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT; and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

  17. Proteolytic cleavage and PKA phosphorylation of α1C subunit are not required for adrenergic regulation of CaV1.2 in the heart.

    Science.gov (United States)

    Katchman, Alexander; Yang, Lin; Zakharov, Sergey I; Kushner, Jared; Abrams, Jeffrey; Chen, Bi-Xing; Liu, Guoxia; Pitt, Geoffrey S; Colecraft, Henry M; Marx, Steven O

    2017-08-22

    Calcium influx through the voltage-dependent L-type calcium channel (Ca V 1.2) rapidly increases in the heart during "fight or flight" through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of β-adrenergic activation of cardiac Ca V 1.2, however, are incompletely known, but are presumed to require phosphorylation of residues in α 1C and C-terminal proteolytic cleavage of the α 1C subunit. We generated transgenic mice expressing an α 1C with alanine substitutions of all conserved serine or threonine, which is predicted to be a potential PKA phosphorylation site by at least one prediction tool, while sparing the residues previously shown to be phosphorylated but shown individually not to be required for β-adrenergic regulation of Ca V 1.2 current (17-mutant). A second line included these 17 putative sites plus the five previously identified phosphoregulatory sites (22-mutant), thus allowing us to query whether regulation requires their contribution in combination. We determined that acute β-adrenergic regulation does not require any combination of potential PKA phosphorylation sites conserved in human, guinea pig, rabbit, rat, and mouse α 1C subunits. We separately generated transgenic mice with inducible expression of proteolytic-resistant α 1C Prevention of C-terminal cleavage did not alter β-adrenergic stimulation of Ca V 1.2 in the heart. These studies definitively rule out a role for all conserved consensus PKA phosphorylation sites in α 1C in β-adrenergic stimulation of Ca V 1.2, and show that phosphoregulatory sites on α 1C are not redundant and do not each fractionally contribute to the net stimulatory effect of β-adrenergic stimulation. Further, proteolytic cleavage of α 1C is not required for β-adrenergic stimulation of Ca V 1.2.

  18. CaV3.1 isoform of T-type calcium channels supports excitability of rat and mouse ventral tegmental area neurons.

    Science.gov (United States)

    Tracy, Matthew E; Tesic, Vesna; Stamenic, Tamara Timic; Joksimovic, Srdjan M; Busquet, Nicolas; Jevtovic-Todorovic, Vesna; Todorovic, Slobodan M

    2018-03-23

    Recent data have implicated voltage-gated calcium channels in the regulation of the excitability of neurons within the mesolimbic reward system. While the attention of most research has centered on high voltage L-type calcium channel activity, the presence and role of the low voltage-gated T-type calcium channel (T-channels) has not been well explored. Hence, we investigated T-channel properties in the neurons of the ventral tegmental area (VTA) utilizing wild-type (WT) rats and mice, Ca V 3.1 knock-out (KO) mice, and TH-eGFP knock-in (KI) rats in acute horizontal brain slices of adolescent animals. In voltage-clamp experiments, we first assessed T-channel activity in WT rats with characteristic properties of voltage-dependent activation and inactivation, as well as characteristic crisscrossing patterns of macroscopic current kinetics. T-current kinetics were similar in WT mice and WT rats but T-currents were abolished in Ca V 3.1 KO mice. In ensuing current-clamp experiments, we observed the presence of hyperpolarization-induced rebound burst firing in a subset of neurons in WT rats, as well as dopaminergic and non-dopaminergic neurons in TH-eGFP KI rats. Following the application of a pan-selective T-channel blocker TTA-P2, rebound bursting was significantly inhibited in all tested cells. In a behavioral assessment, the acute locomotor increase induced by a MK-801 (Dizocilpine) injection in WT mice was abolished in Ca V 3.1 KO mice, suggesting a tangible role for 3.1 T-type channels in drug response. We conclude that pharmacological targeting of Ca V 3.1 isoform of T-channels may be a novel approach for the treatment of disorders of mesolimbic reward system. Copyright © 2018. Published by Elsevier Ltd.

  19. The hippocampal CA2 ensemble is sensitive to contextual change.

    Science.gov (United States)

    Wintzer, Marie E; Boehringer, Roman; Polygalov, Denis; McHugh, Thomas J

    2014-02-19

    Contextual learning involves associating cues with an environment and relating them to past experience. Previous data indicate functional specialization within the hippocampal circuit: the dentate gyrus (DG) is crucial for discriminating similar contexts, whereas CA3 is required for associative encoding and recall. Here, we used Arc/H1a catFISH imaging to address the contribution of the largely overlooked CA2 region to contextual learning by comparing ensemble codes across CA3, CA2, and CA1 in mice exposed to familiar, altered, and novel contexts. Further, to manipulate the quality of information arriving in CA2 we used two hippocampal mutant mouse lines, CA3-NR1 KOs and DG-NR1 KOs, that result in hippocampal CA3 neuronal activity that is uncoupled from the animal's sensory environment. Our data reveal largely coherent responses across the CA axis in control mice in purely novel or familiar contexts; however, in the mutant mice subject to these protocols the CA2 response becomes uncoupled from CA1 and CA3. Moreover, we show in wild-type mice that the CA2 ensemble is more sensitive than CA1 and CA3 to small changes in overall context. Our data suggest that CA2 may be tuned to remap in response to any conflict between stored and current experience.

  20. A L-type lectin gene is involved in the response to hormonal treatment and water deficit in Volkamer lemon.

    Science.gov (United States)

    Vieira, Dayse Drielly Sousa Santana; Emiliani, Giovanni; Bartolini, Paola; Podda, Alessandra; Centritto, Mauro; Luro, François; Carratore, Renata Del; Morillon, Raphaël; Gesteira, Abelmon; Maserti, Biancaelena

    2017-11-01

    Combination of biotic and abiotic stress is a major challenge for crop and fruit production. Thus, identification of genes involved in cross-response to abiotic and biotic stress is of great importance for breeding superior genotypes. Lectins are glycan-binding proteins with a functions in the developmental processes as well as in the response to biotic and abiotic stress. In this work, a lectin like gene, namely ClLectin1, was characterized in Volkamer lemon and its expression was studied in plants exposed to either water stress, hormonal elicitors (JA, SA, ABA) or wounding to understand whether this gene may have a function in the response to multiple stress combination. Results showed that ClLectin1 has 100% homology with a L-type lectin gene from C. sinensis and the in silico study of the 5'UTR region showed the presence of cis-responsive elements to SA, DRE2 and ABA. ClLectin1 was rapidly induced by hormonal treatments and wounding, at local and systemic levels, suggesting an involvement in defence signalling pathways and a possible role as fast detection biomarker of biotic stress. On the other hand, the induction of ClLectin1 by water stress pointed out a role of the gene in the response to drought. The simultaneous response of ClLectin1 expression to water stress and SA treatment could be further investigated to assess whether a moderate drought stress may be useful to improve citrus performance by stimulating the SA-dependent response to biotic stress. Copyright © 2017 Elsevier GmbH. All rights reserved.

  1. Imaging the L-type amino acid transporter-1 (LAT1 with Zr-89 immunoPET.

    Directory of Open Access Journals (Sweden)

    Oluwatayo F Ikotun

    Full Text Available The L-type amino acid transporter-1 (LAT1, SLC7A5 is upregulated in a wide range of human cancers, positively correlated with the biological aggressiveness of tumors, and a promising target for both imaging and therapy. Radiolabeled amino acids such as O-(2-[(18F]fluoroethyl-L-tyrosine (FET that are transport substrates for system L amino acid transporters including LAT1 have met limited success for oncologic imaging outside of the brain, and thus new strategies are needed for imaging LAT1 in systemic cancers. Here, we describe the development and biological evaluation of a novel zirconium-89 labeled antibody, [(89Zr]DFO-Ab2, targeting the extracellular domain of LAT1 in a preclinical model of colorectal cancer. This tracer demonstrated specificity for LAT1 in vitro and in vivo with excellent tumor imaging properties in mice with xenograft tumors. PET imaging studies showed high tumor uptake, with optimal tumor-to-non target contrast achieved at 7 days post administration. Biodistribution studies demonstrated tumor uptake of 10.5 ± 1.8 percent injected dose per gram (%ID/g at 7 days with a tumor to muscle ratio of 13 to 1. In contrast, the peak tumor uptake of the radiolabeled amino acid [(18F]FET was 4.4 ± 0.5 %ID/g at 30 min after injection with a tumor to muscle ratio of 1.4 to 1. Blocking studies with unlabeled anti-LAT1 antibody demonstrated a 55% reduction of [(89Zr]DFO-Ab2 accumulation in the tumor at 7 days. These results are the first report of direct PET imaging of LAT1 and demonstrate the potential of immunoPET agents for imaging specific amino acid transporters.

  2. crdi.ca

    International Development Research Centre (IDRC) Digital Library (Canada)

    et des enfants d'Afrique. INITIATIVE CONCERTÉE. Innovation pour la santé des mères et des enfants d'Afrique. Centre de recherches pour le développement international. CP Box 8500 Ottawa ON Canada K1G 3H9. Téléphone : +1 613 236 6163 • Télécopieur : +1 613 657 7749 ismea@crdi.ca | www.crdi.ca/ismea crdi.ca.

  3. INTRACELLULAR Ca2+ HOMEOSTASIS

    Directory of Open Access Journals (Sweden)

    Shahdevi Nandar Kurniawan

    2015-01-01

    Full Text Available Ca2+ signaling functions to regulate many cellular processes. Dynamics of Ca2+ signaling or homeostasis is regulated by the interaction between ON and OFF reactions that control Ca2+ flux in both the plasma membrane and internal organelles such as the endoplasmic reticulum (ER and mitochondria. External stimuli activate the ON reactions, which include Ca2+ into the cytoplasm either through channels in the plasma membrane or from internal storage like in ER. Most of the cells utilize both channels/sources, butthere area few cells using an external or internal source to control certain processes. Most of the Ca2+ entering the cytoplasm adsorbed to the buffer, while a smaller part activate effect or to stimulate cellular processes. Reaction OFF is pumping of cytoplasmic Ca2+ using a combination mechanism of mitochondrial and others. Changes in Ca2+ signal has been detected in various tissues isolated from animals induced into diabetes as well as patients with diabetes. Ca2+ signal interference is also found in sensory neurons of experimental animals with diabetes. Ca2+ signaling is one of the main signaling systems in the cell.

  4. Phenotypic analyses of Arabidopsis T-DNA insertion lines and expression profiling reveal that multiple L-type lectin receptor kinases are involved in plant immunity

    NARCIS (Netherlands)

    Wang, Y.; Bouwmeester, K.; Beseh, P.; Shan, W.; Govers, F.

    2014-01-01

    L-type lectin receptor kinases (LecRKs) are membrane-spanning receptor-like kinases with putative roles in biotic and abiotic stress responses and in plant development. In Arabidopsis, 45 LecRKs were identified but their functions are largely unknown. Here, a systematic functional analysis was

  5. Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart

    NARCIS (Netherlands)

    Schultz, D; Mikala, G; Yatani, A; Engle, D B; Iles, D E; Segers, B; Sinke, R J; Weghuis, D O; Klöckner, U; Wakamori, M

    1993-01-01

    A unique structural variant of the cardiac L-type voltage-dependent calcium channel alpha 1 subunit cDNA was isolated from libraries derived from normal human heart mRNA. The deduced amino acid sequence shows significant homology to other calcium channel alpha 1 subunits. However, differences from

  6. Epigallocatechin-3-gallate increases intracellular [Ca2+] in U87 cells mainly by influx of extracellular Ca2+ and partly by release of intracellular stores.

    Science.gov (United States)

    Kim, Hee Jung; Yum, Keun Sang; Sung, Jong-Ho; Rhie, Duck-Joo; Kim, Myung-Jun; Min, Do Sik; Hahn, Sang June; Kim, Myung-Suk; Jo, Yang-Hyeok; Yoon, Shin Hee

    2004-02-01

    Green tea has been receiving considerable attention as a possible preventive agent against cancer and cardiovascular disease. Epigallocatechin-3-gallate (EGCG) is a major polyphenol component of green tea. Using digital calcium imaging and an assay for [3H]-inositol phosphates, we determined whether EGCG increases intracellular [Ca2+] ([Ca2+]i) in non-excitable human astrocytoma U87 cells. EGCG induced concentration-dependent increases in [Ca2+]i. The EGCG-induced [Ca2+]i increases were reduced to 20.9% of control by removal of extracellular Ca2+. The increases were also inhibited markedly by treatment with the non-specific Ca2+ channel inhibitors cobalt (3 mM) for 3 min and lanthanum (1 mM) for 5 min. The increases were not significantly inhibited by treatment for 10 min with the L-type Ca2+ channel blocker nifedipine (100 nM). Treatment with the inhibitor of endoplasmic reticulum Ca2+-ATPase thapsigargin (1 micro M) also significantly inhibited the EGCG-induced [Ca2+]i increases. Treatment for 15 min with the phospholipase C (PLC) inhibitor neomycin (300 micro M) attenuated the increases significantly, while the tyrosine kinase inhibitor genistein (30 micro M) had no effect. EGCG increased [3H]-inositol phosphates formation via PLC activation. Treatment for 10 min with mefenamic acid (100 micro M) and flufenamic acid (100 micro M), derivatives of diphenylamine-2-carboxylate, blocked the EGCG-induced [Ca2+]i increase in non-treated and thapsigargin-treated cells but indomethacin (100 micro M) did not affect the increases. Collectively, these data suggest that EGCG increases [Ca2+]i in non-excitable U87 cells mainly by eliciting influx of extracellular Ca2+ and partly by mobilizing intracellular Ca2+ stores by PLC activation. The EGCG-induced [Ca2+]i influx is mediated mainly through channels sensitive to diphenylamine-2-carboxylate derivatives.

  7. Urocortin2 prolongs action potential duration and modulates potassium currents in guinea pig myocytes and HEK293 cells.

    Science.gov (United States)

    Yang, Li-Zhen; Zhu, Yi-Chun

    2015-07-05

    We previously reported that activation of corticotropin releasing factor receptor type 2 by urocortin2 up-regulates both L-type Ca(2+) channels and intracellular Ca(2+) concentration in ventricular myocytes and plays an important role in cardiac contractility and arrhythmogenesis. This study goal was to further test the hypothesis that urocortin2 may modulate action potentials as well as rapidly and slowly activating delayed rectifier potassium currents. With whole cell patch-clamp techniques, action potentials and slowly activating delayed rectifier potassium currents were recorded in isolated guinea pig ventricular myocytes, respectively. And rapidly activating delayed rectifier potassium currents were tested in hERG-HEK293 cells. Urocortin2 produced a time- and concentration-dependent prolongation of action potential duration. The EC50 values of action potential duration and action potential duration at 90% of repolarization were 14.73 and 24.3nM respectively. The prolongation of action potential duration of urocortin2 was almost completely or partly abolished by H-89 (protein kinase A inhibitor) or KB-R7943 (Na(+)/Ca(2+) exchange inhibitor) pretreatment respectively. And urocortin2 caused reduction of rapidly activating delayed rectifier potassium currents in hERG-HEK293 cells. In addition, urocortin2 slowed the rate of slowly activating delayed rectifier potassium channel activation, and rightward shifted the threshold of slowly activating delayed rectifier potassium currents to more positive potentials. Urocortin2 prolonged action potential duration via activation of protein kinase A and Na(+)/ Ca(2+) exchange in isolated guinea pig ventricular myocytes in a time- and concentration- dependent manner. In hERG-HEK293 cells, urocortin2 reduced rapidly activating delayed rectifier potassium current density which may contribute to action potential duration prolongation. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Nanomolar bifenthrin alters synchronous Ca2+ oscillations and cortical neuron development independent of sodium channel activity.

    Science.gov (United States)

    Cao, Zhengyu; Cui, Yanjun; Nguyen, Hai M; Jenkins, David Paul; Wulff, Heike; Pessah, Isaac N

    2014-04-01

    Bifenthrin, a relatively stable type I pyrethroid that causes tremors and impairs motor activity in rodents, is broadly used. We investigated whether nanomolar bifenthrin alters synchronous Ca(2+) oscillations (SCOs) necessary for activity-dependent dendritic development. Primary mouse cortical neurons were cultured 8 or 9 days in vitro (DIV), loaded with the Ca(2+) indicator Fluo-4, and imaged using a Fluorescence Imaging Plate Reader Tetra. Acute exposure to bifenthrin rapidly increased the frequency of SCOs by 2.7-fold (EC50 = 58 nM) and decreased SCO amplitude by 36%. Changes in SCO properties were independent of modifications in voltage-gated sodium channels since 100 nM bifenthrin had no effect on the whole-cell Na(+) current, nor did it influence neuronal resting membrane potential. The L-type Ca(2+) channel blocker nifedipine failed to ameliorate bifenthrin-triggered SCO activity. By contrast, the metabotropic glutamate receptor (mGluR)5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine] normalized bifenthrin-triggered increase in SCO frequency without altering baseline SCO activity, indicating that bifenthrin amplifies mGluR5 signaling independent of Na(+) channel modification. Competitive [AP-5; (-)-2-amino-5-phosphonopentanoic acid] and noncompetitive (dizocilpine, or MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]) N-methyl-d-aspartate antagonists partially decreased both basal and bifenthrin-triggered SCO frequency increase. Bifenthrin-modified SCO rapidly enhanced the phosphorylation of cAMP response element-binding protein (CREB). Subacute (48 hours) exposure to bifenthrin commencing 2 DIV-enhanced neurite outgrowth and persistently increased SCO frequency and reduced SCO amplitude. Bifenthrin-stimulated neurite outgrowth and CREB phosphorylation were dependent on mGluR5 activity since MPEP normalized both responses. Collectively these data identify a new mechanism by which bifenthrin potently alters Ca(2

  9. Isosteviol prevents the prolongation of action potential in hypertrophied cardiomyoctyes by regulating transient outward potassium and L-type calcium channels.

    Science.gov (United States)

    Fan, Zhuo; Lv, Nanying; Luo, Xiao; Tan, Wen

    2017-10-01

    Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of I to is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for I to and I CaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of I to and I CaL are correlated to the alterations of the mRNA transcription level. Copyright © 2017. Published by Elsevier B.V.

  10. BiCaSrCuO superconductors

    International Nuclear Information System (INIS)

    Polvi, V.M.; Niemi, K.J.

    1989-01-01

    BiCaSrCuO and BiPbCaSrCuO powders have been synthesized. Different research methods (SEM,EDS,XRF,SRD,DTA) have been used to characterize the bulk specimen and wires. Resistance and current density measured as a function of temperature are reported. The ceramic products contained several phases. Lead containing specimen gave the best results and the synthesis was easily reproducible

  11. Role of action potential configuration and the contribution of C²⁺a and K⁺ currents to isoprenaline-induced changes in canine ventricular cells.

    Science.gov (United States)

    Szentandrássy, N; Farkas, V; Bárándi, L; Hegyi, B; Ruzsnavszky, F; Horváth, B; Bányász, T; Magyar, J; Márton, I; Nánási, P P

    2012-10-01

    Although isoprenaline (ISO) is known to activate several ion currents in mammalian myocardium, little is known about the role of action potential morphology in the ISO-induced changes in ion currents. Therefore, the effects of ISO on action potential configuration, L-type Ca²⁺ current (I(Ca)), slow delayed rectifier K⁺ current (I(Ks)) and fast delayed rectifier K⁺ current (I(Kr)) were studied and compared in a frequency-dependent manner using canine isolated ventricular myocytes from various transmural locations. Action potentials were recorded with conventional sharp microelectrodes; ion currents were measured using conventional and action potential voltage clamp techniques. In myocytes displaying a spike-and-dome action potential configuration (epicardial and midmyocardial cells), ISO caused reversible shortening of action potentials accompanied by elevation of the plateau. ISO-induced action potential shortening was absent in endocardial cells and in myocytes pretreated with 4-aminopyridine. Application of the I(Kr) blocker E-4031 failed to modify the ISO effect, while action potentials were lengthened by ISO in the presence of the I(Ks) blocker HMR-1556. Both action potential shortening and elevation of the plateau were prevented by pretreatment with the I(Ca) blocker nisoldipine. Action potential voltage clamp experiments revealed a prominent slowly inactivating I(Ca) followed by a rise in I(Ks) , both currents increased with increasing the cycle length. The effect of ISO in canine ventricular cells depends critically on action potential configuration, and the ISO-induced activation of I(Ks) - but not I(Kr) - may be responsible for the observed shortening of action potentials. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

  12. Ca isotopes in refractory inclusions

    International Nuclear Information System (INIS)

    Niederer, F.R.; Papanastassiou, D.A.

    1984-01-01

    We report measurements of the absolute isotope abundance of Ca in Ca-Al-rich inclusions from the Allende and Leoville meteorites. Improved high precision measurements are reported also for 46 Ca. We find that nonlinear isotope effects in Ca are extremely rare in these inclusions. The absence of nonlinear effects in Ca, except for the effects in FUN inclusions, is in sharp contrast to the endemic effects in Ti. One fine-grained inclusion shows an excess of 46 Ca of (7 +- 1) per mille, which is consistent with addition of only 46 Ca or of an exotic (*) component with 46 Ca* approx. 48 Ca*. FUN inclusion EK-1-4-1 shows a small 46 Ca excess of (3.3 +- 1.0) per mille; this confirms that the exotic Ca components in EK-1-4-1 were even more deficient in 46 Ca relative to 48 Ca than is the case for normal Ca. The Ca in the Ca-Al-rich inclusions shows mass dependent isotope fractionation effects which have a range from -3.8 to +6.7 per mille per mass unit difference. This range is a factor of 20 wider than the range previously established for bulk meteorites and for terrestrial and lunar samples. Ca and Mg isotope fractionation effects in the Ca-Al-rich inclusions are common and attributed to kinetic isotope effects. (author)

  13. SWFSC/MMTD/CCE: Oregon, California, and Washington Line-transect Experiment (ORCAWALE) 1996, 2001, 2008 and CA Current Cetacean and Ecosystem Assessment Survey (CalCurCEAS) 2014

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The California Current Cetacean and Ecosystem Assessment Survey (CalCurCEAS) is a marine mammal assessment survey of the U.S. West Coast waters. Similar research in...

  14. Large-conductance Ca2+-activated K+ channel β1-subunit knockout mice are not hypertensive

    Science.gov (United States)

    Garver, Hannah; Galligan, James J.; Fink, Gregory D.

    2011-01-01

    Large-conductance Ca2+-activated K+ (BK) channels are composed of pore-forming α-subunits and accessory β1-subunits that modulate Ca2+ sensitivity. BK channels regulate arterial myogenic tone and renal Na+ clearance/K+ reabsorption. Previous studies using indirect or short-term blood pressure measurements found that BK channel β1-subunit knockout (BK β1-KO) mice were hypertensive. We evaluated 24-h mean arterial pressure (MAP) and heart rate in BK β1-KO mice using radiotelemetry. BK β1-KO mice did not have a higher 24-h average MAP when compared with wild-type (WT) mice, although MAP was ∼10 mmHg higher at night. The dose-dependent peak declines in MAP by nifedipine were only slightly larger in BK β1-KO mice. In BK β1-KO mice, giving 1% NaCl to mice to drink for 7 days caused a transient (5 days) elevation of MAP (∼5 mmHg); MAP returned to pre-saline levels by day 6. BK β1-KO mesenteric arteries in vitro demonstrated diminished contractile responses to paxilline, increased reactivity to Bay K 8644 and norepinephrine (NE), and maintained relaxation to isoproterenol. Paxilline and Bay K 8644 did not constrict WT or BK β1-KO mesenteric veins (MV). BK β1-subunits are not expressed in MV. The results indicate that BK β1-KO mice are not hypertensive on normal or high-salt intake. BK channel deficiency increases arterial reactivity to NE and L-type Ca2+ channel function in vitro, but the L-type Ca2+ channel modulation of MAP is not altered in BK β1-KO mice. BK and L-type Ca2+ channels do not modulate murine venous tone. It appears that selective loss of BK channel function in arteries only is not sufficient to cause sustained hypertension. PMID:21131476

  15. Ca(2+) influx and neurotransmitter release at ribbon synapses.

    Science.gov (United States)

    Cho, Soyoun; von Gersdorff, Henrique

    2012-01-01

    Ca(2+) influx through voltage-gated Ca(2+) channels triggers the release of neurotransmitters at presynaptic terminals. Some sensory receptor cells in the peripheral auditory and visual systems have specialized synapses that express an electron-dense organelle called a synaptic ribbon. Like conventional synapses, ribbon synapses exhibit SNARE-mediated exocytosis, clathrin-mediated endocytosis, and short-term plasticity. However, unlike non-ribbon synapses, voltage-gated L-type Ca(2+) channel opening at ribbon synapses triggers a form of multiquantal release that can be highly synchronous. Furthermore, ribbon synapses appear to be specialized for fast and high throughput exocytosis controlled by graded membrane potential changes. Here we will discuss some of the basic aspects of synaptic transmission at different types of ribbon synapses, and we will emphasize recent evidence that auditory and retinal ribbon synapses have marked differences. This will lead us to suggest that ribbon synapses are specialized for particular operating ranges and frequencies of stimulation. We propose that different types of ribbon synapses transfer diverse rates of sensory information by expressing a particular repertoire of critical components, and by placing them at precise and strategic locations, so that a continuous supply of primed vesicles and Ca(2+) influx leads to fast, accurate, and ongoing exocytosis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Short-time relaxation of the critical current in oriented grained YBa2Cu3Ox and granular (Bi,Pb)2 Sr2Ca2Cu3Ox

    International Nuclear Information System (INIS)

    Kuepfer, H.; Keller, C.; Meier-Hirmer, R.; Wiech, U.; Salama, K.; Selvamanickam, V.; Green, S.M.; Luo, H.L.; Politis, C.

    1990-01-01

    The time-dependent behavior of the critical current density j c is investigated by ac inductive measurements. The variation of db/dt of the ac field between 0.1 and 3 T/s reveals a short-time relaxation in the millisecond regime before j c exhibits the familiar logarithmic decay. At fields above the irreversibility line only this short-time relaxation is observed. Our experimental time scale allows us to obtain the unrelaxed critical current density j c0 at certain fields and temperatures

  17. The Role of Ca2+ and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO2 Chemosensitivity Response of Rats.

    Science.gov (United States)

    Imber, Ann N; Patrone, Luis G A; Li, Ke-Yong; Gargaglioni, Luciane H; Putnam, Robert W

    2018-06-15

    The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K + channels or activation of Na + and Ca +2 channels to depolarize CO 2 -sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. Hypercapnic acidosis activates L-type Ca 2+ channels and large conductance Ca-activated K + (BK) channels, which function as a "brake" on the chemosensitive response of LC neurons. Our findings indicate that both Ca 2+ and BK currents develop over the first 2 weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. No apparent role for T-type Ca2+ channels in renal autoregulation

    DEFF Research Database (Denmark)

    Frandsen, Rasmus Hassing; Salomonsson, Max; Hansen, Pernille B. Lærkegaard

    2016-01-01

    -type and CaV3.1 knockout mice were assessed. Autoregulation of renal blood flow was examined during acute increases in RPP in normo- and hypertensive rats under pharmacological blockade of T- and L-type calcium channels using mibefradil (0.1 μM) and nifedipine (1 μM). In contrast to the results from previous......Renal autoregulation protects glomerular capillaries against increases in renal perfusion pressure (RPP). In the mesentery, both L- and T-type calcium channels are involved in autoregulation. L-type calcium channels participate in renal autoregulation, but the role of T-type channels is not fully...... pharmacological studies, genetic deletion of T-type channels CaV3.1 did not affect renal autoregulation. Pharmacological blockade of T-type channels using concentrations of mibefradil which specifically blocks T-type channels also had no effect in wild-type or knockout mice. Blockade of L-type channels...

  19. Development and function of the voltage-gated sodium current in immature mammalian cochlear inner hair cells.

    Directory of Open Access Journals (Sweden)

    Tobias Eckrich

    Full Text Available Inner hair cells (IHCs, the primary sensory receptors of the mammalian cochlea, fire spontaneous Ca(2+ action potentials before the onset of hearing. Although this firing activity is mainly sustained by a depolarizing L-type (Ca(V1.3 Ca(2+ current (I(Ca, IHCs also transiently express a large Na(+ current (I(Na. We aimed to investigate the specific contribution of I(Na to the action potentials, the nature of the channels carrying the current and whether the biophysical properties of I(Na differ between low- and high-frequency IHCs. We show that I(Na is highly temperature-dependent and activates at around -60 mV, close to the action potential threshold. Its size was larger in apical than in basal IHCs and between 5% and 20% should be available at around the resting membrane potential (-55 mV/-60 mV. However, in vivo the availability of I(Na could potentially increase to >60% during inhibitory postsynaptic potential activity, which transiently hyperpolarize IHCs down to as far as -70 mV. When IHCs were held at -60 mV and I(Na elicited using a simulated action potential as a voltage command, we found that I(Na contributed to the subthreshold depolarization and upstroke of an action potential. We also found that I(Na is likely to be carried by the TTX-sensitive channel subunits Na(V1.1 and Na(V1.6 in both apical and basal IHCs. The results provide insight into how the biophysical properties of I(Na in mammalian cochlear IHCs could contribute to the spontaneous physiological activity during cochlear maturation in vivo.

  20. Comparison of phosgene, chlorine, and hydrogen chloride as reagents for converting molten CaO.CaCl2 to CaCl2

    International Nuclear Information System (INIS)

    Fife, K.W.

    1985-01-01

    One method at Los Alamos for preparing impure plutonium metal from the impure oxide is by batch reduction with calcium metal at 850 0 C in a CaCl 2 solvent. The solvent salt from this reduction is currently discarded as low-level radioactivity waste only because it is saturated with the CaO byproduct. We have demonstrated a pyrochemical technique for converting the CaO to CaCl 2 thereby incorporating solvent recycling into the batch reduction process. We will discuss the effectiveness of HCl, Cl 2 , and COCl 2 as chlorinating agents and recycling actual spent process solvent salts. 6 refs., 8 figs

  1. Numerical model of Ca(OH)

    NARCIS (Netherlands)

    Koster, T.; Peelen, W.; Larbi, J.; Rooij, M. de; Polder, R.

    2010-01-01

    A mathematical model is being developed to describe a repair method in concrete, called cathodic protection (CP). The model is in principle also useful to describe electrodeposition in concrete, e.g. the process of re-precipitation of Ca(OH)2 invoked by an electrical current. In CP, the

  2. Model study of ATP and ADP buffering, transport of Ca(2+) and Mg(2+), and regulation of ion pumps in ventricular myocyte

    Science.gov (United States)

    Michailova, A.; McCulloch, A.

    2001-01-01

    We extended the model of the ventricular myocyte by Winslow et al. (Circ. Res 1999, 84:571-586) by incorporating equations for Ca(2+) and Mg(2+) buffering and transport by ATP and ADP and equations for MgATP regulation of ion transporters (Na(+)-K(+) pump, sarcolemmal and sarcoplasmic Ca(2+) pumps). The results indicate that, under normal conditions, Ca(2+) binding by low-affinity ATP and diffusion of CaATP may affect the amplitude and time course of intracellular Ca(2+) signals. The model also suggests that a fall in ATP/ADP ratio significantly reduces sarcoplasmic Ca(2+) content, increases diastolic Ca(2+), lowers systolic Ca(2+), increases Ca(2+) influx through L-type channels, and decreases the efficiency of the Na(+)/Ca(2+) exchanger in extruding Ca(2+) during periodic voltage-clamp stimulation. The analysis suggests that the most important reason for these changes during metabolic inhibition is the down-regulation of the sarcoplasmic Ca(2+)-ATPase pump by reduced diastolic MgATP levels. High Ca(2+) concentrations developed near the membrane might have a greater influence on Mg(2+), ATP, and ADP concentrations than that of the lower Ca(2+) concentrations in the bulk myoplasm. The model predictions are in general agreement with experimental observations measured under normal and pathological conditions.

  3. Simultaneous mapping of membrane voltage and calcium in zebrafish heart in vivo reveals chamber-specific developmental transitions in ionic currents

    Directory of Open Access Journals (Sweden)

    Jennifer H Hou

    2014-09-01

    Full Text Available The cardiac action potential (AP and the consequent cytosolic Ca2+ transient are key indicators of cardiac function. Natural developmental processes, as well as many drugs and pathologies change the waveform, propagation, or variability (between cells or over time of these parameters. Here we apply a genetically encoded dual-function calcium and voltage reporter (CaViar to study the development of the zebrafish heart in vivo between 1.5 and 4 days post fertilization (dpf. We developed a high-sensitivity spinning disk confocal microscope and associated software for simultaneous three-dimensional optical mapping of voltage and calcium. We produced a transgenic zebrafish line expressing CaViar under control of the heart-specific cmlc2 promoter, and applied ion channel blockers at a series of developmental stages to map the maturation of the action potential in vivo. Early in development, the AP initiated via a calcium current through L-type calcium channels. Between 90 – 102 hours post fertilization (hpf, the ventricular AP switched to a sodium-driven upswing, while the atrial AP remained calcium driven. In the adult zebrafish heart, a sodium current drives the AP in both the atrium and ventricle. Simultaneous voltage and calcium imaging with genetically encoded reporters provides a new approach for monitoring cardiac development, and the effects of drugs on cardiac function.

  4. Analysis of stress- strain distribution of dowel and glue line in L-type furniture joint by means of finite element method

    Directory of Open Access Journals (Sweden)

    mossayeb dalvand

    2017-08-01

    Full Text Available In this study 3D stress-strain distribution of dowel and glue line on L-type joints made of plywood doweled was investigated. Members of joints made of 11-ply hardwood plywood (Hornbeam, Beech and Alder that were 19 mm in thickness. In this study effect of beech dowels in three levels diameters (6, 8 and 10 mm and penetration of depth (9, 13 and 17 mm on bending moment capacity of L-type joints under compression loading was investigated as experimental test, then stress-strain distribution of wood dowel and glue line in specimens were simulated by means of ANSYS 15 software with finite element method (FEM.Results have shown that bending moment resistance increased with increasing dowel diameter from 6 to 8 mm, but downward trend was observed with increasing 8 to 10 mm in dowel diameter. Bending moment resistance increased with increasing penetration depth. Also, result obtained of simulation by means of ANSYS software have shown that stress-strain in dowel and glue line increased with increasing diameter of dowel and Increasing stress in joints made of diameter dowel 10 mm due to fracture in joints and decrease in resistance once. According to results obtained of model analysis, the ultimate stress of dowel and glue line occurred in the area that joints were contacted.

  5. Influence of the constant load sintering on the improvement of the transport critical current in Ag-(Bi,Pb)[sub 2]Sr[sub 2]Ca[sub 2]Cu[sub 3]O[sub x] tape form conductor

    Energy Technology Data Exchange (ETDEWEB)

    Jackiewicz, J [IRC in Superconductivity, Univ. of Cambridge (United Kingdom); Glowacki, B A [IRC in Superconductivity, Univ. of Cambridge (United Kingdom) Dept. of Materials Science and Metallurgy, Univ. of Cambridge (United Kingdom)

    1993-05-10

    The effects of the short time, low value constant load pressing process of cold rolled silver clad wires conducted at temperatures close to the partial melting point of the ceramic core, from 800 C to 866 C on the microstructure and critical current anisotropy have been studied in detail. The strong influence of the constant load sintering at up to 2 MPa for 1 hour on the improvement of the alignment of the ceramic core in the tape form conductors was confirmred by microstructure investigations and also by the I[sub c] versus [mu][sub 0]H measurements. The magnetic field dependence of the transport critical current, for [mu][sub 0]H parallel to the surface of the tape and also for [mu][sub 0]H perpendicular to the surface of the tape, is very significantly reduced in the tapes sintered under constant load. The analysis of the mechanical creep of silver and ceramic core versus temperature allowed us to optimise the densification conditions of the investigated single core Ag-''2223'' tape form conductor for the load used. (orig.)

  6. caGrid 1.0: a Grid enterprise architecture for cancer research.

    Science.gov (United States)

    Oster, Scott; Langella, Stephen; Hastings, Shannon; Ervin, David; Madduri, Ravi; Kurc, Tahsin; Siebenlist, Frank; Covitz, Peter; Shanbhag, Krishnakant; Foster, Ian; Saltz, Joel

    2007-10-11

    caGrid is the core Grid architecture of the NCI-sponsored cancer Biomedical Informatics Grid (caBIG) program. The current release, caGrid version 1.0, is developed as the production Grid software infrastructure of caBIG. Based on feedback from adopters of the previous version (caGrid 0.5), it has been significantly enhanced with new features and improvements to existing components. This paper presents an overview of caGrid 1.0, its main components, and enhancements over caGrid 0.5.

  7. CaMKII determines mitochondrial stress responses in heart

    Science.gov (United States)

    Joiner, Mei-ling A.; Koval, Olha M.; Jingdong, Li; He, B. Julie; Allamargot, Chantal; Gao, Zhan; Luczak, Elizabeth D.; Hall, Duane D.; Fink, Brian D.; Chen, Biyi; Yang, Jinying; Moore, Steven A.; Scholz, Thomas D.; Strack, Stefan; Mohler, Peter J.; Sivitz, William I.; Song, Long-Sheng; Anderson, Mark E.

    2012-01-01

    Myocardial cell death is initiated by excessive mitochondrial Ca2+ entry, causing Ca2+ overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (ΔΨm)1,2. However, the signaling pathways that control mitochondrial Ca2+ entry through the inner membrane mitochondrial Ca2+ uniporter (MCU)3–5 are not known. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is activated in ischemia reperfusion (I/R), myocardial infarction (MI) and neurohumoral injury, common causes of myocardial death and heart failure, suggesting CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (IMCU). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A (CsA), an mPTP antagonist with clinical efficacy in I/R injury6, equivalently prevent mPTP opening, ΔΨm deterioration and diminish mitochondrial disruption and programmed cell death in response to I/R injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition are resistant to I/R injury, MI and neurohumoral injury, suggesting pathological actions of CaMKII are substantially mediated by increasing IMCU. Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca2+ entry and suggest mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure dysfunction in response to common experimental forms of pathophysiological stress. PMID:23051746

  8. Crosstalk between mitochondrial and sarcoplasmic reticulum Ca2+ cycling modulates cardiac pacemaker cell automaticity.

    Directory of Open Access Journals (Sweden)

    Yael Yaniv

    Full Text Available Mitochondria dynamically buffer cytosolic Ca(2+ in cardiac ventricular cells and this affects the Ca(2+ load of the sarcoplasmic reticulum (SR. In sinoatrial-node cells (SANC the SR generates periodic local, subsarcolemmal Ca(2+ releases (LCRs that depend upon the SR load and are involved in SANC automaticity: LCRs activate an inward Na(+-Ca(2+ exchange current to accelerate the diastolic depolarization, prompting the ensemble of surface membrane ion channels to generate the next action potential (AP.To determine if mitochondrial Ca(2+ (Ca(2+ (m, cytosolic Ca(2+ (Ca(2+ (c-SR-Ca(2+ crosstalk occurs in single rabbit SANC, and how this may relate to SANC normal automaticity.Inhibition of mitochondrial Ca(2+ influx into (Ru360 or Ca(2+ efflux from (CGP-37157 decreased [Ca(2+](m to 80 ± 8% control or increased [Ca(2+](m to 119 ± 7% control, respectively. Concurrent with inhibition of mitochondrial Ca(2+ influx or efflux, the SR Ca(2+ load, and LCR size, duration, amplitude and period (imaged via confocal linescan significantly increased or decreased, respectively. Changes in total ensemble LCR Ca(2+ signal were highly correlated with the change in the SR Ca(2+ load (r(2 = 0.97. Changes in the spontaneous AP cycle length (Ru360, 111 ± 1% control; CGP-37157, 89 ± 2% control in response to changes in [Ca(2+](m were predicted by concurrent changes in LCR period (r(2 = 0.84.A change in SANC Ca(2+ (m flux translates into a change in the AP firing rate by effecting changes in Ca(2+ (c and SR Ca(2+ loading, which affects the characteristics of spontaneous SR Ca(2+ release.

  9. Is there a role for T-type Ca2+ channels in regulation of vasomotor tone in mesenteric arterioles?

    DEFF Research Database (Denmark)

    Jensen, Lars Jørn; Holstein-Rathlou, Niels-Henrik

    2009-01-01

    The largest peripheral blood pressure drop occurs in terminal arterioles (microm lumen diameter). L-type voltage-dependent Ca2+ channels (VDCCs) are considered the primary pathway for Ca2+ influx during physiologic activation of vascular smooth muscle cells (VSMC). Recent evidence suggests...... was predominantly expressed in endothelial cells. Voltage-dependent Ca2+ entry was inhibited by the new specific T-type blockers R(-)-efonidipine and NNC 55-0396. The effect of NNC 55-0396 persisted in depolarized arterioles, suggesting an unusually high activation threshold of mesenteric T-type channels. T...... that T-type VDCCs are expressed in renal afferent and efferent arterioles, mesenteric arterioles, and skeletal muscle arterioles. T-type channels are small-conductance, low voltage-activated, fast-inactivating channels. Thus, their role in supplying Ca2+ for contraction of VSMC has been disputed. However...

  10. Channeling Vision: CaV1.4—A Critical Link in Retinal Signal Transmission

    Directory of Open Access Journals (Sweden)

    D. M. Waldner

    2018-01-01

    Full Text Available Voltage-gated calcium channels (VGCC are key to many biological functions. Entry of Ca2+ into cells is essential for initiating or modulating important processes such as secretion, cell motility, and gene transcription. In the retina and other neural tissues, one of the major roles of Ca2+-entry is to stimulate or regulate exocytosis of synaptic vesicles, without which synaptic transmission is impaired. This review will address the special properties of one L-type VGCC, CaV1.4, with particular emphasis on its role in transmission of visual signals from rod and cone photoreceptors (hereafter called “photoreceptors,” to the exclusion of intrinsically photoreceptive retinal ganglion cells to the second-order retinal neurons, and the pathological effects of mutations in the CACNA1F gene which codes for the pore-forming α1F subunit of CaV1.4.

  11. Solubility of calcium in CaO-CaCl2

    International Nuclear Information System (INIS)

    Perry, G.S.; Shaw, S.J.

    1991-06-01

    The Direct Oxide Reduction (DOR) process is well established as a process to produce plutonium metal from plutonium dioxide by reaction with calcium. Calcium chloride is added to dissolve the calcium oxide produced, allowing the metal to coalesce into a button. Since calcium metal melts at 840 0 C and DOR can take place successfully below this temperature, it is likely calcium dissolved in calcium chloride reacts with the plutonium dioxide. The solubility of calcium in calcium chloride is reasonably well established but the effect of the CaO formed during the DOR process on the solubility of calcium has not been previously determined. For this reason the solubility of calcium in CaCl 2 -CaO melts at 800 o C has been studied. The solubility decreases from 2.7 mol % in CaCl 2 to 0.4 mol % in 9 mol % CaO-CaCl 2 . (author)

  12. Astrocyte Ca2+ signalling: an unexpected complexity

    OpenAIRE

    Volterra, Andrea; Liaudet, Nicolas; Savtchouk, Iaroslav

    2014-01-01

    Astrocyte Ca(2+) signalling has been proposed to link neuronal information in different spatial-temporal dimensions to achieve a higher level of brain integration. However, some discrepancies in the results of recent studies challenge this view and highlight key insufficiencies in our current understanding. In parallel, new experimental approaches that enable the study of astrocyte physiology at higher spatial-temporal resolution in intact brain preparations are beginning to reveal an unexpec...

  13. A new functional role for mechanistic/mammalian target of rapamycin complex 1 (mTORC1 in the circadian regulation of L-type voltage-gated calcium channels in avian cone photoreceptors.

    Directory of Open Access Journals (Sweden)

    Cathy Chia-Yu Huang

    Full Text Available In the retina, the L-type voltage-gated calcium channels (L-VGCCs are responsible for neurotransmitter release from photoreceptors and are under circadian regulation. Both the current densities and protein expression of L-VGCCs are significantly higher at night than during the day. However, the underlying mechanisms of circadian regulation of L-VGCCs in the retina are not completely understood. In this study, we demonstrated that the mechanistic/mammalian target of rapamycin complex (mTORC signaling pathway participated in the circadian phase-dependent modulation of L-VGCCs. The activities of the mTOR cascade, from mTORC1 to its downstream targets, displayed circadian oscillations throughout the course of a day. Disruption of mTORC1 signaling dampened the L-VGCC current densities, as well as the protein expression of L-VGCCs at night. The decrease of L-VGCCs at night by mTORC1 inhibition was in part due to a reduction of L-VGCCα1 subunit translocation from the cytosol to the plasma membrane. Finally, we showed that mTORC1 was downstream of the phosphatidylionositol 3 kinase-protein kinase B (PI3K-AKT signaling pathway. Taken together, mTORC1 signaling played a role in the circadian regulation of L-VGCCs, in part through regulation of ion channel trafficking and translocation, which brings to light a new functional role for mTORC1: the modulation of ion channel activities.

  14. Semantic web data warehousing for caGrid.

    Science.gov (United States)

    McCusker, James P; Phillips, Joshua A; González Beltrán, Alejandra; Finkelstein, Anthony; Krauthammer, Michael

    2009-10-01

    The National Cancer Institute (NCI) is developing caGrid as a means for sharing cancer-related data and services. As more data sets become available on caGrid, we need effective ways of accessing and integrating this information. Although the data models exposed on caGrid are semantically well annotated, it is currently up to the caGrid client to infer relationships between the different models and their classes. In this paper, we present a Semantic Web-based data warehouse (Corvus) for creating relationships among caGrid models. This is accomplished through the transformation of semantically-annotated caBIG Unified Modeling Language (UML) information models into Web Ontology Language (OWL) ontologies that preserve those semantics. We demonstrate the validity of the approach by Semantic Extraction, Transformation and Loading (SETL) of data from two caGrid data sources, caTissue and caArray, as well as alignment and query of those sources in Corvus. We argue that semantic integration is necessary for integration of data from distributed web services and that Corvus is a useful way of accomplishing this. Our approach is generalizable and of broad utility to researchers facing similar integration challenges.

  15. Effects of luminal flow and nucleotides on [Ca(2+)](i) in rabbit cortical collecting duct.

    Science.gov (United States)

    Woda, Craig B; Leite, Maurilo; Rohatgi, Rajeev; Satlin, Lisa M

    2002-09-01

    Nucleotide binding to purinergic P2 receptors contributes to the regulation of a variety of physiological functions in renal epithelial cells. Whereas P2 receptors have been functionally identified at the basolateral membrane of the cortical collecting duct (CCD), a final regulatory site of urinary Na(+), K(+), and acid-base excretion, controversy exists as to whether apical purinoceptors exist in this segment. Nor has the distribution of receptor subtypes present on the unique cell populations that constitute Ca(2+) the CCD been established. To examine this, we measured nucleotide-induced changes in intracellular Ca(2+) concentration ([Ca(2+)](i)) in fura 2-loaded rabbit CCDs microperfused in vitro. Resting [Ca(2+)](i) did not differ between principal and intercalated cells, averaging approximately 120 nM. An acute increase in tubular fluid flow rate, associated with a 20% increase in tubular diameter, led to increases in [Ca(2+)](i) in both cell types. Luminal perfusion of 100 microM UTP or ATP-gamma-S, in the absence of change in flow rate, caused a rapid and transient approximately fourfold increase in [Ca(2+)](i) in both cell types (P < 0.05). Luminal suramin, a nonspecific P2 receptor antagonist, blocked the nucleotide- but not flow-induced [Ca(2+)](i) transients. Luminal perfusion with a P2X (alpha,beta-methylene-ATP), P2X(7) (benzoyl-benzoyl-ATP), P2Y(1) (2-methylthio-ATP), or P2Y(4)/P2Y(6) (UDP) receptor agonist had no effect on [Ca(2+)](i). The nucleotide-induced [Ca(2+)](i) transients were inhibited by the inositol-1,4,5-triphosphate receptor blocker 2-aminoethoxydiphenyl borate, thapsigargin, which depletes internal Ca(2+) stores, luminal perfusion with a Ca(2+)-free perfusate, or the L-type Ca(2+) channel blocker nifedipine. These results suggest that luminal nucleotides activate apical P2Y(2) receptors in the CCD via pathways that require both internal Ca(2+) mobilization and extracellular Ca(2+) entry. The flow-induced rise in [Ca(2+)](i) is

  16. A close association of RyRs with highly dense clusters of Ca2+-activated Cl- channels underlies the activation of STICs by Ca2+ sparks in mouse airway smooth muscle.

    Science.gov (United States)

    Bao, Rongfeng; Lifshitz, Lawrence M; Tuft, Richard A; Bellvé, Karl; Fogarty, Kevin E; ZhuGe, Ronghua

    2008-07-01

    Ca(2+) sparks are highly localized, transient releases of Ca(2+) from sarcoplasmic reticulum through ryanodine receptors (RyRs). In smooth muscle, Ca(2+) sparks trigger spontaneous transient outward currents (STOCs) by opening nearby clusters of large-conductance Ca(2+)-activated K(+) channels, and also gate Ca(2+)-activated Cl(-) (Cl((Ca))) channels to induce spontaneous transient inward currents (STICs). While the molecular mechanisms underlying the activation of STOCs by Ca(2+) sparks is well understood, little information is available on how Ca(2+) sparks activate STICs. In the present study, we investigated the spatial organization of RyRs and Cl((Ca)) channels in spark sites in airway myocytes from mouse. Ca(2+) sparks and STICs were simultaneously recorded, respectively, with high-speed, widefield digital microscopy and whole-cell patch-clamp. An image-based approach was applied to measure the Ca(2+) current underlying a Ca(2+) spark (I(Ca(spark))), with an appropriate correction for endogenous fixed Ca(2+) buffer, which was characterized by flash photolysis of NPEGTA. We found that I(Ca(spark)) rises to a peak in 9 ms and decays with a single exponential with a time constant of 12 ms, suggesting that Ca(2+) sparks result from the nonsimultaneous opening and closure of multiple RyRs. The onset of the STIC lags the onset of the I(Ca(spark)) by less than 3 ms, and its rising phase matches the duration of the I(Ca(spark)). We further determined that Cl((Ca)) channels on average are exposed to a [Ca(2+)] of 2.4 microM or greater during Ca(2+) sparks. The area of the plasma membrane reaching this level is <600 nm in radius, as revealed by the spatiotemporal profile of [Ca(2+)] produced by a reaction-diffusion simulation with measured I(Ca(spark)). Finally we estimated that the number of Cl((Ca)) channels localized in Ca(2+) spark sites could account for all the Cl((Ca)) channels in the entire cell. Taken together these results lead us to propose a model in which

  17. Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

    Science.gov (United States)

    Kistamás, Kornél; Szentandrássy, Norbert; Hegyi, Bence; Ruzsnavszky, Ferenc; Váczi, Krisztina; Bárándi, László; Horváth, Balázs; Szebeni, Andrea; Magyar, János; Bányász, Tamás; Kecskeméti, Valéria; Nánási, Péter P

    2013-06-15

    Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM. Action potentials were shortened by pioglitazone at concentrations ≥10 μM, which effect was accompanied with significant reduction of beat-to-beat variability of action potential duration. Several transmembrane ion currents, including the transient outward K(+) current (Ito), the L-type Ca(2+) current (ICa), the rapid and slow components of the delayed rectifier K(+) current (IKr and IKs, respectively), and the inward rectifier K(+) current (IK1) were inhibited by pioglitazone under conventional voltage clamp conditions. Ito was blocked significantly at concentrations ≥3 μM, ICa, IKr, IKs at concentrations ≥10 μM, while IK1 at concentrations ≥30 μM. Suppression of Ito, ICa, IKr, and IK1 has been confirmed also under action potential voltage clamp conditions. ATP-sensitive K(+) current, when activated by lemakalim, was effectively blocked by pioglitazone. Accordingly, action potentials were prolonged by 10 μM pioglitazone when the drug was applied in the presence of lemakalim. All these effects developed rapidly and were readily reversible upon washout. In conclusion, pioglitazone seems to be a harmless agent at usual therapeutic concentrations. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Gene of the month: PIK3CA.

    Science.gov (United States)

    Lai, K; Killingsworth, M C; Lee, C S

    2015-04-01

    PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K) which through its role in the PI3K/Akt pathway is important for the regulation of important cellular functions such as proliferation, metabolism and protein synthesis, angiogenesis and apoptosis. Mutations in PIK3CA are known to be involved in a wide range of human cancers and mutant PIK3CA is thought to act as an oncogene. The specific PIK3CA inhibitor, NVP-BYL719, has displayed promising results in cancer therapy and is currently under clinical trials. Furthermore, PI3K regulates autophagy, a cellular process that recycles proteins and organelles through lysosomal degradation and has recently been recognised as an attractive therapeutic target due to its pro- and anti-cancer properties. Several studies have attempted to investigate the effects of combining the inhibition of both PI3K and autophagy in cancer therapy, and an in vivo model has demonstrated that the combined use of a concomitant PI3K and autophagy inhibitor induced apoptosis in glioma cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  19. Accessing the nuclear symmetry energy in Ca+Ca collisions

    Directory of Open Access Journals (Sweden)

    Chbihi A.

    2012-07-01

    Full Text Available The status of the analysis of the INDRA-VAMOS experiement performed at GANIL, using the reactions 40,48Ca+40,48Ca reactions at 35AMeV, are presented. Isotopic distributions of fragments produced in multifragmentation events provide information on the importance of the surface term contribution in the symmetry energy by comparison to AMD predictions.

  20. Serum tumor marker CA 125 for monitoring ovarian cancer during follow-up

    DEFF Research Database (Denmark)

    Tuxen, Malgorzata K.; Sölétormos, G; Dombernowsky, P

    2002-01-01

    CA 125 is currently widely applied in the management of patients with ovarian cancer. However, a change in results of CA 125, which should be considered significant, has not been defined. The aim of this study was to investigate the ability of CA 125 to signal progressive ovarian cancer during fo...... utility of serological tumor markers in patients with ovarian cancer....

  1. Cloud Atlas: Discovery of Rotational Spectral Modulations in a Low-mass, L-type Brown Dwarf Companion to a Star

    Science.gov (United States)

    Manjavacas, Elena; Apai, Dániel; Zhou, Yifan; Karalidi, Theodora; Lew, Ben W. P.; Schneider, Glenn; Cowan, Nicolas; Metchev, Stan; Miles-Páez, Paulo A.; Burgasser, Adam J.; Radigan, Jacqueline; Bedin, Luigi R.; Lowrance, Patrick J.; Marley, Mark S.

    2018-01-01

    Observations of rotational modulations of brown dwarfs and giant exoplanets allow the characterization of condensate cloud properties. As of now, rotational spectral modulations have only been seen in three L-type brown dwarfs. We report here the discovery of rotational spectral modulations in LP261-75B, an L6-type intermediate surface gravity companion to an M4.5 star. As a part of the Cloud Atlas Treasury program, we acquired time-resolved Wide Field Camera 3 grism spectroscopy (1.1–1.69 μm) of LP261-75B. We find gray spectral variations with the relative amplitude displaying only a weak wavelength dependence and no evidence for lower-amplitude modulations in the 1.4 μm water band than in the adjacent continuum. The likely rotational modulation period is 4.78 ± 0.95 hr, although the rotational phase is not well sampled. The minimum relative amplitude in the white light curve measured over the whole wavelength range is 2.41% ± 0.14%. We report an unusual light curve, which seems to have three peaks approximately evenly distributed in rotational phase. The spectral modulations suggests that the upper atmosphere cloud properties in LP261-75B are similar to two other mid-L dwarfs of typical infrared colors, but differ from that of the extremely red L-dwarf WISE0047.

  2. The role of L-type calcium channels in the vascular effect of Trigonella foenum-graecum L. in diabetic rats

    Directory of Open Access Journals (Sweden)

    Mehrdad Roghani

    2006-03-01

    Full Text Available Some ion channels like voltage-operated calcium channels (VOCC within the plasma membrane of vascular muscle cells from the walls of resistance arteries and arterioles play a central role in the regulation of vascular tone. On the basis of reports about the beneficial attenuating effect of fenugreek (Trigonella foenum-graecum L.; TFG on the contractile reactivity of aortic rings of diabetic rats, this study was carried out to evaluate the possible involvement of L-type voltage-operated calcium channels in the vascular effect of this medicinal plant. For this purpose, male Wistar rats were made diabetic using streptozotocin (STZ, 60 mg/Kg, i.p. The extract-treated control and diabetic rats received aqueous leaf extract of TFG (200 mg/Kg, i.p. every other day for two months. At the end of the study, contractile response of isolated aortic rings to KCl and noreadrenaline (NA was determined in the absence and presence of the calcium channel blocker nifedipine. The results showed that aortic rings from diabetic rats are more responsive to the effect of KCl and NA than those of controls, TFG extract treatment could attenuate the enhanced contractile response of aortic rings of diabetic rats, and nifedipine pretreatment could partially neutralize the beneficial effect of this extract. It is concluded that TFG extract attenuates the enhanced vascular reactivity in chronic diabetic rats and voltage-operated calcium channels are in part responsible for this effect of TFG extract.

  3. Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

    Directory of Open Access Journals (Sweden)

    Hamid Gholami Pourbadie

    Full Text Available The entorhinal cortex (EC is one of the earliest affected brain regions in Alzheimer's disease (AD. EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs, nimodipine and isradipine, were investigated. The amyloid beta (Aβ 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days, almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.

  4. Macrophage activation by a vanadyl-aspirin complex is dependent on L-type calcium channel and the generation of nitric oxide

    International Nuclear Information System (INIS)

    Molinuevo, Maria Silvina; Etcheverry, Susana Beatriz; Cortizo, Ana Maria

    2005-01-01

    Bone homeostasis is the result of a tight balance between bone resorption and bone formation where macrophage activation is believed to contribute to bone resorption. We have previously shown that a vanadyl(IV)-aspirin complex (VOAspi) regulates cell proliferation and differentiation of osteoblasts in culture. In this study, we assessed VOAspi and VO effects and their possible mechanism of action on a mouse macrophage cell line RAW 264.7. Both vanadium compounds inhibited cell proliferation in a dose-dependent manner. Nifedipine completely reversed the VOAspi-induced macrophage cytotoxicity, while it could not block the effect of VO. VOAspi also stimulated nitric oxide (NO) production, the oxidation of dihydrorhodamine 123 (DHR-123) and enhanced the expression of both constitutive and inducible isoforms of nitric oxide syntases (NOS). All these effects were abolished by nifedipine. Althogether our finding give evidence that VOAspi-induced macrophage cytotoxicity is dependent on L-type calcium channel and the generation of NO though the induction of eNOS and iNOS. Contrary, the parent compound VO exerted a cytotoxic effect by mechanisms independent of a calcium entry and the NO/NOS activation

  5. LecRK-V, an L-type lectin receptor kinase in Haynaldia villosa, plays positive role in resistance to wheat powdery mildew.

    Science.gov (United States)

    Wang, Zongkuan; Cheng, Jiangyue; Fan, Anqi; Zhao, Jia; Yu, Zhongyu; Li, Yingbo; Zhang, Heng; Xiao, Jin; Muhammad, Faheem; Wang, Haiyan; Cao, Aizhong; Xing, Liping; Wang, Xiue

    2018-01-01

    Plant sense potential microbial pathogen using pattern recognition receptors (PRRs) to recognize pathogen-associated molecular patterns (PAMPs). The Lectin receptor-like kinase genes (LecRKs) are involved in various cellular processes mediated by signal transduction pathways. In the present study, an L-type lectin receptor kinase gene LecRK-V was cloned from Haynaldia villosa, a diploid wheat relative which is highly resistant to powdery mildew. The expression of LecRK-V was rapidly up-regulated by Bgt inoculation and chitin treatment. Its transcript level was higher in the leaves than in roots, culms, spikes and callus. Single-cell transient overexpression of LecRK-V led to decreased haustorium index in wheat variety Yangmai158, which is powdery mildew susceptible. Stable transformation LecRK-V into Yangmai158 significantly enhanced the powdery mildew resistance at both seedling and adult stages. At seedling stage, the transgenic line was highly resistance to 18 of the tested 23 Bgt isolates, hypersensitive responses (HR) were observed for 22 Bgt isolates, and more ROS at the Bgt infection sites was accumulated. These indicated that LecRK-V confers broad-spectrum resistance to powdery mildew, and ROS and SA pathways contribute to the enhanced powdery mildew resistance in wheat. © 2017 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.

  6. NMDA receptors in mouse anterior piriform cortex initialize early odor preference learning and L-type calcium channels engage for long-term memory.

    Science.gov (United States)

    Mukherjee, Bandhan; Yuan, Qi

    2016-10-14

    The interactions of L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) in memories are poorly understood. Here we investigated the specific roles of anterior piriform cortex (aPC) LTCCs and NMDARs in early odor preference memory in mice. Using calcium imaging in aPC slices, LTCC activation was shown to be dependent on NMDAR activation. Either D-APV (NMDAR antagonist) or nifedipine (LTCC antagonist) reduced somatic calcium transients in pyramidal cells evoked by lateral olfactory tract stimulation. However, nifedipine did not further reduce calcium in the presence of D-APV. In mice that underwent early odor preference training, blocking NMDARs in the aPC prevented short-term (3 hr) and long-term (24 hr) odor preference memory, and both memories were rescued when BayK-8644 (LTCC agonist) was co-infused. However, activating LTCCs in the absence of NMDARs resulted in loss of discrimination between the conditioned odor and a similar odor mixture at 3 hr. Elevated synaptic AMPAR expression at 3 hr was prevented by D-APV infusion but restored when LTCCs were directly activated, mirroring the behavioral outcomes. Blocking LTCCs prevented 24 hr memory and spared 3 hr memory. These results suggest that NMDARs mediate stimulus-specific encoding of odor memory while LTCCs mediate intracellular signaling leading to long-term memory.

  7. An Improved Targeted cAMP Sensor to Study the Regulation of Adenylyl Cyclase 8 by Ca2+ Entry through Voltage-Gated Channels

    Science.gov (United States)

    Everett, Katy L.; Cooper, Dermot M. F.

    2013-01-01

    Here we describe an improved sensor with reduced pH sensitivity tethered to adenylyl cyclase (AC) 8. The sensor was used to study cAMP dynamics in the AC8 microdomain of MIN6 cells, a pancreatic β-cell line. In these cells, AC8 was activated by Ca2+ entry through L-type voltage-gated channels following depolarisation. This activation could be reconstituted in HEK293 cells co-expressing AC8 and either the α1C or α1D subunit of L-type voltage-gated Ca2+ channels. The development of this improved sensor opens the door to the study of cAMP microdomains in excitable cells that have previously been challenging due to the sensitivity of fluorescent proteins to pH changes. PMID:24086669

  8. An improved targeted cAMP sensor to study the regulation of adenylyl cyclase 8 by Ca2+ entry through voltage-gated channels.

    Directory of Open Access Journals (Sweden)

    Katy L Everett

    Full Text Available Here we describe an improved sensor with reduced pH sensitivity tethered to adenylyl cyclase (AC 8. The sensor was used to study cAMP dynamics in the AC8 microdomain of MIN6 cells, a pancreatic β-cell line. In these cells, AC8 was activated by Ca(2+ entry through L-type voltage-gated channels following depolarisation. This activation could be reconstituted in HEK293 cells co-expressing AC8 and either the α1C or α1D subunit of L-type voltage-gated Ca(2+ channels. The development of this improved sensor opens the door to the study of cAMP microdomains in excitable cells that have previously been challenging due to the sensitivity of fluorescent proteins to pH changes.

  9. Enhanced basal late sodium current appears to underlie the age-related prolongation of action potential duration in guinea pig ventricular myocytes.

    Science.gov (United States)

    Song, Yejia; Belardinelli, Luiz

    2017-12-14

    Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na + current (I NaL ); 3) inhibition of I NaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H 2 O 2 ). Experiments were performed on ventricular myocytes isolated from one-month (young) and one-year (old) guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the I NaL inhibitors GS967 and tetrodotoxin. The magnitude of I NaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the Na V 1.5-channel blocker MTSEA blocked the I NaL . There were no significant differences between myocytes from young and old GPs in L-type Ca 2+ current and the rapidly- and slowly-activating delayed rectifier K + currents, although the inward rectifier K + current was slightly decreased in myocytes from old GPs. H 2 O 2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H 2 O 2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in Na V 1.5-channel I NaL is responsible for the prolongation of APD, and 3) Inhibition of I NaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs.

  10. Novel method of generation of Ca(HCO32 and CaCO3 aerosols and first determination of hygroscopic and cloud condensation nuclei activation properties

    Directory of Open Access Journals (Sweden)

    A. Trimborn

    2010-09-01

    Full Text Available Atmospheric mineral aerosols contain CaCO3 as a reactive component. A novel method to produce CaCO3 aerosol was developed by spraying Ca(HCO32 solution, which was generated from a CaCO3 suspension and CO2. By aerosol mass spectrometry the freshly sprayed and dried aerosol was characterized to consist of pure Ca(HCO32 which under annealing in a tube furnace transformed into CaCO3. Transmission Electron Microscopy demonstrated that the particles produced were spherical. The method was able to generate aerosol of sufficient concentration and proper size for the study of physiochemical properties and investigations of heterogeneous reactions of mineral aerosol. The dried Ca(HCO32 particles were somewhat more hygroscopic than CaCO3 particles. However, during humidification a restructuring took place and ∼2/3 of the Ca(HCO32 was transformed to CaCO3. The mixed Ca(HCO32/CaCO3(s particles were insoluble with a growth factor of 1.03 at 95% (hygroscopicity parameter κ=0.011±0.007 relative humidity. This compares to a corresponding growth factor of 1.01 for CaCO3(s (κ=0.0016±0.0004. Mass spectrometric composition analysis, restructuring, and insolubility of the mixed particles suggested that solid Ca(HCO32(s was observed. This would be in contrast to the current belief that Ca(HCO32(s is thermodynamically instable. The CCN activity of Ca(HCO32(s aerosol (κ≈0.15 is remarkably higher than that of CaCO3 aerosol (κ=0.0019±0.0007 and less than that of Ca(NO32. The noticeable but limited solubility of Ca(HCO32 of ≈0.01 mol/l explains limited hygroscopic growth and good CCN activity. Experiments in the Large Jülich Aerosol Chamber indicated that Ca(HCO32(s could exist for several hours under dry atmospheric conditions. However, it was likely buried in a protective layer of CaCO3(s. We conclude that Ca(HCO32 may be formed in the atmosphere in cloud droplets of activated mineral dust by reaction of CaCO3 with CO2 and H2O. The presence of Ca(HCO32 and

  11. Ca2+-induced uncoupling of Aplysia bag cell neurons.

    Science.gov (United States)

    Dargaei, Zahra; Standage, Dominic; Groten, Christopher J; Blohm, Gunnar; Magoski, Neil S

    2015-02-01

    Electrical transmission is a dynamically regulated form of communication and key to synchronizing neuronal activity. The bag cell neurons of Aplysia are a group of electrically coupled neuroendocrine cells that initiate ovulation by secreting egg-laying hormone during a prolonged period of synchronous firing called the afterdischarge. Accompanying the afterdischarge is an increase in intracellular Ca2+ and the activation of protein kinase C (PKC). We used whole cell recording from paired cultured bag cell neurons to demonstrate that electrical coupling is regulated by both Ca2+ and PKC. Elevating Ca2+ with a train of voltage steps, mimicking the onset of the afterdischarge, decreased junctional current for up to 30 min. Inhibition was most effective when Ca2+ entry occurred in both neurons. Depletion of Ca2+ from the mitochondria, but not the endoplasmic reticulum, also attenuated the electrical synapse. Buffering Ca2+ with high intracellular EGTA or inhibiting calmodulin kinase prevented uncoupling. Furthermore, activating PKC produced a small but clear decrease in junctional current, while triggering both Ca2+ influx and PKC inhibited the electrical synapse to a greater extent than Ca2+ alone. Finally, the amplitude and time course of the postsynaptic electrotonic response were attenuated after Ca2+ influx. A mathematical model of electrically connected neurons showed that excessive coupling reduced recruitment of the cells to fire, whereas less coupling led to spiking of essentially all neurons. Thus a decrease in electrical synapses could promote the afterdischarge by ensuring prompt recovery of electrotonic potentials or making the neurons more responsive to current spreading through the network. Copyright © 2015 the American Physiological Society.

  12. Glucose decouples intracellular Ca2+ activity from glucagon secretion in mouse pancreatic islet alpha-cells.

    Directory of Open Access Journals (Sweden)

    Sylvain J Le Marchand

    Full Text Available The mechanisms of glucagon secretion and its suppression by glucose are presently unknown. This study investigates the relationship between intracellular calcium levels ([Ca(2+](i and hormone secretion under low and high glucose conditions. We examined the effects of modulating ion channel activities on [Ca(2+](i and hormone secretion from ex vivo mouse pancreatic islets. Glucagon-secreting α-cells were unambiguously identified by cell specific expression of fluorescent proteins. We found that activation of L-type voltage-gated calcium channels is critical for α-cell calcium oscillations and glucagon secretion at low glucose levels. Calcium channel activation depends on K(ATP channel activity but not on tetrodotoxin-sensitive Na(+ channels. The use of glucagon secretagogues reveals a positive correlation between α-cell [Ca(2+](i and secretion at low glucose levels. Glucose elevation suppresses glucagon secretion even after treatment with secretagogues. Importantly, this inhibition is not mediated by K(ATP channel activity or reduction in α-cell [Ca(2+](i. Our results demonstrate that glucose uncouples the positive relationship between [Ca(2+](i and secretory activity. We conclude that glucose suppression of glucagon secretion is not mediated by inactivation of calcium channels, but instead, it requires a calcium-independent inhibitory pathway.

  13. LaNiO{sub 3} buffer layers for high critical current density YBa{sub 2}Cu{sub 3}O{sub 7{minus}{delta}} and Tl{sub 2}Ba{sub 2}CaCu{sub 2}O{sub 8{minus}{delta}} films

    Energy Technology Data Exchange (ETDEWEB)

    Carlson, C.M.; Parilla, P.A.; Siegal, M.P.; Ginley, D.S.; Wang, Y.; Blaugher, R.D.; Price, J.C.; Overmyer, D.L.; Venturini, E.L.

    1999-10-01

    We demonstrate high critical current density superconducting films of YBa{sub 2}Cu{sub 3}O{sub 7{minus}{delta}} (YBCO) and Tl{sub 2}Ba{sub 2}CaCu{sub 2}O{sub 8{minus}{delta}} (Tl-2212) using LaNiO{sub 3} (LNO) buffer layers. YBCO films grown on an LNO buffer layer have only a slightly lower J{sub c} (5 K, H=0) than films grown directly on a bare LaAlO{sub 3} substrate. YBCO films grown on LNO buffer layers exhibit minor microstructural disorder and enhanced flux pinning. LNO-buffered Tl-2212 samples show large reductions in J{sub c} at all temperatures and fields compared to those grown on bare LaAlO{sub 3}, correlating to both {ital a}-axis grain and nonsuperconducting phase formation. LNO could be a promising buffer layer for both YBCO and Tl-based superconducting films in coated conductor applications. {copyright} {ital 1999 American Institute of Physics.}

  14. A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model

    International Nuclear Information System (INIS)

    Fukumoto, Shinya; Hanazono, Kiwamu; Fu, Dah-Renn; Endo, Yoshifumi; Kadosawa, Tsuyoshi; Iwano, Hidetomo; Uchide, Tsuyoshi

    2013-01-01

    Highlights: •LAT1 is highly expressed in tumors but at low levels in normal tissues. •We examine LAT1 expression and function in malignant melanoma (MM). •LAT1 expression in MM tissues and cell lines is higher than those in normal tissues. •LAT1 selective inhibitors inhibit amino acid uptake and cell growth in MM cells. •New chemotherapeutic protocols including LAT1 inhibitors are effective for treatment. -- Abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P 3 H]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM

  15. Diagnostic usefulness of 18F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Nobusawa, Aiko; Kim, Mai; Kaira, Kyoichi; Miyashita, Go; Negishi, Akihide; Yokoo, Satoshi; Oriuchi, Noboru; Higuchi, Tetsuya; Tsushima, Yoshito; Kanai, Yoshikatsu; Oyama, Tetsunari

    2013-01-01

    l-[3- 18 F]-α-Methyltyrosine ( 18 F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[ 18 F]fluoro-2-deoxy-d-glucose ( 18 F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of 18 F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of 18 F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. The study group comprised 68 OSCC patients who underwent both 18 F-FAMT and 18 F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. The sensitivity of primary tumour detection by 18 F-FAMT and 18 F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of 18 F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for 18 F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of 18 F-FAMT were significantly higher than those of 18 F-FDG. The uptake of 18 F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. 18 F-FAMT PET showed higher specificity for detecting malignant lesions than 18 F-FDG PET. The uptake of 18 F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation. (orig.)

  16. Diagnostic usefulness of {sup 18}F-FAMT PET and L-type amino acid transporter 1 (LAT1) expression in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Nobusawa, Aiko [Gunma University Graduate School of Medicine, Department of Stomatology and Maxillofacial Surgery, Maebashi, Gunma (Japan); Gunma University Graduate School of Medicine, Department of Diagnostic Pathology, Maebashi, Gunma (Japan); Kim, Mai [Gunma University Graduate School of Medicine, Department of Stomatology and Maxillofacial Surgery, Maebashi, Gunma (Japan); Gunma University Graduate School of Medicine, Department of Diagnostic Radiology and Nuclear Medicine, Maebashi, Gunma (Japan); Kaira, Kyoichi [Gunma University Graduate School of Medicine, Department of Diagnostic Pathology, Maebashi, Gunma (Japan); Gunma University Hospital, Oncology Center, Maebashi, Gunma (Japan); Miyashita, Go; Negishi, Akihide; Yokoo, Satoshi [Gunma University Graduate School of Medicine, Department of Stomatology and Maxillofacial Surgery, Maebashi, Gunma (Japan); Oriuchi, Noboru; Higuchi, Tetsuya; Tsushima, Yoshito [Gunma University Graduate School of Medicine, Department of Diagnostic Radiology and Nuclear Medicine, Maebashi, Gunma (Japan); Kanai, Yoshikatsu [Osaka University, Division of Bio-system Pharmacology, Graduate School of Medicine, Osaka (Japan); Oyama, Tetsunari [Gunma University Graduate School of Medicine, Department of Diagnostic Pathology, Maebashi, Gunma (Japan)

    2013-10-15

    l-[3-{sup 18}F]-{alpha}-Methyltyrosine ({sup 18}F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[{sup 18}F]fluoro-2-deoxy-d-glucose ({sup 18}F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of {sup 18}F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of {sup 18}F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. The study group comprised 68 OSCC patients who underwent both {sup 18}F-FAMT and {sup 18}F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. The sensitivity of primary tumour detection by {sup 18}F-FAMT and {sup 18}F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of {sup 18}F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for {sup 18}F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of {sup 18}F-FAMT were significantly higher than those of {sup 18}F-FDG. The uptake of {sup 18}F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. {sup 18}F-FAMT PET showed higher specificity for detecting malignant lesions than {sup 18}F-FDG PET. The uptake of {sup 18}F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation. (orig.)

  17. The site of net absorption of Ca from the intestinal tract of growing pigs and effect of phytic acid, Ca level and Ca source on Ca digestibility.

    Science.gov (United States)

    González-Vega, J Caroline; Walk, Carrie L; Liu, Yanhong; Stein, Hans H

    2014-01-01

    An experiment was conducted to test the hypothesis that the standardised digestibility of Ca in calcium carbonate and Lithothamnium calcareum Ca is not different regardless of the level of dietary Ca, and that phytic acid affects the digestibility of Ca in these two ingredients to the same degree. The objectives were to determine where in the intestinal tract Ca absorption takes place and if there are measurable quantities of basal endogenous Ca fluxes in the stomach, small intestine or large intestine. Diets contained calcium carbonate or L. calcareum Ca as the sole source of Ca, 0% or 1% phytic acid and 0.4% or 0.8% Ca. A Ca-free diet was also formulated and used to measure endogenous fluxes and losses of Ca. Nine growing pigs (initial body weight 23.8 ± 1.3 kg) were cannulated in the duodenum and in the distal ileum, and faecal, ileal and duodenal samples were collected. Duodenal endogenous fluxes of Ca were greater (p calcareum Ca diets, but that was not the case if calcium carbonate was the source of Ca (interaction, p calcareum Ca was greater (p calcareum Ca. In conclusion, under the conditions of this experiment, standardised digestibility of Ca is not affected by the level of phytic acid, but may be affected by dietary Ca level depending on the Ca source. Calcium from calcium carbonate is mostly absorbed before the duodenum, but Ca from L. calcareum Ca is mostly absorbed in the jejunum and ileum.

  18. CORRELATION OF 48Ca, 50Ti, AND 138La HETEROGENEITY IN THE ALLENDE REFRACTORY INCLUSIONS

    International Nuclear Information System (INIS)

    Chen, Hsin-Wei; Lee, Typhoon; Lee, Der-Chuen; Chen, Jiang-Chang

    2015-01-01

    Precise determinations of 48 Ca anomalies in Allende calcium–aluminum-rich inclusions (CAIs) are reported in this work. There are endemic positive 48 Ca/ 44 Ca anomalies in all analyzed CAIs after normalization to 42 Ca/ 44 Ca, and it is clearly shown that there is no simple correlation between 48 Ca/ 44 Ca and 50 Ti/ 48 Ti anomalies, in agreement with Jungck et al. Compared to the 48 Ca/ 44 Ca versus 50 Ti/ 48 Ti correlation line defined by differentiated meteorites, reported by Chen et al., the CAIs plot to elevated 50 Ti/ 48 Ti. Assuming the 48 Ca/ 44 Ca anomalies of both CAIs and differentiated meteorites came from the same source, excess 50 Ti anomalies in CAIs can be calculated by subtracting the part associated with 48 Ca/ 44 Ca. These excesses show a linear correlation with 138 La anomalies, a neutrino-process nuclide. According to current stellar nucleosynthetic models, we therefore suggest that the solar system 48 Ca, 50 Ti, and 138 La isotopic variations are made of mixtures between grains condensed from ejecta of neutron-rich accretion-induced SNe Ia and the O/Ne–O/C zone of core-collapse SNe II

  19. Rates for some reactions involving 42Ca and 44Ca

    International Nuclear Information System (INIS)

    Cheng, C.W.; King, J.D.

    1980-01-01

    Ground-state reaction rates have been deduced from recent cross section measurements for the 42 CA(α, n) 45 Ti, 42 Ca(p, γ) 43 Sc, and 44 Ca(p, n) 44 Sc reactions. Comparison of these rates with those calculated from a statistical model of nuclear reactions. (Woosley et al) shows good agreement for the first two, but the 44 Ca(p, n) rate is more than a factor of 2 less than the theoretical prediction. Stellar reaction rates have been derived from the ground-state rates by multiplying the ground-state rates by the ratio of stellar to ground-state rates given by the statistical model. Both ground-state and stellar rates have been represented by analytic functions of the temperature. The role of these reactions in the approach to quasi-equilibrium during explosive silicon burning is discussed

  20. Store-operated calcium entry is required for sustained contraction and Ca2+ oscillations of airway smooth muscle.

    Science.gov (United States)

    Chen, Jun; Sanderson, Michael J

    2017-05-15

    Airway hyper-responsiveness in asthma is driven by excessive contraction of airway smooth muscle cells (ASMCs). Agonist-induced Ca 2+ oscillations underlie this contraction of ASMCs and the magnitude of this contraction is proportional to the Ca 2+ oscillation frequency. Sustained contraction and Ca 2+ oscillations require an influx of extracellular Ca 2+ , although the mechanisms and pathways mediating this Ca 2+ influx during agonist-induced ASMC contraction are not well defined. By inhibiting store-operated calcium entry (SOCE) or voltage-gated Ca 2+ channels (VGCCs), we show that SOCE, rather than Ca 2+ influx via VGCCs, provides the major Ca 2+ entry pathway into ASMCs to sustain ASMCs contraction and Ca 2+ oscillations. SOCE may therefore serve as a potential target for new bronchodilators to reduce airway hyper-responsiveness in asthma. Asthma is characterized by airway hyper-responsiveness: the excessive contraction of airway smooth muscle. The extent of this airway contraction is proportional to the frequency of Ca 2+ oscillations within airway smooth muscle cells (ASMCs). Sustained Ca 2+ oscillations require a Ca 2+ influx to replenish Ca 2+ losses across the plasma membrane. Our previous studies implied store-operated calcium entry (SOCE) as the major pathway for this Ca 2+ influx. In the present study, we explore this hypothesis, by examining the effects of SOCE inhibitors (GSK7975A and GSK5498A) as well as L-type voltage-gated Ca 2+ channel inhibitors (nifedipine and nimodipine) on airway contraction and Ca 2+ oscillations and SOCE-mediated Ca 2+ influx in ASMCs within mouse precision-cut lung slices. We found that both GSK7975A and GSK5498A were able to fully relax methacholine-induced airway contraction by abolishing the Ca 2+ oscillations, in a manner similar to that observed in zero extracellular Ca 2+ ([Ca 2+ ] e ). In addition, GSK7975A and GSK5498A inhibited increases in intracellular Ca 2+ ([Ca 2+ ] i ) in ASMCs with depleted Ca 2+ -stores in

  1. Temperature- and field-dependent critical currents in [(Bi,Pb)2Sr2Ca2Cu3Ox]0.07(La0.7Sr0.3MnO3)0.03 thick films grown on LaAlO3 substrates

    Science.gov (United States)

    Paredes, Omar; Morán, Oswaldo; Baca, Eval

    2013-01-01

    La0.7Sr0.3MnO3 (LSMO) nanoparticles were embedded in (Bi,Pb)2Sr2Ca2Cu3Ox (Bi2223) thick films, which were grown by simple melting-quenching-annealing (MQA) method on (001)-oriented LaAlO3 (LAO) substrates. The nominal composition of the composite-like hybrid system was (Bi2223)1-x(LSMO)x with x = 0.03. The constituent elements, Bi2223 and LSMO, were prepared separately by standard solid state reaction and Pechini's method, respectively. The analysis of the X-ray diffraction patterns suggested a polycrystalline growth mode of the thick films on the LAO substrates. From electric transport measurements, the superconducting onset temperature and the superconducting critical temperature (ρ = 0) ended up being 105 and 62 K, respectively. The flux pinning energy U was determined using the Anderson-Kim model. The value of U was compared with those obtained for similar samples with concentrations x = 0.01 and x = 0.05. Current-voltage characteristics were recorded at different temperatures in order to analyze the behavior of the superconducting current (Ic) of the films. A dramatic drop of Ic was observed at ˜20 K. This seems to be linked to the presence of flux creep acting as dissipation factors attributed to LSMO nanoparticles. Isothermal magnetization loops recorded at T Tc showed clear diamagnetic and ferromagnetic signals, which verify the multifunctional character of the system. Based on the isothermal M(H)-loops recorded at 5, 20, and 40 K and taking Kim's model into account, the dependence of superconducting current density (Jc), and the volume pinning force (Fp) on the magnetic field were calculated. The dependence Jc(B) at 5 K showed an exponential-type behavior, which is described by an empirical equation. This empirical equation considers the maximum value of Fp, which may be scaled with the Kramer's expression for Fp. From this scaling procedure, diverse exponents, associated with different pinning mechanisms, were determined. The drastic fall of Jc(B) at T

  2. Ca2+ sparks act as potent regulators of excitation-contraction coupling in airway smooth muscle.

    Science.gov (United States)

    Zhuge, Ronghua; Bao, Rongfeng; Fogarty, Kevin E; Lifshitz, Lawrence M

    2010-01-15

    Ca2+ sparks are short lived and localized Ca2+ transients resulting from the opening of ryanodine receptors in sarcoplasmic reticulum. These events relax certain types of smooth muscle by activating big conductance Ca2+-activated K+ channels to produce spontaneous transient outward currents (STOCs) and the resultant closure of voltage-dependent Ca2+ channels. But in many smooth muscles from a variety of organs, Ca2+ sparks can additionally activate Ca2+-activated Cl(-) channels to generate spontaneous transient inward current (STICs). To date, the physiological roles of Ca2+ sparks in this latter group of smooth muscle remain elusive. Here, we show that in airway smooth muscle, Ca2+ sparks under physiological conditions, activating STOCs and STICs, induce biphasic membrane potential transients (BiMPTs), leading to membrane potential oscillations. Paradoxically, BiMPTs stabilize the membrane potential by clamping it within a negative range and prevent the generation of action potentials. Moreover, blocking either Ca2+ sparks or hyperpolarization components of BiMPTs activates voltage-dependent Ca2+ channels, resulting in an increase in global [Ca2+](i) and cell contraction. Therefore, Ca2+ sparks in smooth muscle presenting both STICs and STOCs act as a stabilizer of membrane potential, and altering the balance can profoundly alter the status of excitability and contractility. These results reveal a novel mechanism underlying the control of excitability and contractility in smooth muscle.

  3. A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): A pilot study in a canine model

    Energy Technology Data Exchange (ETDEWEB)

    Fukumoto, Shinya; Hanazono, Kiwamu [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Fu, Dah-Renn; Endo, Yoshifumi; Kadosawa, Tsuyoshi [Veterinary Oncology, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Iwano, Hidetomo [Veterinary Biochemistry, Department of Basic Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan); Uchide, Tsuyoshi, E-mail: uchide@rakuno.ac.jp [Veterinary Internal Medicine, Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501 (Japan)

    2013-09-13

    Highlights: •LAT1 is highly expressed in tumors but at low levels in normal tissues. •We examine LAT1 expression and function in malignant melanoma (MM). •LAT1 expression in MM tissues and cell lines is higher than those in normal tissues. •LAT1 selective inhibitors inhibit amino acid uptake and cell growth in MM cells. •New chemotherapeutic protocols including LAT1 inhibitors are effective for treatment. -- Abstract: L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25 MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P < 0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [{sup 3}H]L-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P < 0.05) enhanced by combination use with BCH or LPM

  4. Initiation and growth of thermal fatigue crack networks in an AISI 304 L type austenitic stainless steel (X2 CrNi18-09)

    International Nuclear Information System (INIS)

    Maillot, V.

    2004-01-01

    We studied the behaviour of a 304 L type austenitic stainless steel submitted to thermal fatigue. Using the SPLASH equipment of CEA/SRMA we tested parallelepipedal specimens on two sides: the specimens are continuously heated by Joule effect, while two opposites faces are cyclically. cooled by a mixed spray of distilled water and compressed air. This device allows the reproduction and the study of crack networks similar to those observed in nuclear power plants, on the inner side of circuits fatigued by mixed pressurized water flows at different temperatures. The crack initiation and the network constitution at the surface were observed under different thermal conditions (Tmax = 320 deg C, ΔT between 125 and 200 deg C). The experiment produced a stress gradient in the specimen, and due to this gradient, the in-depth growth of the cracks finally stopped. The obtained crack networks were studied quantitatively by image analysis, and different parameters were studied: at the surface during the cycling, and post mortem by step-by-step layer removal by grinding. The maximal depth obtained experimentally, 2.5 mm, is relatively coherent with the finite element modelling of the SPLASH test, in which compressive stresses appear at a depth of 2 mm. Some of the crack networks obtained by thermal fatigue were also tested in isothermal fatigue crack growth under 4-point bending, at imposed load. The mechanisms of the crack selection, and the appearance of the dominating crack are described. Compared to the propagation of a single crack, the crack networks delay the propagation, depending on the severity of the crack competition for domination. The dominating crack can be at the network periphery, in that case it is not as shielded by its neighbours as a crack located in the center of the network. It can also be a straight crack surrounded by more sinuous neighbours. Indeed, on sinuous cracks, the loading is not the same all along the crack path, leading to some morphological

  5. Divalent metal (Ca, Cd, Mn, Zn) uptake and interactions in the aquatic insect Hydropsyche sparna.

    Science.gov (United States)

    Poteat, Monica D; Díaz-Jaramillo, Mauricio; Buchwalter, David B

    2012-05-01

    Despite their ecological importance and prevalent use as ecological indicators, the trace element physiology of aquatic insects remains poorly studied. Understanding divalent metal transport processes at the water-insect interface is important because these metals may be essential (e.g. Ca), essential and potentially toxic (e.g. Zn) or non-essential and toxic (e.g. Cd). We measured accumulation kinetics of Zn and Cd across dissolved concentrations ranging 4 orders of magnitude and examined interactions with Ca and Mn in the caddisfly Hydropsyche sparna. Here, we provide evidence for at least two transport systems for both Zn and Cd, the first of which operates at concentrations below 0.8 μmol l(-1) (and is fully saturable for Zn). We observed no signs of saturation of a second lower affinity transport system at concentrations up to 8.9 μmol l(-1) Cd and 15.3 μmol l(-1) Zn. In competition studies at 0.6 μmol l(-1) Zn and Cd, the presence of Cd slowed Zn accumulation by 35% while Cd was unaffected by Zn. At extreme concentrations (listed above), Cd accumulation was unaffected by the presence of Zn whereas Zn accumulation rates were reduced by 58%. Increasing Ca from 31.1 μmol l(-1) to 1.35 mmol l(-1) resulted in only modest decreases in Cd and Zn uptake. Mn decreased adsorption of Cd and Zn to the integument but not internalization. The L-type Ca(2+) channel blockers verapamil and nifedipine and the plasma membrane Ca(2+)-ATPase inhibitor carboxyeosin had no influence on Ca, Cd or Zn accumulation rates, while Ruthenium Red, a Ca(2+)-ATPase inhibitor, significantly decreased the accumulation of all three in a concentration-dependent manner.

  6. A Close Association of RyRs with Highly Dense Clusters of Ca2+-activated Cl− Channels Underlies the Activation of STICs by Ca2+ Sparks in Mouse Airway Smooth Muscle

    Science.gov (United States)

    Bao, Rongfeng; Lifshitz, Lawrence M.; Tuft, Richard A.; Bellvé, Karl; Fogarty, Kevin E.; ZhuGe, Ronghua

    2008-01-01

    Ca2+ sparks are highly localized, transient releases of Ca2+ from sarcoplasmic reticulum through ryanodine receptors (RyRs). In smooth muscle, Ca2+ sparks trigger spontaneous transient outward currents (STOCs) by opening nearby clusters of large-conductance Ca2+-activated K+ channels, and also gate Ca2+-activated Cl− (Cl(Ca)) channels to induce spontaneous transient inward currents (STICs). While the molecular mechanisms underlying the activation of STOCs by Ca2+ sparks is well understood, little information is available on how Ca2+ sparks activate STICs. In the present study, we investigated the spatial organization of RyRs and Cl(Ca) channels in spark sites in airway myocytes from mouse. Ca2+ sparks and STICs were simultaneously recorded, respectively, with high-speed, widefield digital microscopy and whole-cell patch-clamp. An image-based approach was applied to measure the Ca2+ current underlying a Ca2+ spark (ICa(spark)), with an appropriate correction for endogenous fixed Ca2+ buffer, which was characterized by flash photolysis of NPEGTA. We found that ICa(spark) rises to a peak in 9 ms and decays with a single exponential with a time constant of 12 ms, suggesting that Ca2+ sparks result from the nonsimultaneous opening and closure of multiple RyRs. The onset of the STIC lags the onset of the ICa(spark) by less than 3 ms, and its rising phase matches the duration of the ICa(spark). We further determined that Cl(Ca) channels on average are exposed to a [Ca2+] of 2.4 μM or greater during Ca2+ sparks. The area of the plasma membrane reaching this level is <600 nm in radius, as revealed by the spatiotemporal profile of [Ca2+] produced by a reaction-diffusion simulation with measured ICa(spark). Finally we estimated that the number of Cl(Ca) channels localized in Ca2+ spark sites could account for all the Cl(Ca) channels in the entire cell. Taken together these results lead us to propose a model in which RyRs and Cl(Ca) channels in Ca2+ spark sites localize

  7. Distal C terminus of CaV1.2 channels plays a crucial role in the neural differentiation of dental pulp stem cells.

    Directory of Open Access Journals (Sweden)

    Jianping Ge

    Full Text Available L-type voltage-dependent CaV1.2 channels play an important role in the maintenance of intracellular calcium homeostasis, and influence multiple cellular processes. C-terminal cleavage of CaV1.2 channels was reported in several types of excitable cells, but its expression and possible roles in non-excitable cells is still not clear. The aim of this study was to determine whether distal C-terminal fragment of CaV1.2 channels is present in rat dental pulp stem cells and its possible role in the neural differentiation of rat dental pulp stem cells. We generated stable CaV1.2 knockdown cells via short hairpin RNA (shRNA. Rat dental pulp stem cells with deleted distal C-terminal of CaV1.2 channels lost the potential of differentiation to neural cells. Re-expression of distal C-terminal of CaV1.2 rescued the effect of knocking down the endogenous CaV1.2 on the neural differentiation of rat dental pulp stem cells, indicating that the distal C-terminal of CaV1.2 is required for neural differentiation of rat dental pulp stem cells. These results provide new insights into the role of voltage-gated Ca(2+ channels in stem cells during differentiation.

  8. Atrial remodelling in atrial fibrillation: CaMKII as a nodal proarrhythmic signal

    Science.gov (United States)

    Mesubi, Olurotimi O.; Anderson, Mark E.

    2016-01-01

    CaMKII is a serine–threonine protein kinase that is abundant in myocardium. Emergent evidence suggests that CaMKII may play an important role in promoting atrial fibrillation (AF) by targeting a diverse array of proteins involved in membrane excitability, cell survival, calcium homeostasis, matrix remodelling, inflammation, and metabolism. Furthermore, CaMKII inhibition appears to protect against AF in animal models and correct proarrhythmic, defective intracellular Ca2+ homeostasis in fibrillating human atrial cells. This review considers current concepts and evidence from animal and human studies on the role of CaMKII in AF. PMID:26762270

  9. In vitro degradation and cytotoxicity of Mg/Ca composites produced by powder metallurgy.

    Science.gov (United States)

    Zheng, Y F; Gu, X N; Xi, Y L; Chai, D L

    2010-05-01

    Mg/Ca (1 wt.%, 5 wt.%, 10 wt.% Ca) composites were prepared from pure magnesium and calcium powders using the powder metallurgy method, aiming to enlarge the addition of Ca content without the formation of Mg(2)Ca. The microstructures, mechanical properties and cytotoxicities of Mg/Ca composite samples were investigated. The corrosion of Mg/Ca composites in Dulbecco's modified Eagle's medium (DMEM) for various immersion intervals was studied by electrochemical impedance spectroscopy measurements and environmental scanning electron microscope, with the concentrations of released Mg and Ca ions in DMEM for various immersion time intervals being measured. It was shown that the main constitutional phases were Mg and Ca, which were uniformly distributed in the Mg matrix. The ultimate tensile strength (UTS) and elongation of experimental composites decreased with increasing Ca content, and the UTS of Mg/1Ca composite was comparable with that of as-extruded Mg-1Ca alloy. The corrosion potential increased with increasing Ca content, whereas the current density and the impedance decreased. It was found that the protective surface film formed quickly at the initial immersion stage. With increasing immersion time, the surface film became compact, and the corrosion rate of Mg/Ca composites slowed down. The surface film consisted mainly of CaCO(3), MgCO(3)x3H(2)O, HA and Mg(OH)(2) after 72 h immersion in DMEM. Mg/1Ca and Mg/5Ca composite extracts had no significant toxicity (p>0.05) to L-929 cells, whereas Mg/10Ca composite extract induced approximately 40% reduced cell viability. Copyright (c) 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  10. CaWingz user's guide

    International Nuclear Information System (INIS)

    Cha, Ben-chin.

    1994-01-01

    This document assumes that you have read and understood the Wingz user's manuals. CaWingz is an external Wingz program which, when combined with a set of script files, provides easy-to-use EPICS channel access interface functions for Wingz users. The external function run allows Wingz user to invoke any Unix processor within caWingz. Few additional functions for accessing static database field and monitoring of value change event is available for EPICS users after release 3.11. The functions, script files, and usage are briefly described in this document. The script files supplied here serve as examples only. Users are responsible for generating their own spreadsheet and script files. CaWingz communicates with IOC through channel access function calls

  11. Basal activity of voltage-gated Ca(2+) channels controls the IP3-mediated contraction by α(1)-adrenoceptor stimulation of mouse aorta segments.

    Science.gov (United States)

    Leloup, Arthur J; Van Hove, Cor E; De Meyer, Guido R Y; Schrijvers, Dorien M; Fransen, Paul

    2015-08-05

    α1-Adrenoceptor stimulation of mouse aorta causes intracellular Ca(2+) release from sarcoplasmic reticulum Ca(2+) stores via stimulation of inositoltriphosphate (IP3) receptors. It is hypothesized that this Ca(2+) release from the contractile and IP3-sensitive Ca(2+) store is under the continuous dynamic control of time-independent basal Ca(2+) influx via L-type voltage-gated Ca(2+) channels (LCC) residing in their window voltage range. Mouse aortic segments were α1-adrenoceptor stimulated with phenylephrine in the absence of external Ca(2+) (0Ca) to measure phasic isometric contractions. They gradually decreased with time in 0Ca, were inhibited with 2-aminoethoxydiphenyl borate, and declined with previous membrane potential hyperpolarization (levcromakalim) or with previous inhibition of LCC (diltiazem). Former basal stimulation of LCC with depolarization (15 mM K(+)) or with BAY K8644 increased the subsequent phasic contractions by phenylephrine in 0Ca. Although exogenous NO (diethylamine NONOate) reduced the phasic contractions by phenylephrine, stimulation of endothelial cells with acetylcholine in 0Ca failed to attenuate these phasic contractions. Finally, inhibition of the basal release of NO with N(Ω)-nitro-L-arginine methyl ester also attenuated the phasic contractions by phenylephrine. Results indicated that α1-adrenoceptor stimulation with phenylephrine causes phasic contractions, which are controlled by basal LCC and endothelial NO synthase activity. Endothelial NO release by acetylcholine was absent in 0Ca. Given the growing interest in the active regulation of arterial compliance, the dependence of contractile SR Ca(2+) store-refilling in basal conditions on the activity of LCC and basal eNOS may contribute to a more thorough understanding of physiological mechanisms leading to arterial stiffness. Copyright © 2015. Published by Elsevier B.V.

  12. Weak currents

    International Nuclear Information System (INIS)

    Leite Lopes, J.

    1976-01-01

    A survey of the fundamental ideas on weak currents such as CVC and PCAC and a presentation of the Cabibbo current and the neutral weak currents according to the Salam-Weinberg model and the Glashow-Iliopoulos-Miami model are given [fr

  13. Spin current

    CERN Document Server

    Valenzuela, Sergio O; Saitoh, Eiji; Kimura, Takashi

    2012-01-01

    In a new branch of physics and technology called spin-electronics or spintronics, the flow of electrical charge (usual current) as well as the flow of electron spin, the so-called 'spin current', are manipulated and controlled together. This book provides an introduction and guide to the new physics and application of spin current.

  14. Weak transitions in 44Ca

    International Nuclear Information System (INIS)

    Tauhata, L.; Marques, A.

    1972-01-01

    Energy levels and gamma radiation transitions of Ca 44 are experimentally determined, mainly the weak transition at 564 KeV and 728 KeV. The decay scheme and the method used (coincidence with Ge-Li detector) are also presented [pt

  15. Ca(2+ release events in cardiac myocytes up close: insights from fast confocal imaging.

    Directory of Open Access Journals (Sweden)

    Vyacheslav M Shkryl

    Full Text Available The spatio-temporal properties of Ca(2+ transients during excitation-contraction coupling and elementary Ca(2+ release events (Ca(2+ sparks were studied in atrial and ventricular myocytes with ultra-fast confocal microscopy using a Zeiss LSM 5 LIVE system that allows sampling rates of up to 60 kHz. Ca(2+ sparks which originated from subsarcolemmal junctional sarcoplasmic reticulum (j-SR release sites in atrial myocytes were anisotropic and elongated in the longitudinal direction of the cell. Ca(2+ sparks in atrial cells originating from non-junctional SR and in ventricular myocytes were symmetrical. Ca(2+ spark recording in line scan mode at 40,000 lines/s uncovered step-like increases of [Ca(2+]i. 2-D imaging of Ca(2+ transients revealed an asynchronous activation of release sites and allowed the sequential recording of Ca(2+ entry through surface membrane Ca(2+ channels and subsequent activation of Ca(2+-induced Ca(2+ release. With a latency of 2.5 ms after application of an electrical stimulus, Ca(2+ entry could be detected that was followed by SR Ca(2+ release after an additional 3 ms delay. Maximum Ca(2+ release was observed 4 ms after the beginning of release. The timing of Ca(2+ entry and release was confirmed by simultaneous [Ca(2+]i and membrane current measurements using the whole cell voltage-clamp technique. In atrial cells activation of discrete individual release sites of the j-SR led to spatially restricted Ca(2+ release events that fused into a peripheral ring of elevated [Ca(2+]i that subsequently propagated in a wave-like fashion towards the center of the cell. In ventricular myocytes asynchronous Ca(2+ release signals from discrete sites with no preferential subcellular location preceded the whole-cell Ca(2+ transient. In summary, ultra-fast confocal imaging allows investigation of Ca(2+ signals with a time resolution similar to patch clamp technique, however in a less invasive fashion.

  16. Regulation of the voltage-gated Ca2+ channel CaVα2δ-1 subunit expression by the transcription factor Egr-1.

    Science.gov (United States)

    González-Ramírez, Ricardo; Martínez-Hernández, Elizabeth; Sandoval, Alejandro; Gómez-Mora, Kimberly; Felix, Ricardo

    2018-04-23

    It is well known that the Ca V α 2 δ auxiliary subunit regulates the density of high voltage-activated Ca 2+ channels in the plasma membrane and that alterations in their functional expression might have implications in the pathophysiology of diverse human diseases such as neuropathic pain. However, little is known concerning the transcriptional regulation of this protein. We previously characterized the promoter of Ca V α 2 δ, and here we report its regulation by the transcription factor Egr-1. Using the neuroblastoma N1E-115 cells, we found that Egr-1 interacts specifically with its binding site in the promoter, affecting the transcriptional regulation of Ca V α 2 δ. Overexpression and knockdown analysis of Egr-1 showed significant changes in the transcriptional activity of the Ca V α 2 δ promoter. Egr-1 also regulated the expression of Ca V α 2 δ at the level of protein. Also, functional studies showed that Egr-1 knockdown significantly decreases Ca 2+ currents in dorsal root ganglion (DRG) neurons, while overexpression of the transcription factor increased Ca 2+ currents in the F11 cell line, a hybrid of DRG and N18TG2 neuroblastoma cells. Studying the effects of Egr-1 on the transcriptional expression of Ca V α 2 δ could help to understand the regulatory mechanisms of this protein in both health and disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. Ca2+ transport and signalling in enamel cells

    Science.gov (United States)

    Nurbaeva, Meerim K.; Eckstein, Miriam; Feske, Stefan

    2016-01-01

    Abstract Dental enamel is one of the most remarkable examples of matrix‐mediated biomineralization. Enamel crystals form de novo in a rich extracellular environment in a stage‐dependent manner producing complex microstructural patterns that are visually stunning. This process is orchestrated by specialized epithelial cells known as ameloblasts which themselves undergo striking morphological changes, switching function from a secretory role to a cell primarily engaged in ionic transport. Ameloblasts are supported by a host of cell types which combined represent the enamel organ. Fully mineralized enamel is the hardest tissue found in vertebrates owing its properties partly to the unique mixture of ionic species represented and their highly organized assembly in the crystal lattice. Among the main elements found in enamel, Ca2+ is the most abundant ion, yet how ameloblasts modulate Ca2+ dynamics remains poorly known. This review describes previously proposed models for passive and active Ca2+ transport, the intracellular Ca2+ buffering systems expressed in ameloblasts and provides an up‐dated view of current models concerning Ca2+ influx and extrusion mechanisms, where most of the recent advances have been made. We also advance a new model for Ca2+ transport by the enamel organ. PMID:27510811

  18. Ca isotopic fractionation patterns in forest ecosystems

    Science.gov (United States)

    Kurtz, A. C.; Takagi, K.

    2012-12-01

    Calcium stable isotope ratios are an emerging tracer of the biogeochemical cycle of Ca that are just beginning to see significant application to forest ecosystems. The primary source of isotopic fractionation in these systems is discrimination against light Ca during uptake by plant roots. Cycling of vegetation-fractionated Ca establishes isotopically distinct Ca pools within a forest ecosystem. In some systems, the shallow soil exchangeable Ca pool is isotopically heavy relative to Ca inputs. This has been explained by preferential removal of light Ca from the soil. In other systems, the soil exchange pool is isotopically light relative to inputs, which is explained by recycling of plant-fractionated light Ca back into soil. Thus vegetation uptake of light Ca has been called on to account for both isotopically heavy and light Ca in the shallow soil exchange pools. We interpret patterns in ecosystem δ44Ca with the aid of a simple box model of the forest Ca cycle. We suggest that the δ44Ca of exchangeable Ca in the shallow soil pool primarily reflects the relative magnitude of three key fluxes in a forest Ca cycle, 1) the flux of external Ca into the system via weathering or atmospheric deposition, 2) the uptake flux of Ca from soils into the vegetation pool, and 3) the return flux of Ca to shallow soils via remineralization of leaf litter. Two observations that emerge from our model may aid in the application of Ca isotopes to provide insight into the forest Ca cycle. First, regardless of the magnitude of both vegetation Ca uptake and isotopic fractionation, the δ44Ca of the soil exchange pool will equal the input δ44Ca unless the plant uptake and remineralization fluxes are out of balance. A second observation is that the degree to which the shallow soil exchange pool δ44Ca can differ from the input ratio is controlled by the relative rates of biological uptake and external Ca input. Significant differences between soil exchange and input δ44Ca are seen only

  19. Accelerator mass spectrometry of 41Ca with a positive-ion source and the UNILAC accelerator

    International Nuclear Information System (INIS)

    Steinhof, A.; Henning, W.; Mueller, M.; Roeckl, E.; Schuell, D.; Korschinek, G.; Nolte, E.; Paul, M.

    1987-06-01

    We have made first tests investigating the performance characteristics of the UNILAC accelerator system at GSI, in order to explore the sensitivity achievable in accelerator mass spectrometry (AMS) of 41 Ca with high-current positive-ion sources. Positively charged Ca 3+ ions of up to about 100 micro-amperes electrical current were injected from a penning-sputter source and, after further stripping to Ca 9+ , accelerated to 14.3 MeV/nucleon. The combination of velocity-focussing accelerator and magnetic ion-beam transport system completely eliminated background from the other calcium isotopes. Full-stripping and detection of 41 Ca 20+ ions with a magnetic spectrograph provides separation from isobaric 41 K and, at present, a level of sensitivity of 41 Ca/Ca ≅ 2x10 -15 . Future improvements and implications for dating of Pleistoscene samples will be discussed. (orig.)

  20. Unresolved problems in superconductivity of CaC6

    NARCIS (Netherlands)

    Mazin, I.I.; Boen, L.; Dolgov, O.V.; Golubov, Alexandre Avraamovitch; Bachelet, G.B.; Giantomassi, M.; Andersen, O.K.

    2007-01-01

    We discuss the current status of the theory of the “high-temperature” superconductivity in intercalated graphites YbC6 and CaC6. We emphasize that while the general picture of conventional, phonon-driven superconductivity has already emerged and is generally accepted, there are still interesting

  1. Detection of TRPV4 channel current-like activity in Fawn Hooded hypertensive (FHH rat cerebral arterial muscle cells.

    Directory of Open Access Journals (Sweden)

    Debebe Gebremedhin

    Full Text Available The transient receptor potential vallinoid type 4 (TRPV4 is a calcium entry channel known to modulate vascular function by mediating endothelium-dependent vasodilation. The present study investigated if isolated cerebral arterial myocytes of the Fawn Hooded hypertensive (FHH rat, known to display exaggerated KCa channel current activity and impaired myogenic tone, express TRPV4 channels at the transcript and protein level and exhibit TRPV4-like single-channel cationic current activity. Reverse transcription polymerase chain reaction (RT-PCR, Western blot, and immunostaining analysis detected the expression of mRNA transcript and translated protein of TRPV4 channel in FHH rat cerebral arterial myocytes. Patch clamp recording of single-channel current activity identified the presence of a single-channel cationic current with unitary conductance of ~85 pS and ~96 pS at hyperpolarizing and depolarizing potentials, respectively, that was inhibited by the TRPV4 channel antagonist RN 1734 or HC 067074 and activated by the potent TRPV4 channel agonist GSK1016790A. Application of negative pressure via the interior of the patch pipette increased the NPo of the TRPV4-like single-channel cationic current recorded in cell-attached patches at a patch potential of 60 mV that was inhibited by prior application of the TRPV4 channel antagonist RN 1734 or HC 067047. Treatment with the TRPV4 channel agonist GSK1016790A caused concentration-dependent increase in the NPo of KCa single-channel current recorded in cell-attached patches of cerebral arterial myocytes at a patch potential of 40 mV, which was not influenced by pretreatment with the voltage-gated L-type Ca2+ channel blocker nifedipine or the T-type Ca2+ channel blocker Ni2+. These findings demonstrate that FHH rat cerebral arterial myocytes express mRNA transcript and translated protein for TRPV4 channel and display TRPV4-like single-channel cationic current activity that was stretch-sensitive and

  2. A Devil in the Details: Matrix-Dependent 40Ca42Ca++/42Ca+ and Its Effects on Estimates of the Initial 41Ca/40Ca in the Solar System

    Science.gov (United States)

    McKeegan, K. D.; Liu, M.-C.

    2015-07-01

    Ian Hutcheon established that the molecular ion interference 40Ca42Ca++/42Ca+ on 41K+ is strongly dependent on the mineral analyzed. Correction for this "matrix effect" led to a downward revision of the initial 41Ca/40Ca of the solar system.

  3. Common barrel and forward CA tracking algorithm

    Energy Technology Data Exchange (ETDEWEB)

    Mykhailo, Pugach [Goethe-Universitaet, Frankfurt (Germany); Frankfurt Institute for Advanced Studies, Frankfurt (Germany); KINR, Kyiv (Ukraine); Gorbunov, Sergey; Kisel, Ivan [Goethe-Universitaet, Frankfurt (Germany); Frankfurt Institute for Advanced Studies, Frankfurt (Germany); Collaboration: PANDA-Collaboration

    2016-07-01

    There are complex detector setups which consist of barrel (cylindrical) and forward parts, and such systems require a special approach in the registered charged particles track finding procedure. Currently the tracking procedure might be performed in both parts of such detector independently from each other, but the final goal on this direction is a creation of a combined tracking, which will work in both parts of the detector simultaneously. The basic algorithm is based on Kalman Filter (KF) and Cellular Automata (CA). And the tracking procedure in such a complex system is rather extraordinary as far as it requires 2 different models to describe the state vector of segments of the reconstructed track in the mathematical apparatus of the KF-algorithm. To overcome this specifics a mathematical apparatus of transition matrices must be developed and implemented, so that one can transfer from one track model to another. Afterwards the work of the CA is performed, which reduces to segments sorting, their union into track-candidates and selection of the best candidates by the chi-square criteria after fitting of the track-candidate by the KF. In this report the algorithm, status and perspectives of such combined tracking are described.

  4. Physical interaction of junctophilin and the CaV1.1 C terminus is crucial for skeletal muscle contraction.

    Science.gov (United States)

    Nakada, Tsutomu; Kashihara, Toshihide; Komatsu, Masatoshi; Kojima, Katsuhiko; Takeshita, Toshikazu; Yamada, Mitsuhiko

    2018-04-24

    Close physical association of Ca V 1.1 L-type calcium channels (LTCCs) at the sarcolemmal junctional membrane (JM) with ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR) is crucial for excitation-contraction coupling (ECC) in skeletal muscle. However, the molecular mechanism underlying the JM targeting of LTCCs is unexplored. Junctophilin 1 (JP1) and JP2 stabilize the JM by bridging the sarcolemmal and SR membranes. Here, we examined the roles of JPs in localization and function of LTCCs. Knockdown of JP1 or JP2 in cultured myotubes inhibited LTCC clustering at the JM and suppressed evoked Ca 2+ transients without disrupting JM structure. Coimmunoprecipitation and GST pull-down assays demonstrated that JPs physically interacted with 12-aa residues in the proximal C terminus of the Ca V 1.1. A JP1 mutant lacking the C terminus including the transmembrane domain (JP1ΔCT) interacted with the sarcolemmal/T-tubule membrane but not the SR membrane. Expression of this mutant in adult mouse muscles in vivo exerted a dominant-negative effect on endogenous JPs, impairing LTCC-RyR coupling at triads without disrupting JM morphology, and substantially reducing Ca 2+ transients without affecting SR Ca 2+ content. Moreover, the contractile force of the JP1ΔCT-expressed muscle was dramatically reduced compared with the control. Taken together, JPs recruit LTCCs to the JM through physical interaction and ensure robust ECC at triads in skeletal muscle.

  5. Pb2+ Modulates Ca2+ Membrane Permeability In Paramecium

    Science.gov (United States)

    Bernal-Martínez, Juan; Ortega Soto, Arturo

    2004-09-01

    Intracellular recording experiments in current clamp configuration were done to evaluate whether Pb2+ modulates ionic membrane permeability in the fresh water Paramecium tetraurelia. It was found that Pb2+ triggers in a dose-dependent manner, a burst of spontaneous action potentials followed by a robust and sustained after hyper-polarization. In addition, Pb2+ increased the frequency of firing the spontaneous Ca2+-Action Potential and also, the duration of Ca2+-Action Potential, in a dose and reversibly-dependent manner. These results suggest that Pb2+ increases calcium membrane permeability of Paramecium and probably activates a calcium-dependent-potassium conductance in the ciliate.

  6. Lattice Dynamics of fcc Ca

    DEFF Research Database (Denmark)

    Stassis, C.; Zaretsky, J.; Misemer, D. K.;

    1983-01-01

    A large single crystal of FCC Ca was grown and was used to study the lattice dynamics of this divalent metal by coherent inelastic neutron scattering. The phonon dispersion curves were measured, at room temperature, along the [ξ00], [ξξ0], [ξξξ], and [0ξ1] symmetry directions. The dispersion curves...... to the propagation of elastic waves. The frequencies of the T1[ξξ0] branch for ξ between approximately 0.5 and 0.8 are slightly above the velocity-of-sound line determined from the low-frequency measurements. Since a similar effect has been observed in FCC Yb, it is natural to assume that the anomalous dispersion...... bear a striking resemblance to those of FCC Yb, which is also a divalent metal with an electronic band structure similar to that of Ca. In particular, the shear moduli c44 and (c11-c 12)/2 differ by a factor of 3.4, which implies that FCC Ca (like FCC Yb) is very anisotropic with regard...

  7. CORRELATION OF {sup 48}Ca, {sup 50}Ti, AND {sup 138}La HETEROGENEITY IN THE ALLENDE REFRACTORY INCLUSIONS

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Hsin-Wei; Lee, Typhoon; Lee, Der-Chuen; Chen, Jiang-Chang, E-mail: hart.chen@bristol.ac.uk [Institute of Earth Sciences, Academia Sinica, Taipei, Taiwan, ROC (China)

    2015-06-10

    Precise determinations of {sup 48}Ca anomalies in Allende calcium–aluminum-rich inclusions (CAIs) are reported in this work. There are endemic positive {sup 48}Ca/{sup 44}Ca anomalies in all analyzed CAIs after normalization to {sup 42}Ca/{sup 44}Ca, and it is clearly shown that there is no simple correlation between {sup 48}Ca/{sup 44}Ca and {sup 50}Ti/{sup 48}Ti anomalies, in agreement with Jungck et al. Compared to the {sup 48}Ca/{sup 44}Ca versus {sup 50}Ti/{sup 48}Ti correlation line defined by differentiated meteorites, reported by Chen et al., the CAIs plot to elevated {sup 50}Ti/{sup 48}Ti. Assuming the {sup 48}Ca/{sup 44}Ca anomalies of both CAIs and differentiated meteorites came from the same source, excess {sup 50}Ti anomalies in CAIs can be calculated by subtracting the part associated with {sup 48}Ca/{sup 44}Ca. These excesses show a linear correlation with {sup 138}La anomalies, a neutrino-process nuclide. According to current stellar nucleosynthetic models, we therefore suggest that the solar system {sup 48}Ca, {sup 50}Ti, and {sup 138}La isotopic variations are made of mixtures between grains condensed from ejecta of neutron-rich accretion-induced SNe Ia and the O/Ne–O/C zone of core-collapse SNe II.

  8. RFX6 Regulates Insulin Secretion by Modulating Ca2+ Homeostasis in Human β Cells

    Directory of Open Access Journals (Sweden)

    Vikash Chandra

    2014-12-01

    Full Text Available Development and function of pancreatic β cells involve the regulated activity of specific transcription factors. RFX6 is a transcription factor essential for mouse β cell differentiation that is mutated in monogenic forms of neonatal diabetes. However, the expression and functional roles of RFX6 in human β cells, especially in pathophysiological conditions, are poorly explored. We demonstrate the presence of RFX6 in adult human pancreatic endocrine cells. Using the recently developed human β cell line EndoC-βH2, we show that RFX6 regulates insulin gene transcription, insulin content, and secretion. Knockdown of RFX6 causes downregulation of Ca2+-channel genes resulting in the reduction in L-type Ca2+-channel activity that leads to suppression of depolarization-evoked insulin exocytosis. We also describe a previously unreported homozygous missense RFX6 mutation (p.V506G that is associated with neonatal diabetes, which lacks the capacity to activate the insulin promoter and to increase Ca2+-channel expression. Our data therefore provide insights for understanding certain forms of neonatal diabetes.

  9. Current limiters

    Energy Technology Data Exchange (ETDEWEB)

    Loescher, D.H. [Sandia National Labs., Albuquerque, NM (United States). Systems Surety Assessment Dept.; Noren, K. [Univ. of Idaho, Moscow, ID (United States). Dept. of Electrical Engineering

    1996-09-01

    The current that flows between the electrical test equipment and the nuclear explosive must be limited to safe levels during electrical tests conducted on nuclear explosives at the DOE Pantex facility. The safest way to limit the current is to use batteries that can provide only acceptably low current into a short circuit; unfortunately this is not always possible. When it is not possible, current limiters, along with other design features, are used to limit the current. Three types of current limiters, the fuse blower, the resistor limiter, and the MOSFET-pass-transistor limiters, are used extensively in Pantex test equipment. Detailed failure mode and effects analyses were conducted on these limiters. Two other types of limiters were also analyzed. It was found that there is no best type of limiter that should be used in all applications. The fuse blower has advantages when many circuits must be monitored, a low insertion voltage drop is important, and size and weight must be kept low. However, this limiter has many failure modes that can lead to the loss of over current protection. The resistor limiter is simple and inexpensive, but is normally usable only on circuits for which the nominal current is less than a few tens of milliamperes. The MOSFET limiter can be used on high current circuits, but it has a number of single point failure modes that can lead to a loss of protective action. Because bad component placement or poor wire routing can defeat any limiter, placement and routing must be designed carefully and documented thoroughly.

  10. Spin current

    CERN Document Server

    Valenzuela, Sergio O; Saitoh, Eiji; Kimura, Takashi

    2017-01-01

    Since the discovery of the giant magnetoresistance effect in magnetic multilayers in 1988, a new branch of physics and technology, called spin-electronics or spintronics, has emerged, where the flow of electrical charge as well as the flow of electron spin, the so-called “spin current,” are manipulated and controlled together. The physics of magnetism and the application of spin current have progressed in tandem with the nanofabrication technology of magnets and the engineering of interfaces and thin films. This book aims to provide an introduction and guide to the new physics and applications of spin current, with an emphasis on the interaction between spin and charge currents in magnetic nanostructures.

  11. Regulation of Ca2+ channels by SNAP-25 via recruitment of syntaxin-1 from plasma membrane clusters

    DEFF Research Database (Denmark)

    Toft-Bertelsen, Trine Lisberg; Ziomkiewicz, Iwona; Houy, Sébastien

    2016-01-01

    expression recruits syntaxin-1 from clusters on the plasma membrane, thereby increasing the immunoavailability of syntaxin-1 and leading indirectly to Ca(2+) current inhibition. Expression of Munc18-1, which recruits syntaxin-1 within the exocytotic pathway, does not modulate Ca(2+) channels, whereas...... overexpression of the syntaxin-binding protein Doc2B or ubMunc13-2 increases syntaxin-1 immunoavailability and concomitantly down-regulates Ca(2+) currents. Similar findings were obtained upon chemical cholesterol depletion, leading directly to syntaxin-1 cluster dispersal and Ca(2+) current inhibition. We...

  12. Heart failure-induced changes of voltage-gated Ca2+ channels and cell excitability in rat cardiac postganglionic neurons.

    Science.gov (United States)

    Tu, Huiyin; Liu, Jinxu; Zhang, Dongze; Zheng, Hong; Patel, Kaushik P; Cornish, Kurtis G; Wang, Wei-Zhong; Muelleman, Robert L; Li, Yu-Long

    2014-01-15

    Chronic heart failure (CHF) is characterized by decreased cardiac parasympathetic and increased cardiac sympathetic nerve activity. This autonomic imbalance increases the risk of arrhythmias and sudden death in patients with CHF. We hypothesized that the molecular and cellular alterations of cardiac postganglionic parasympathetic (CPP) neurons located in the intracardiac ganglia and sympathetic (CPS) neurons located in the stellate ganglia (SG) possibly link to the cardiac autonomic imbalance in CHF. Rat CHF was induced by left coronary artery ligation. Single-cell real-time PCR and immunofluorescent data showed that L (Ca(v)1.2 and Ca(v)1.3), P/Q (Ca(v)2.1), N (Ca(v)2.2), and R (Ca(v)2.3) types of Ca2+ channels were expressed in CPP and CPS neurons, but CHF decreased the mRNA and protein expression of only the N-type Ca2+ channels in CPP neurons, and it did not affect mRNA and protein expression of all Ca2+ channel subtypes in the CPS neurons. Patch-clamp recording confirmed that CHF reduced N-type Ca2+ currents and cell excitability in the CPP neurons and enhanced N-type Ca2+ currents and cell excitability in the CPS neurons. N-type Ca2+ channel blocker (1 μM ω-conotoxin GVIA) lowered Ca2+ currents and cell excitability in the CPP and CPS neurons from sham-operated and CHF rats. These results suggest that CHF reduces the N-type Ca2+ channel currents and cell excitability in the CPP neurons and enhances the N-type Ca2+ currents and cell excitability in the CPS neurons, which may contribute to the cardiac autonomic imbalance in CHF.

  13. Spontaneous release from mossy fiber terminals inhibits Ni2+-sensitive T-type Ca2+ channels of CA3 pyramidal neurons in the rat organotypic hippocampal slice.

    Science.gov (United States)

    Reid, Christopher A; Xu, Shenghong; Williams, David A

    2008-01-01

    Mossy fibers (axons arising from dentate granule cells) form large synaptic contacts exclusively onto the proximal apical dendrites of CA3 pyramidal neurons. They can generate large synaptic currents that occur in close proximity to the soma. These properties mean that active conductance in the proximal apical dendrite could have a disproportionate influence on CA3 pyramidal neuron excitability. Ni(2+)-sensitive T-type Ca(2+) channels are important modulators of dendritic excitability. Here, we use an optical approach to determine the contribution of Ni(2+) (100 microM)-sensitive Ca(2+) channels to action potential (AP) elicited Ca(2+) flux in the soma, proximal apical and distal apical dendrites. At resting membrane potentials Ni(2+)-sensitive Ca(2+) channels do not contribute to the Ca(2+) signal in the proximal apical dendrite, but do contribute in the other cell regions. Spontaneous release from mossy fiber terminals acting on 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)-sensitive postsynaptic channels underlies a tonic inhibition of Ni(2+)-sensitive channels. Chelating Zn(2+) with CaEDTA blocks CNQX-sensitive changes in Ca(2+) flux implicating a mechanistic role of this ion in T-type Ca(2+) channel block. To test if this inhibition influenced excitability, progressively larger depolarizing pulses were delivered to CA3 pyramidal neurons. CNQX significantly reduced the size of the depolarizing step required to generate APs and increased the absolute number of APs per depolarizing step. This change in AP firing was completely reversed by the addition of Ni(2+). This mechanism may reduce the impact of T-type Ca(2+) channels in a region where large synaptic events are common.

  14. Multiple C-terminal tail Ca(2+)/CaMs regulate Ca(V)1.2 function but do not mediate channel dimerization.

    Science.gov (United States)

    Kim, Eun Young; Rumpf, Christine H; Van Petegem, Filip; Arant, Ryan J; Findeisen, Felix; Cooley, Elizabeth S; Isacoff, Ehud Y; Minor, Daniel L

    2010-12-01

    Interactions between voltage-gated calcium channels (Ca(V)s) and calmodulin (CaM) modulate Ca(V) function. In this study, we report the structure of a Ca(2+)/CaM Ca(V)1.2 C-terminal tail complex that contains two PreIQ helices bridged by two Ca(2+)/CaMs and two Ca(2+)/CaM-IQ domain complexes. Sedimentation equilibrium experiments establish that the complex has a 2:1 Ca(2+)/CaM:C-terminal tail stoichiometry and does not form higher order assemblies. Moreover, subunit-counting experiments demonstrate that in live cell membranes Ca(V)1.2s are monomers. Thus, contrary to previous proposals, the crystallographic dimer lacks physiological relevance. Isothermal titration calorimetry and biochemical experiments show that the two Ca(2+)/CaMs in the complex have different properties. Ca(2+)/CaM bound to the PreIQ C-region is labile, whereas Ca(2+)/CaM bound to the IQ domain is not. Furthermore, neither of lobes of apo-CaM interacts strongly with the PreIQ domain. Electrophysiological studies indicate that the PreIQ C-region has a role in calcium-dependent facilitation. Together, the data show that two Ca(2+)/CaMs can bind the Ca(V)1.2 tail simultaneously and indicate a functional role for Ca(2+)/CaM at the C-region site.

  15. Multiple Ca2+ sensors in secretion

    DEFF Research Database (Denmark)

    Walter, Alexander M; Groffen, Alexander J; Sørensen, Jakob Balslev

    2011-01-01

    Regulated neurotransmitter secretion depends on Ca(2+) sensors, C2 domain proteins that associate with phospholipids and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complexes to trigger release upon Ca(2+) binding. Ca(2+) sensors are thought to prevent spontaneous...

  16. An inhibitory effect of extracellular Ca2+ on Ca2+-dependent exocytosis.

    Directory of Open Access Journals (Sweden)

    Wei Xiong

    Full Text Available AIM: Neurotransmitter release is elicited by an elevation of intracellular Ca(2+ concentration ([Ca(2+](i. The action potential triggers Ca(2+ influx through Ca(2+ channels which causes local changes of [Ca(2+](i for vesicle release. However, any direct role of extracellular Ca(2+ (besides Ca(2+ influx on Ca(2+-dependent exocytosis remains elusive. Here we set out to investigate this possibility on rat dorsal root ganglion (DRG neurons and chromaffin cells, widely used models for studying vesicle exocytosis. RESULTS: Using photolysis of caged Ca(2+ and caffeine-induced release of stored Ca(2+, we found that extracellular Ca(2+ inhibited exocytosis following moderate [Ca(2+](i rises (2-3 µM. The IC(50 for extracellular Ca(2+ inhibition of exocytosis (ECIE was 1.38 mM and a physiological reduction (∼30% of extracellular Ca(2+ concentration ([Ca(2+](o significantly increased the evoked exocytosis. At the single vesicle level, quantal size and release frequency were also altered by physiological [Ca(2+](o. The calcimimetics Mg(2+, Cd(2+, G418, and neomycin all inhibited exocytosis. The extracellular Ca(2+-sensing receptor (CaSR was not involved because specific drugs and knockdown of CaSR in DRG neurons did not affect ECIE. CONCLUSION/SIGNIFICANCE: As an extension of the classic Ca(2+ hypothesis of synaptic release, physiological levels of extracellular Ca(2+ play dual roles in evoked exocytosis by providing a source of Ca(2+ influx, and by directly regulating quantal size and release probability in neuronal cells.

  17. Collective flow in central Ca + Ca and Nb + Nb collisions

    International Nuclear Information System (INIS)

    Fai, G.; Csernai, L.P.; Kapusta, J.I.

    1986-01-01

    Questions related to the entropy, equation of state and collective flow of nuclear matter are important to the authors understanding of high energy nuclear collisions. Completion of the analysis of exclusive measurements on central Ca + Ca and Nb + Nb collisions triggered renewed interest in these problems. In order to address the results of exclusive measurements, however, the complex multifragment final states of high energy nuclear collisions need to be incorporated in a theoretical description. The microcanonical event generator model provides statistically generated complete events that can be compared to the exclusive data on an event-by-event basis. To describe the disassembly of hot nuclear matter the model uses an approximate scheme in which the available final states are populated according to their microcanonical weight in phase space. This statistical description is front-ended with simple geometric ideas to divide the collision system into subsystems and with a prescription to share energy and momentum among the subsystems. Any physical quantity of interest is in principle calculable in the model if sufficient statistics is accumulated

  18. Hexagonal perovskites with cationic vacancies. 4. Ba/sub 8/Re/sub 3/Msup(V)Wvacant/sub 3/O/sub 24/ with Msup(V) = Nb, Ta - perovskite stacking polytypes of 24 L type

    Energy Technology Data Exchange (ETDEWEB)

    Kemmler-Sack, S [Tuebingen Univ. (Germany, F.R.). Inst. fuer Chemie

    1978-11-01

    The yellow perovskite stacking polytypes Ba/sub 8/Re/sub 3/NbWvacant/sub 3/O/sub 24/ and Ba/sub 8/Re/sub 3/TaWvacant/sub 3/O/sub 24/ have a rhombohedral layer structure of 24 L type with 3 formula units in the trigonal setting (Ba/sub 8/Re/sub 3/NbWvacant/sub 3/O/sub 24/: a = 5,82 A; c = 55.6 A; Ba/sub 8/Re/sub 3/TaWvacant/sub 3/O/sub 24/; a = 5,81 A; c = 55.6 A).

  19. Hexagonal perovskites with cationic vacancies. 2. Ba/sub 8/Re/sub 2/W/sub 3/vacant/sub 3/O/sub 24/ - a novel hexagonal perovskite (24 L-type)

    Energy Technology Data Exchange (ETDEWEB)

    Kemmler-Sack, S [Tuebingen Univ. (Germany, F.R.). Inst. fuer Chemie

    1978-07-01

    The yellow Ba/sub 8/Re/sub 2/W/sub 3/vacant/sub 3/O/sub 24/ crystallizes in a rhombohedral layer structure of 24 L-type with a = 5.81/sub 3/ A; c = 55.52/sub 5/ A for the unit cell in trigonal setting and 3 formula units in the cell (rhosub(gef.) = 7.2/sub 6/ g/cm/sup 3/; rhosub(ber.) = 7.37/sub 8/ g/cm/sup 3/).

  20. Hexagonal perovskites with cationic vacancies. 15. Ba/sub 9/Nb/sub 6/Wvacant/sub 2/O/sub 27/ - the first perovskite stacking polytype of rhombohedral 27 L-type

    Energy Technology Data Exchange (ETDEWEB)

    Kemmler-Sack, S [Tuebingen Univ. (Germany, F.R.). Lehrstuhl fuer Anorganische Chemie 2

    1980-02-01

    The perovskite stacking polytype Ba/sub 9/Nb/sub 6/sup(V)Wsup(VI)vacant/sub 2/O/sub 27/ (white) is the first representative of a rhombohedral 27 L-type. The lattice parameters (trigonal setting) are: a = 5.79/sub 3/ A; c = 63.4/sub 1/ A; Z = 3 (rhosub(exp) = 6.4/sub 6/ g/cm/sup 3/; rhosub(calc) = 6.51/sub 2/ g/cm/sup 3/). The corresponding Tasup(V)-compound is isotypic; it tends to develop stacking faults.

  1. Cerebellar Kainate Receptor-Mediated Facilitation of Glutamate Release Requires Ca2+-Calmodulin and PKA

    Directory of Open Access Journals (Sweden)

    Rafael Falcón-Moya

    2018-06-01

    Full Text Available We elucidated the mechanisms underlying the kainate receptor (KAR-mediated facilitatory modulation of synaptic transmission in the cerebellum. In cerebellar slices, KA (3 μM increased the amplitude of evoked excitatory postsynaptic currents (eEPSCs at synapses between axon terminals of parallel fibers (PF and Purkinje neurons. KA-mediated facilitation was antagonized by NBQX under condition where AMPA receptors were previously antagonized. Inhibition of protein kinase A (PKA suppressed the effect of KA on glutamate release, which was also obviated by the prior stimulation of adenylyl cyclase (AC. KAR-mediated facilitation of synaptic transmission was prevented by blocking Ca2+ permeant KARs using philanthotoxin. Furthermore, depletion of intracellular Ca2+ stores by thapsigargin, or inhibition of Ca2+-induced Ca2+-release by ryanodine, abrogated the synaptic facilitation by KA. Thus, the KA-mediated modulation was conditional on extracellular Ca2+ entry through Ca2+-permeable KARs, as well as and mobilization of Ca2+ from intracellular stores. Finally, KAR-mediated facilitation was sensitive to calmodulin inhibitors, W-7 and calmidazolium, indicating that the increased cytosolic [Ca2+] sustaining KAR-mediated facilitation of synaptic transmission operates through a downstream Ca2+/calmodulin coupling. We conclude that, at cerebellar parallel fiber-Purkinje cell synapses, presynaptic KARs mediate glutamate release facilitation, and thereby enhance synaptic transmission through Ca2+-calmodulin dependent activation of adenylyl cyclase/cAMP/protein kinase A signaling.

  2. β-Adrenergic induced SR Ca2+ leak is mediated by an Epac-NOS pathway.

    Science.gov (United States)

    Pereira, Laëtitia; Bare, Dan J; Galice, Samuel; Shannon, Thomas R; Bers, Donald M

    2017-07-01

    Cardiac β-adrenergic receptors (β-AR) and Ca 2+ -Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca 2+ signaling. Elevated diastolic Ca 2+ leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca 2+ leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1). Here we tested whether Epac and NOS function in a single series pathway to increase β-AR induced and CaMKII-dependent SR Ca 2+ leak. Leak was measured as both Ca 2+ spark frequency and tetracaine-induced shifts in SR Ca 2+ , in mouse and rabbit ventricular myocytes. Direct Epac activation by 8-CPT (8-(4-chlorophenylthio)-2'-O-methyl-cAMP) mimicked β-AR-induced SR Ca 2+ leak, and both were blocked by NOS inhibition. The same was true for myocyte CaMKII activation (assessed via a FRET-based reporter) and ryanodine receptor phosphorylation. Inhibitor and phosphorylation studies also implicated phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) downstream of Epac and above NOS activation in this pathway. We conclude that these two independently characterized parallel pathways function mainly via a single series arrangement (β-AR-cAMP-Epac-PI3K-Akt-NOS1-CaMKII) to mediate increased SR Ca 2+ leak. Thus, for β-AR activation the cAMP-PKA branch effects inotropy and lusitropy (by effects on Ca 2+ current and SR Ca 2+ -ATPase), this cAMP-Epac-NOS pathway increases pathological diastolic SR Ca 2+ leak. This pathway distinction may allow novel SR Ca 2+ leak therapeutic targeting in treatment of arrhythmias in heart failure that spare the inotropic and lusitropic effects of the PKA branch. Copyright © 2017 Elsevier Ltd. All

  3. Neutral currents

    International Nuclear Information System (INIS)

    Paschos, E.A.

    1977-01-01

    It is stated that over the past few years considerable progress has been made in the field of weak interactions. The existence of neutral currents involving leptons and hadrons has been established and some of the questions concerning their detailed structure have been answered. This imposes constraints on the gauge theories and has eliminated large classes of models. New questions have also been raised, one of which concerns the conservation laws obeyed by neutral currents. The wide range of investigations is impressive and is expected to continue with new results from particle, nuclear, and atomic physics. Headings include - various aspects of a gauge theory (choice of group, the symmetry breaking scheme, representation assignments for fermion fields); space-time structure; isospin structure; leptonic neutral currents; and atomic experiments. (U.K.)

  4. 2016 Summer California Current Ecosystem CPS Survey (RL1606, EK60)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The cruise sampled the California Current Ecosystem from San Diego, CA to Vancouver Island, BC, CA. Multi-frequency (18-, 38-, 70-, 120-, 200-, and 333-) General...

  5. 2016 Summer California Current Ecosystem CPS Survey (RL1606, EK80)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The cruise sampled the California Current Ecosystem from San Diego, CA to Vancouver Island, BC, CA. Multi-frequency (18-, 38-, 70-, 120-, 200-, and 333-) General...

  6. Neutral currents

    International Nuclear Information System (INIS)

    Aubert, B.

    1994-11-01

    The evidence for the existence of weak neutral current has been a very controverted topics in the early 1970's, as well as the muon did in the 1930's. The history is very rich considering the evolution of the experimental techniques in high energy particle physics. The history of the discovery and the study of weak neutral current is reviewed. Later the quest of the intermediate vector boson continues with the decision of the community to build a large proton antiproton collider. (K.A.). 14 refs., 1 fig

  7. Zebrafish CaV2.1 Calcium Channels Are Tailored for Fast Synchronous Neuromuscular Transmission

    Science.gov (United States)

    Naranjo, David; Wen, Hua; Brehm, Paul

    2015-01-01

    The CaV2.2 (N-type) and CaV2.1 (P/Q-type) voltage-dependent calcium channels are prevalent throughout the nervous system where they mediate synaptic transmission, but the basis for the selective presence at individual synapses still remains an open question. The CaV2.1 channels have been proposed to respond more effectively to brief action potentials (APs), an idea supported by computational modeling. However, the side-by-side comparison of CaV2.1 and CaV2.2 kinetics in intact neurons failed to reveal differences. As an alternative means for direct functional comparison we expressed zebrafish CaV2.1 and CaV2.2 α-subunits, along with their accessory subunits, in HEK293 cells. HEK cells lack calcium currents, thereby circumventing the need for pharmacological inhibition of mixed calcium channel isoforms present in neurons. HEK cells also have a simplified morphology compared to neurons, which improves voltage control. Our measurements revealed faster kinetics and shallower voltage-dependence of activation and deactivation for CaV2.1. Additionally, recordings of calcium current in response to a command waveform based on the motorneuron AP show, directly, more effective activation of CaV2.1. Analysis of calcium currents associated with the AP waveform indicate an approximately fourfold greater open probability (PO) for CaV2.1. The efficient activation of CaV2.1 channels during APs may contribute to the highly reliable transmission at zebrafish neuromuscular junctions. PMID:25650925

  8. Current algebra

    International Nuclear Information System (INIS)

    Jacob, M.

    1967-01-01

    The first three chapters of these lecture notes are devoted to generalities concerning current algebra. The weak currents are defined, and their main properties given (V-A hypothesis, conserved vector current, selection rules, partially conserved axial current,...). The SU (3) x SU (3) algebra of Gell-Mann is introduced, and the general properties of the non-leptonic weak Hamiltonian are discussed. Chapters 4 to 9 are devoted to some important applications of the algebra. First one proves the Adler- Weisberger formula, in two different ways, by either the infinite momentum frame, or the near-by singularities method. In the others chapters, the latter method is the only one used. The following topics are successively dealt with: semi leptonic decays of K mesons and hyperons, Kroll- Ruderman theorem, non leptonic decays of K mesons and hyperons ( ΔI = 1/2 rule), low energy theorems concerning processes with emission (or absorption) of a pion or a photon, super-convergence sum rules, and finally, neutrino reactions. (author) [fr

  9. Current Titles

    Energy Technology Data Exchange (ETDEWEB)

    Various

    2006-06-01

    This booklet is published for those interested in current research being conducted at the National Center for Electron Microscopy. The NCEM is a DOE-designated national user facility and is available at no charge to qualified researchers. Access is controlled by an external steering committee. Interested researchers may contact Jane Cavlina, Administrator, at 510/486-6036.

  10. Current scenario

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Current scenario. India , like other parts of the world, is also facing the problem of increase in the incidence of drug resistance in tuberculosis. Multi-drug resistance (MDR, resistance to RIF & INH) and extensively drug resistant strains (X-DR, resistance to RIF, INH, FQs ...

  11. Hydrolysis of molten CaCl2-CaF2 with additions of CaO

    Directory of Open Access Journals (Sweden)

    Espen Olsen

    2017-10-01

    Full Text Available Calcium halide based molten salts have recently attracted interest for a number of applications such as direct reduction of oxides for metal production and as liquefying agent in cyclic sorption processes for CO2 by CaO from dilute flue gases (Ca-looping. A fundamental aspect of these melts is the possible hydrolysis reaction upon exposure to gaseous H2O forming corrosive and poisonous hydrogen halides. In this work experiments have been performed investigating the formation of HCl and HF from a molten salt consisting of a 13.8 wt% CaF2 in CaCl2 eutectic exposed to a flowing gas consisting of 10 vol% H2O in N2. Hydrolysis has been investigated as function of content of CaO and temperature. HCl and HF are shown to be formed at elevated temperatures; HCl forms to a substantially larger extent than HF. Addition of CaO has a marked, limiting effect on the hydrolysis. Thermodynamic modeling of the reaction indicates activity coefficients for CaO above unity in the system. For cyclic CO2-capture based on thermal swing, it is advisable to keep the temperature in the carbonation (absorption reactor well below 850 ℃ while maintaining a high CaO content if molten CaCl2 is employed. Similar conclusions can be drawn with regards to CaF2.

  12. Photoemission study of Ca-intercalated graphite superconductor CaC6

    International Nuclear Information System (INIS)

    Okazaki, Hiroyuki; Yoshida, Rikiya; Iwai, Keisuke; Noami, Kengo; Muro, Takayuki; Nakamura, Tetsuya; Wakita, Takanori; Muraoka, Yuji; Hirai, Masaaki; Tomioka, Fumiaki; Takano, Yoshihiko; Takenaka, Asami; Toyoda, Masahiro; Oguchi, Tamio; Yokoya, Takayoshi

    2010-01-01

    In this work, we have performed resonant photoemission studies of Ca-intercalated graphite superconductor CaC 6 . Using photon energy of the Ca 2p-3d threshold, the photoemission intensity of the peak at Fermi energy (E F ) is resonantly enhanced. This result provides spectroscopic evidence for the existence of Ca 3d states at E F , and strongly supports that Ca 3d state plays a crucial role for the superconductivity of this material with relatively high T c .

  13. Reactivation of Rate Remapping in CA3.

    Science.gov (United States)

    Schwindel, C Daniela; Navratilova, Zaneta; Ali, Karim; Tatsuno, Masami; McNaughton, Bruce L

    2016-09-07

    The hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as "global" and "rate" remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific "index codes" to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience. The hippocampus is required for memory of events and their spatial contexts. The primary correlate of hippocampal activity is location in space, but multiple memories can occur in the same location. To be useful

  14. Ca2+/cation antiporters (CaCA: Identification, characterization and expression profiling in bread wheat (Triticum aestivum L.

    Directory of Open Access Journals (Sweden)

    Mehak Taneja

    2016-11-01

    Full Text Available The Ca2+/cation antiporters (CaCA superfamily proteins play vital function in Ca2+ ion homeostasis, which is an important event during development and defense response. Molecular characterization of these proteins has been performed in certain plants, but they are still not characterized in Triticum aestivum (bread wheat. Herein, we identified thirty four TaCaCA superfamily proteins, which were classified into TaCAX, TaCCX, TaNCL and TaMHX protein families based on their structural organization and evolutionary relation with earlier reported proteins. Since the T. aestivum comprises an allohexaploid genome, TaCaCA genes were derived from each A, B and D subgenome and homeologous chromosome (HC, except chromosome-group 1. Majority of genes were derived from more than one HCs in each family that were considered as homeologous genes (HGs due to their high similarity with each other. These HGs showed comparable gene and protein structures in terms of exon/intron organization and domain architecture. Majority of TaCaCA proteins comprised two Na_Ca_ex domains. However, TaNCLs consisted of an additional EF-hand domain with calcium binding motifs. Each TaCaCA protein family consisted of about ten transmembrane and two α-repeat regions with specifically conserved signature motifs except TaNCL, which had single α-repeat. Variable expression of most of the TaCaCA genes during various developmental stages suggested their specified role in development. However, constitutively high expression of a few genes like TaCAX1-A and TaNCL1-B indicated their role throughout the plant growth and development. The modulated expression of certain genes during biotic (fungal infections and abiotic stresses (heat, drought, salt suggested their role in stress response. Majority of TaCCX and TaNCL family genes were found highly affected during various abiotic stresses. However the role of individual gene needs to be established. The present study unfolded the opportunity

  15. Ca2+/Cation Antiporters (CaCA): Identification, Characterization and Expression Profiling in Bread Wheat (Triticum aestivum L.).

    Science.gov (United States)

    Taneja, Mehak; Tyagi, Shivi; Sharma, Shailesh; Upadhyay, Santosh Kumar

    2016-01-01

    The Ca 2+ /cation antiporters (CaCA) superfamily proteins play vital function in Ca 2+ ion homeostasis, which is an important event during development and defense response. Molecular characterization of these proteins has been performed in certain plants, but they are still not characterized in Triticum aestivum (bread wheat). Herein, we identified 34 TaCaCA superfamily proteins, which were classified into TaCAX, TaCCX, TaNCL, and TaMHX protein families based on their structural organization and evolutionary relation with earlier reported proteins. Since the T. aestivum comprises an allohexaploid genome, TaCaCA genes were derived from each A, B, and D subgenome and homeologous chromosome (HC), except chromosome-group 1. Majority of genes were derived from more than one HCs in each family that were considered as homeologous genes (HGs) due to their high similarity with each other. These HGs showed comparable gene and protein structures in terms of exon/intron organization and domain architecture. Majority of TaCaCA proteins comprised two Na_Ca_ex domains. However, TaNCLs consisted of an additional EF-hand domain with calcium binding motifs. Each TaCaCA protein family consisted of about 10 transmembrane and two α-repeat regions with specifically conserved signature motifs except TaNCL, which had single α-repeat. Variable expression of most of the TaCaCA genes during various developmental stages suggested their specified role in development. However, constitutively high expression of a few genes like TaCAX1-A and TaNCL1-B indicated their role throughout the plant growth and development. The modulated expression of certain genes during biotic (fungal infections) and abiotic stresses (heat, drought, salt) suggested their role in stress response. Majority of TaCCX and TaNCL family genes were found highly affected during various abiotic stresses. However, the role of individual gene needs to be established. The present study unfolded the opportunity for detail

  16. Aconitine-induced Ca2+ overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats

    International Nuclear Information System (INIS)

    Sun, Gui-bo; Sun, Hong; Meng, Xiang-bao; Hu, Jin; Zhang, Qiang; Liu, Bo; Wang, Min; Xu, Hui-bo; Sun, Xiao-bo

    2014-01-01

    . • Aconitine induces Ca 2+ overload through the activation of L-type Ca 2+ channels. • Aconitine-induced Ca 2+ overload triggers apoptotic responses in vitro and in vivo. • Aconitine promotes apoptotic development via activation of P38 MAPK

  17. Measurements of natural 41Ca concentrations

    International Nuclear Information System (INIS)

    Steinhof, A.

    1989-05-01

    Atomic mass spectroscopic examinations on 41 Ca were carried out in the UNILAC accelerator. A sensitivity of about 10 -15 was achieved. This would allow the measurement of present natural 41 Ca concentrations as soon as the problem of the transmission determination is solved. In this respect suggestions were worked out and their feasibility discussed. The detection of 41 Ca-ions is especially free of background when high UNILAC-energies are applied. An estimation showed a background level corresponding with a 41 Ca concentration of less then 10 -17 referred to 40 Ca. Besides an independent concept for the electromagnetic concentration of 41 Ca with variable concentration factors was developed. After being concentrated up to 50 respectively 25 times the initial concentration in the GSI mass separator, the 41 Ca concentration of three recent deer bones found in the Odenwald was measured by atomic mass spectroscopy in the 14UD-Pelletron Tandem in Rehovot (Israel). The measured 41 Ca concentrations ranged between 10 -14 to 10 -13 with consideration of the concentration factor. A theoretical study of the 41 Ca production in the earth's surface based on cosmic radiation illustrates the influence of trace elements on the neutron flux and thus on the 41 Ca production. This influence might be a possible explanation for the observed amplitude of variation of the 41 Ca concentration in recent bones which are of decisive importance for the feasibility of 41 Ca-related dating. In this work a method is suggested that does not depend on the amplitude of variation mentioned above and which would allow the determination of the erosion rate of rocks by its 41 Ca concentrations. (orig./HP) [de

  18. Bax regulates neuronal Ca2+ homeostasis.

    Science.gov (United States)

    D'Orsi, Beatrice; Kilbride, Seán M; Chen, Gang; Perez Alvarez, Sergio; Bonner, Helena P; Pfeiffer, Shona; Plesnila, Nikolaus; Engel, Tobias; Henshall, David C; Düssmann, Heiko; Prehn, Jochen H M

    2015-01-28

    Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation. Copyright © 2015 the authors 0270-6474/15/351706-17$15.00/0.

  19. The definitive guide to the C&A transformation process

    CERN Document Server

    Mehan, Julie E

    2009-01-01

    'The Definitive Guide to the C&A Transformation' is the first comprehensive manual that sets out to explain the current standards and best practices. The book provides all the information needed to recognize, implement and manage the relevant authorization requirements, and therefore to achieve compliance with federal, local and agency laws and policies. Each chapter not only provides a list of related references but also offers recommendations for additional reading.

  20. Comparative study of anisotropic superconductivity in CaAlSi and CaGaSi

    International Nuclear Information System (INIS)

    Tamegai, T.; Uozato, K.; Kasahara, S.; Nakagawa, T.; Tokunaga, M.

    2005-01-01

    In order to get some insight into the origin of the anomalous angular dependence of H c2 in a layered intermetallic compound CaAlSi, electronic, superconducting, and structural properties are compared between CaAlSi and CaGaSi. The angular dependence of H c2 in CaGaSi is well described by the anisotropic GL model. Parallel to this finding, the pronounced lattice modulation accompanying the superstructure along the c-axis in CaAlSi is absent in CaGaSi. A relatively large specific heat jump at the superconducting transition in CaAlSi compared with CaGaSi indicates the presence of strong electron-phonon coupling in CaAlSi, which may cause the superstructure and the anomalous angular dependence of H c2

  1. Current awareness.

    Science.gov (United States)

    Compagno, C; Brambilla, L; Capitanio, D; Boschi, F; Ranzi, B M; Porro, D

    2001-05-01

    In order to keep subscribers up-to-date with the latest developments in their field, this current awareness service is provided by John Wiley & Sons and contains newly-published material on yeasts. Each bibliography is divided into 10 sections. 1 Books, Reviews & Symposia; 2 General; 3 Biochemistry; 4 Biotechnology; 5 Cell Biology; 6 Gene Expression; 7 Genetics; 8 Physiology; 9 Medical Mycology; 10 Recombinant DNA Technology. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted. (4 weeks journals - search completed 7th Mar. 2001)

  2. Current titles

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-07-01

    This booklet is published for those interested in current research being conducted at the National Center for Electron Microscopy. The NCEM is a DOE-designated national user facility and is available at no charge to qualified researchers. Access is controlled by an external steering committee. Interested researchers may contact Gretchen Hermes at (510) 486-5006 or address below for a User`s Guide. Copies of available papers can be ordered from: Theda Crawford National Center for Electron Microscopy, Lawrence Berkeley Laboratory, One Cyclotron Rd., MS72, Berkeley, California, USA 94720.

  3. Update on vascular endothelial Ca(2+) signalling: A tale of ion channels, pumps and transporters.

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-07-26

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca(2+) signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca(2+) levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca(2+) signals, ranging from brief, localized Ca(2+) pulses to prolonged Ca(2+) oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca(2+) signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca(2+) releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca(2+) removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca(2+) machinery in vascular ECs under both physiological and pathological conditions.

  4. Update on vascular endothelial Ca2+ signalling: A tale of ion channels, pumps and transporters

    Science.gov (United States)

    Moccia, Francesco; Berra-Romani, Roberto; Tanzi, Franco

    2012-01-01

    A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and forms a multifunctional transducing organ that mediates a plethora of cardiovascular processes. The activation of ECs from as state of quiescence is, therefore, regarded among the early events leading to the onset and progression of potentially lethal diseases, such as hypertension, myocardial infarction, brain stroke, and tumor. Intracellular Ca2+ signals have long been know to play a central role in the complex network of signaling pathways regulating the endothelial functions. Notably, recent work has outlined how any change in the pattern of expression of endothelial channels, transporters and pumps involved in the modulation of intracellular Ca2+ levels may dramatically affect whole body homeostasis. Vascular ECs may react to both mechanical and chemical stimuli by generating a variety of intracellular Ca2+ signals, ranging from brief, localized Ca2+ pulses to prolonged Ca2+ oscillations engulfing the whole cytoplasm. The well-defined spatiotemporal profile of the subcellular Ca2+ signals elicited in ECs by specific extracellular inputs depends on the interaction between Ca2+ releasing channels, which are located both on the plasma membrane and in a number of intracellular organelles, and Ca2+ removing systems. The present article aims to summarize both the past and recent literature in the field to provide a clear-cut picture of our current knowledge on the molecular nature and the role played by the components of the Ca2+ machinery in vascular ECs under both physiological and pathological conditions. PMID:22905291

  5. Current ornithology

    CERN Document Server

    1983-01-01

    The appearance of the first volume of a projected series is the occasion for comment on scope, aims, and genesis of the work. The scope of Current Ornithology is all of the biology of birds. Ornithology, as a whole-organism science, is concerned with birds at every level of bi­ ological organization, from the molecular to the community, at least from the Jurassic to the present time, and over every scholarly discipline in which bird biology is done; to say this is merely to expand a dic­ tionary definition of "ornithology. " The aim of the work, to be realized over several volumes, is to present reviews or position statements con­ cerning the active fields of ornithological research. The reviews will be relatively short, and often will be done from the viewpoint of a readily­ identified group or school. Such a work could have come into being at any time within the past fifty years, but that Current Ornithology appears now is a result of events that are only seven to eight years old. One important event wa...

  6. Current Consumption Measurements with a Carrier Aggregation Smartphone

    DEFF Research Database (Denmark)

    Sanchez-Mejias, Rafael; Guo, Yu; Lauridsen, Mads

    2014-01-01

    on this topic. Currently there are only theoretical expansions of LTE release 8 power models available, but this article presents the first publicly available current consumption measurements on a commercial CA-capable UE. In this work it is examined how the activation and use of CA (10 + 10 MHz) affects the UE......Carrier Aggregation (CA) is introduced in LTE release 10 to improve data rates by allowing the User Equipment (UE) to receive data on more than one LTE carrier. The related increased complexity is expected to affect the UE current consumption, but yet no empirical evaluation has been published...

  7. Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak

    Science.gov (United States)

    Sankaranarayanan, Rajiv; Li, Yatong; Greensmith, David J.; Eisner, David A.

    2016-01-01

    Key points Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay.In the presence of β‐adrenergic stimulation, RyR‐mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase.Two forms of Ca leak have been studied, Ca‐sensitising (induced by caffeine) and non‐sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient.Only Ca‐sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine.Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient. Abstract In heart failure, a reduction in Ca transient amplitude and contractile dysfunction can by caused by Ca leak through the sarcoplasmic reticulum (SR) Ca channel (ryanodine receptor, RyR) and/or decreased activity of the SR Ca ATPase (SERCA). We have characterised the effects of two forms of Ca leak (Ca‐sensitising and non‐sensitising) on calcium cycling and compared with those of SERCA inhibition. We measured [Ca2+]i with fluo‐3 in voltage‐clamped rat ventricular myocytes. Increasing SR leak with either caffeine (to sensitise the RyR to Ca activation) or ryanodine (non‐sensitising) had similar effects to SERCA inhibition: decreased systolic [Ca2+]i, increased diastolic [Ca2+]i and slowed decay. However, in the presence of isoproterenol, leak produced a biphasic decay of the Ca transient in the majority of cells while SERCA inhibition produced monophasic decay. Tetracaine reversed the effects of caffeine but not of ryanodine. When caffeine (1 mmol l−1) was added to a cell which displayed Ca waves, the wave frequency initially increased before waves disappeared and biphasic decay developed. Eventually (at higher caffeine concentrations), the

  8. Edward C. Little Water Recycling Plant, El Segundo, CA: CA0063401

    Science.gov (United States)

    Joint EPA and Los Angeles Regional Water Quality Control Board NPDES Permit and Waiver from Secondary Treatment for the West Basin Municipal Water District Edward C. Little Water Recycling Plant, El Segundo, CA: CA0063401

  9. Modeling the current distribution in HTS tapes with transport current and applied magnetic field

    NARCIS (Netherlands)

    Yazawa, T.; Yazawa, Takashi; Rabbers, J.J.; Chevtchenko, O.A.; ten Haken, Bernard; ten Kate, Herman H.J.; Maeda, Hideaki

    1999-01-01

    A numerical model is developed for the current distribution in a high temperature superconducting (HTS) tape, (Bi,Pb)2Sr2 Ca2Cu3Ox-Ag, subjected to a combination of a transport current and an applied magnetic field. This analysis is based on a two-dimensional formulation of Maxwell's equations in

  10. Quantitative assessment of CA1 local circuits: knowledge base for interneuron-pyramidal cell connectivity.

    Science.gov (United States)

    Bezaire, Marianne J; Soltesz, Ivan

    2013-09-01

    In this work, through a detailed literature review, data-mining, and extensive calculations, we provide a current, quantitative estimate of the cellular and synaptic constituents of the CA1 region of the rat hippocampus. Beyond estimating the cell numbers of GABAergic interneuron types, we calculate their convergence onto CA1 pyramidal cells and compare it with the known input synapses on CA1 pyramidal cells. The convergence calculation and comparison are also made for excitatory inputs to CA1 pyramidal cells. In addition, we provide a summary of the excitatory and inhibitory convergence onto interneurons. The quantitative knowledge base assembled and synthesized here forms the basis for data-driven, large-scale computational modeling efforts. Additionally, this work highlights specific instances where the available data are incomplete, which should inspire targeted experimental projects toward a more complete quantification of the CA1 neurons and their connectivity. Copyright © 2013 Wiley Periodicals, Inc.

  11. California Basin Studies (CaBS)

    International Nuclear Information System (INIS)

    Gorsline, D.S.

    1991-01-01

    The California Continental Borderland's present configuration dates from about 4 to 5 X 10 6 years Before Present (B.P.) and is the most recent of several configurations of the southern California margin that have evolved after the North America Plate over-rode the East Pacific Rise about 30 X 10 6 years ago. The present morphology is a series of two to three northwest-southeast trending rows of depressions separated by banks and insular ridges. Two inner basins, Santa Monica and San Pedro, have been the site for the Department of Energy-funded California Basin Study (CaBS) Santa Monica and San Pedro Basins contain post-Miocene sediment thicknesses of about 2.5 and 1.5 km respectively. During the Holocene (past 10,000 years) about 10-12 m have accumulated. The sediment entered the basin by one or a combination of processes including particle infall (mainly as bioaggregates) from surface waters, from nepheloid plumes (surface, mid-depths and near-bottom), from turbidity currents, mass movements, and to a very minor degree direct precipitation. In Santa Monica Basin, during the last century, particle infall and nepheloid plume transport have been the most common processes. The former dominates in the central basin floor in water depths from 900 to 945 m. where a characteristic silt-clay with a typical mean diameter of about 0.006 mm, phi standard deviation

  12. Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling.

    Science.gov (United States)

    Swietach, Pawel; Youm, Jae-Boum; Saegusa, Noriko; Leem, Chae-Hun; Spitzer, Kenneth W; Vaughan-Jones, Richard D

    2013-05-28

    Ca(2+) signaling regulates cell function. This is subject to modulation by H(+) ions that are universal end-products of metabolism. Due to slow diffusion and common buffers, changes in cytoplasmic [Ca(2+)] ([Ca(2+)]i) or [H(+)] ([H(+)]i) can become compartmentalized, leading potentially to complex spatial Ca(2+)/H(+) coupling. This was studied by fluorescence imaging of cardiac myocytes. An increase in [H(+)]i, produced by superfusion of acetate (salt of membrane-permeant weak acid), evoked a [Ca(2+)]i rise, independent of sarcolemmal Ca(2+) influx or release from mitochondria, sarcoplasmic reticulum, or acidic stores. Photolytic H(+) uncaging from 2-nitrobenzaldehyde also raised [Ca(2+)]i, and the yield was reduced following inhibition of glycolysis or mitochondrial respiration. H(+) uncaging into buffer mixtures in vitro demonstrated that Ca(2+) unloading from proteins, histidyl dipeptides (HDPs; e.g., carnosine), and ATP can underlie the H(+)-evoked [Ca(2+)]i rise. Raising [H(+)]i tonically at one end of a myocyte evoked a local [Ca(2+)]i rise in the acidic microdomain, which did not dissipate. The result is consistent with uphill Ca(2+) transport into the acidic zone via Ca(2+)/H(+) exchange on diffusible HDPs and ATP molecules, energized by the [H(+)]i gradient. Ca(2+) recruitment to a localized acid microdomain was greatly reduced during intracellular Mg(2+) overload or by ATP depletion, maneuvers that reduce the Ca(2+)-carrying capacity of HDPs. Cytoplasmic HDPs and ATP underlie spatial Ca(2+)/H(+) coupling in the cardiac myocyte by providing ion exchange and transport on common buffer sites. Given the abundance of cellular HDPs and ATP, spatial Ca(2+)/H(+) coupling is likely to be of general importance in cell signaling.

  13. Cuento: Sangre de caña

    Directory of Open Access Journals (Sweden)

    Segundo Benjamín Corredor

    1967-09-01

    Full Text Available El viento se convertía en murmullo contra las hojas de los cañaverales y contra los techos semipelados del rancho. También menguaba el calor que maduraba los plantíos de caña y que hacía más efusiva la sangre de los moradores.

  14. Impact of seawater [Ca2+] on the calcification and calcite Mg / Ca of Amphistegina lessonii

    NARCIS (Netherlands)

    Mewes, A.; Langer, G.; Thoms, S.; Nehrke, G.; Reichart, G. J.; de Nooijer, L. J.; Bijma, J.

    2015-01-01

    Mg / Ca ratios in foraminiferal tests are routinely used as paleotemperature proxies, but on long timescales, they also hold the potential to reconstruct past seawater Mg / Ca. The impact of both temperature and seawater Mg / Ca on Mg incorporation in Foraminifera has been quantified by a number of

  15. Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines.

    Directory of Open Access Journals (Sweden)

    Brenda L Bloodgood

    2009-09-01

    Full Text Available Excitatory synapses on mammalian principal neurons are typically formed onto dendritic spines, which consist of a bulbous head separated from the parent dendrite by a thin neck. Although activation of voltage-gated channels in the spine and stimulus-evoked constriction of the spine neck can influence synaptic signals, the contribution of electrical filtering by the spine neck to basal synaptic transmission is largely unknown. Here we use spine and dendrite calcium (Ca imaging combined with 2-photon laser photolysis of caged glutamate to assess the impact of electrical filtering imposed by the spine morphology on synaptic Ca transients. We find that in apical spines of CA1 hippocampal neurons, the spine neck creates a barrier to the propagation of current, which causes a voltage drop and results in spatially inhomogeneous activation of voltage-gated Ca channels (VGCCs on a micron length scale. Furthermore, AMPA and NMDA-type glutamate receptors (AMPARs and NMDARs, respectively that are colocalized on individual spine heads interact to produce two kinetically and mechanistically distinct phases of synaptically evoked Ca influx. Rapid depolarization of the spine triggers a brief and large Ca current whose amplitude is regulated in a graded manner by the number of open AMPARs and whose duration is terminated by the opening of small conductance Ca-activated potassium (SK channels. A slower phase of Ca influx is independent of AMPAR opening and is determined by the number of open NMDARs and the post-stimulus potential in the spine. Biphasic synaptic Ca influx only occurs when AMPARs and NMDARs are coactive within an individual spine. These results demonstrate that the morphology of dendritic spines endows associated synapses with specialized modes of signaling and permits the graded and independent control of multiple phases of synaptic Ca influx.

  16. Ca-Dependent Folding of Human Calumenin

    Science.gov (United States)

    Mazzorana, Marco; Hussain, Rohanah; Sorensen, Thomas

    2016-01-01

    Human calumenin (hCALU) is a six EF-hand protein belonging to the CREC family. As other members of the family, it is localized in the secretory pathway and regulates the activity of SERCA2a and of the ryanodine receptor in the endoplasmic reticulum (ER). We have studied the effects of Ca2+ binding to the protein and found it to attain a more compact structure upon ion binding. Circular Dichroism (CD) measurements suggest a major rearrangement of the protein secondary structure, which reversibly switches from disordered at low Ca2+ concentrations to predominantly alpha-helical when Ca2+ is added. SAXS experiments confirm the transition from an unfolded to a compact structure, which matches the structural prediction of a trilobal fold. Overall our experiments suggest that calumenin is a Ca2+ sensor, which folds into a compact structure, capable of interacting with its molecular partners, when Ca2+ concentration within the ER reaches the millimolar range. PMID:26991433

  17. CaMKII in the Cardiovascular System: Sensing Redox States

    Science.gov (United States)

    Erickson, Jeffrey R.; He, B. Julie; Grumbach, Isabella M.; Anderson, Mark E

    2013-01-01

    The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca2+/CaM). Under conditions of sustained exposure to elevated Ca2+/CaM CaMKII transitions into a Ca2+/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine 287 in the CaMKII regulatory domain ‘traps’ CaMKII into an open configuration even after Ca2+/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca2+/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease. PMID:21742790

  18. Miniature excitatory synaptic currents in cultured hippocampal neurons.

    Science.gov (United States)

    Finch, D M; Fisher, R S; Jackson, M B

    1990-06-04

    We performed patch clamp recordings in the whole cell mode from cultured embryonic mouse hippocampal neurons. In bathing solutions containing tetrodotoxin (TTX), the cells showed spontaneous inward currents (SICs) ranging in size from 1 to 100 pA. Several observations indicated that the SICs were miniature excitatory synaptic currents mediated primarily by non-NMDA (N-methyl-D-aspartate) excitatory amino acid receptors: the rising phase of SICs was fast (1 ms to half amplitude at room temperature) and smooth, suggesting unitary events. The SICs were blocked by the broad-spectrum glutamate receptor antagonist gamma-D-glutamylglycine (DGG), but not by the selective NMDA-receptor antagonist D-2-amino-5-phosphonovaleric acid (5-APV). SICs were also blocked by desensitizing concentrations of quisqualate. Incubating cells in tetanus toxin, which blocks exocytotic transmitter release, eliminated SICs. The presence of SICs was consistent with the morphological arrangement of glutamatergic innervation in the cell cultures demonstrated immunohistochemically. Spontaneous outward currents (SOCs) were blocked by bicuculline and presumed to be mediated by GABAA receptors. This is consistent with immunohistochemical demonstration of GABAergic synapses. SIC frequency was increased in a calcium dependent manner by bathing the cells in a solution high in K+, and application of the dihydropyridine L-type calcium channel agonist BAY K 8644 increased the frequency of SICs. Increases in SIC frequency produced by high K+ solutions were reversed by Cd2+ and omega-conotoxin GVIA, but not by the selective L-type channel antagonist nimodipine. This suggested that presynaptic L-type channels were in a gating mode that was not blocked by nimodipine, and/or that another class of calcium channel makes a dominant contribution to excitatory transmitter release.

  19. Engineering of a novel Ca2+-regulated kinesin molecular motor using a calmodulin dimer linker

    International Nuclear Information System (INIS)

    Shishido, Hideki; Maruta, Shinsaku

    2012-01-01

    Highlights: ► Engineered kinesin–M13 and calmodulin involving single cysteine were prepared. ► CaM mutant was cross-linked to dimer by bifunctional thiol reactive reagent. ► Kinesin–M13 was dimerized via CaM dimer in the presence of calcium. ► Function of the engineered kinesin was regulated by a Ca 2+ -calmodulin dimer linker. -- Abstract: The kinesin–microtubule system holds great promise as a molecular shuttle device within biochips. However, one current barrier is that such shuttles do not have “on–off” control of their movement. Here we report the development of a novel molecular motor powered by an accelerator and brake system, using a kinesin monomer and a calmodulin (CaM) dimer. The kinesin monomer, K355, was fused with a CaM target peptide (M13 peptide) at the C-terminal part of the neck region (K355–M13). We also prepared CaM dimers using CaM mutants (Q3C), (R86C), or (A147C) and crosslinkers that react with cysteine residues. Following induction of K355–M13 dimerization with CaM dimers, we measured K355–M13 motility and found that it can be reversibly regulated in a Ca 2+ -dependent manner. We also found that velocities of K355–M13 varied depending on the type and crosslink position of the CaM dimer used; crosslink length also had a moderate effect on motility. These results suggest Ca 2+ -dependent dimerization of K355–M13 could be used as a novel molecular shuttle, equipped with an accelerator and brake system, for biochip applications.

  20. A quantitative description of tubular system Ca2+ handling in fast‐ and slow‐twitch muscle fibres

    Science.gov (United States)

    Cully, Tanya R.; Edwards, Joshua N.; Murphy, Robyn M.

    2016-01-01

    Key points Current methods do not allow a quantitative description of Ca2+ movements across the tubular (t‐) system membrane without isolating the membranes from their native skeletal muscle fibre.Here we present a fluorescence‐based method that allows determination of the t‐system [Ca2+] transients and derivation of t‐system Ca2+ fluxes in mechanically skinned skeletal muscle fibres. Differences in t‐system Ca2+‐handling properties between fast‐ and slow‐twitch fibres from rat muscle are resolved for the first time using this new technique.The method can be used to study Ca2+ handling of the t‐system and allows direct comparisons of t‐system Ca2+ transients and Ca2+ fluxes between groups of fibres and fibres from different strains of animals. Abstract The tubular (t‐) system of skeletal muscle is an internalization of the plasma membrane that maintains a large Ca2+ gradient and exchanges Ca2+ between the extracellular and intracellular environments. Little is known of the Ca2+‐handling properties of the t‐system as the small Ca2+ fluxes conducted are difficult to resolve with conventional methods. To advance knowledge in this area we calibrated t‐system‐trapped rhod‐5N inside skinned fibres from rat and [Ca2+]t‐sys, allowing confocal measurements of Ca2+‐dependent changes in rhod‐5N fluorescence during rapid changes in the intracellular ionic environment to be converted to [Ca2+] transients in the t‐system ([Ca2+]t‐sys (t)). Furthermore, t‐system Ca2+‐buffering power was determined so that t‐system Ca2+ fluxes could be derived from [Ca2+]t‐sys (t). With this new approach, we show that rapid depletion of sarcoplasmic reticulum (SR) Ca2+ induced a robust store‐operated Ca2+ entry (SOCE) in fast‐ and slow‐twitch fibres, reducing [Ca2+]t‐sys to fibre types. Abruptly introducing internal solutions with 1 mm Mg2+ and [Ca2+]cyto (28 nm–1.3 μm) to Ca2+‐depleted fibres generated t‐system Ca2+ uptake rates

  1. A quantitative description of tubular system Ca(2+) handling in fast- and slow-twitch muscle fibres.

    Science.gov (United States)

    Cully, Tanya R; Edwards, Joshua N; Murphy, Robyn M; Launikonis, Bradley S

    2016-06-01

    Current methods do not allow a quantitative description of Ca(2+) movements across the tubular (t-) system membrane without isolating the membranes from their native skeletal muscle fibre. Here we present a fluorescence-based method that allows determination of the t-system [Ca(2+) ] transients and derivation of t-system Ca(2+) fluxes in mechanically skinned skeletal muscle fibres. Differences in t-system Ca(2+) -handling properties between fast- and slow-twitch fibres from rat muscle are resolved for the first time using this new technique. The method can be used to study Ca(2+) handling of the t-system and allows direct comparisons of t-system Ca(2+) transients and Ca(2+) fluxes between groups of fibres and fibres from different strains of animals. The tubular (t-) system of skeletal muscle is an internalization of the plasma membrane that maintains a large Ca(2+) gradient and exchanges Ca(2+) between the extracellular and intracellular environments. Little is known of the Ca(2+) -handling properties of the t-system as the small Ca(2+) fluxes conducted are difficult to resolve with conventional methods. To advance knowledge in this area we calibrated t-system-trapped rhod-5N inside skinned fibres from rat and [Ca(2+) ]t-sys , allowing confocal measurements of Ca(2+) -dependent changes in rhod-5N fluorescence during rapid changes in the intracellular ionic environment to be converted to [Ca(2+) ] transients in the t-system ([Ca(2+) ]t-sys (t)). Furthermore, t-system Ca(2+) -buffering power was determined so that t-system Ca(2+) fluxes could be derived from [Ca(2+) ]t-sys (t). With this new approach, we show that rapid depletion of sarcoplasmic reticulum (SR) Ca(2+) induced a robust store-operated Ca(2+) entry (SOCE) in fast- and slow-twitch fibres, reducing [Ca(2+) ]t-sys to fibre types. Abruptly introducing internal solutions with 1 mm Mg(2+) and [Ca(2+) ]cyto (28 nm-1.3 μm) to Ca(2+) -depleted fibres generated t-system Ca(2+) uptake rates dependent on [Ca(2

  2. Effects of calcium (Ca(2+)) extrusion mechanisms on electrophysiological properties in a hypoglossal motoneuron: insight from a mathematical model.

    Science.gov (United States)

    Horn, Kyle G; Solomon, Irene C

    2014-01-01

    Spike-frequency dynamics and spike shape can provide insight into the types of ion channels present in any given neuron and give a sense for the precise response any neuron may have to a given input stimulus. Motoneuron firing frequency over time is especially important due to its direct effect on motor output. Of particular interest is intracellular Ca(2+), which exerts a powerful influence on both firing properties over time and spike shape. In order to better understand the cellular mechanisms for the regulation of intracellular Ca(2+) and their effect on spiking behavior, we have modified a computational model of an HM to include a variety of Ca(2+) handling processes. For the current study, a series of HM models that include Ca(2+) pumps, Na(+)/Ca(2+) exchangers, and a generic exponential decay of excess Ca(2+) were generated. Simulations from these models indicate that although each extrusion mechanism exerts a similar effect on voltage, the firing properties change distinctly with the inclusion of additional Ca(2+)-related mechanisms: BK channels, Ca(2+) buffering, and diffusion of [Ca(2+)]i modeled via a linear diffusion partial differential equation. While an exponential decay of Ca(2+) seems to adequately capture short-term changes in firing frequency seen in biological data, internal diffusion of Ca(2+) appears to be necessary for capturing longer term frequency changes. © 2014 Elsevier B.V. All rights reserved.

  3. SNL/CA Facilities Management Design Standards Manual

    Energy Technology Data Exchange (ETDEWEB)

    Rabb, David [Sandia National Lab. (SNL-CA), Livermore, CA (United States); Clark, Eva [Sandia National Lab. (SNL-CA), Livermore, CA (United States)

    2014-12-01

    At Sandia National Laboratories in California (SNL/CA), the design, construction, operation, and maintenance of facilities is guided by industry standards, a graded approach, and the systematic analysis of life cycle benefits received for costs incurred. The design of the physical plant must ensure that the facilities are "fit for use," and provide conditions that effectively, efficiently, and safely support current and future mission needs. In addition, SNL/CA applies sustainable design principles, using an integrated whole-building design approach, from site planning to facility design, construction, and operation to ensure building resource efficiency and the health and productivity of occupants. The safety and health of the workforce and the public, any possible effects on the environment, and compliance with building codes take precedence over project issues, such as performance, cost, and schedule.

  4. Distribution of voltage-dependent and intracellular Ca2+ channels in submucosal neurons from rat distal colon.

    Science.gov (United States)

    Rehn, Matthias; Bader, Sandra; Bell, Anna; Diener, Martin

    2013-09-01

    We recently observed a bradykinin-induced increase in the cytosolic Ca2+ concentration in submucosal neurons of rat colon, an increase inhibited by blockers of voltage-dependent Ca2+ (Ca(v)) channels. As the types of Ca(v) channels used by this part of the enteric nervous system are unknown, the expression of various Ca(v) subunits has been investigated in whole-mount submucosal preparations by immunohistochemistry. Submucosal neurons, identified by a neuronal marker (microtubule-associated protein 2), are immunoreactive for Ca(v)1.2, Ca(v)1.3 and Ca(v)2.2, expression being confirmed by reverse transcription plus the polymerase chain reaction. These data agree with previous observations that the inhibition of L- and N-type Ca2+ currents strongly inhibits the response to bradykinin. However, whole-cell patch-clamp experiments have revealed that bradykinin does not enhance Ca2+ inward currents under voltage-clamp conditions. Consequently, bradykinin does not directly interact with Ca(v) channels. Instead, the kinin-induced Ca2+ influx is caused indirectly by the membrane depolarization evoked by this peptide. As intracellular Ca2+ channels on Ca(2+)-storing organelles can also contribute to Ca2+ signaling, their expression has been investigated by imaging experiments and immunohistochemistry. Inositol 1,4,5-trisphosphate (IP3) receptors (IP3R) have been functionally demonstrated in submucosal neurons loaded with the Ca(2+)-sensitive fluorescent dye, fura-2. Histamine, a typical agonist coupled to the phospholipase C pathway, induces an increase in the fura-2 signal ratio, which is suppressed by 2-aminophenylborate, a blocker of IP3 receptors. The expression of IP3R1 has been confirmed by immunohistochemistry. In contrast, ryanodine, tested over a wide concentration range, evokes no increase in the cytosolic Ca2+ concentration nor is there immunohistochemical evidence for the expression of ryanodine receptors in these neurons. Thus, rat submucosal neurons are equipped

  5. Dysregulation of Neuronal Ca2+ Channel Linked to Heightened Sympathetic Phenotype in Prohypertensive States

    OpenAIRE

    Larsen, Hege E.; Bardsley, Emma N.; Lefkimmiatis, Konstantinos; Paterson, David J.

    2016-01-01

    Hypertension is associated with impaired nitric oxide (NO)–cyclic nucleotide (CN)-coupled intracellular calcium (Ca2+) homeostasis that enhances cardiac sympathetic neurotransmission. Because neuronal membrane Ca2+ currents are reduced by NO-activated S-nitrosylation, we tested whether CNs affect membrane channel conductance directly in neurons isolated from the stellate ganglia of spontaneously hypertensive rats (SHRs) and their normotensive controls. Using voltage-clamp and cAMP–protein kin...

  6. A role for CaV1 and calcineurin signaling in depolarization-induced changes in neuronal DNA methylation.

    Science.gov (United States)

    Hannon, Eilis; Chand, Annisa N; Evans, Mark D; Wong, Chloe C Y; Grubb, Matthew S; Mill, Jonathan

    2015-07-01

    Direct manipulations of neuronal activity have been shown to induce changes in DNA methylation (DNAm), although little is known about the cellular signaling pathways involved. Using reduced representation bisulfite sequencing, we identify DNAm changes associated with moderate chronic depolarization in dissociated rat hippocampal cultures. Consistent with previous findings, these changes occurred primarily in the vicinity of loci implicated in neuronal function, being enriched in intergenic regions and underrepresented in CpG-rich promoter regulatory regions. We subsequently used 2 pharmacological interventions (nifedipine and FK-506) to test whether the identified changes depended on 2 interrelated signaling pathways known to mediate multiple forms of neuronal plasticity. Both pharmacological manipulations had notable effects on the extent and magnitude of depolarization-induced DNAm changes indicating that a high proportion of activity-induced changes are likely to be mediated by calcium entry through L-type Ca V 1 channels and/or downstream signaling via the calcium-dependent phosphatase calcineurin.

  7. Juvenile Hippocampal CA2 Region Expresses Aggrecan

    Directory of Open Access Journals (Sweden)

    Asako Noguchi

    2017-05-01

    Full Text Available Perineuronal nets (PNNs are distributed primarily around inhibitory interneurons in the hippocampus, such as parvalbumin-positive interneurons. PNNs are also present around excitatory neurons in some brain regions and prevent plasticity in these neurons. A recent study demonstrated that PNNs also exist around mouse hippocampal pyramidal cells, which are the principle type of excitatory neurons, in the CA2 subregion and modulate the excitability and plasticity of these neurons. However, the development of PNNs in the CA2 region during postnatal maturation was not fully investigated. This study found that a main component of PNNs, aggrecan, existed in the pyramidal cell layer of the putative CA2 subarea prior to the appearance of the CA2 region, which was defined by the CA2 marker protein regulator of G protein signaling 14 (RGS14. We also found that aggrecan immunoreactivity was more evident in the anterior sections of the CA2 area than the posterior sections, which suggests that the function of CA2 PNNs varies along the anterior-posterior axis.

  8. Blockade of Ca2+-activated K+ channels in T cells: an option for the treatment of multiple sclerosis?

    DEFF Research Database (Denmark)

    Madsen, Lars Siim; Christophersen, Palle; Olesen, Søren-Peter

    2005-01-01

    Voltage- and Ca(2+)-dependent K(+) channels in the membrane of both T and B lymphocytes are important for the cellular immune response. In the current issue of the European Journal of Immunology, Reich et al. demonstrate that selective blockade of the intermediate-conductance Ca(2+)-activated K(+...

  9. Physician Knowledge and Awareness of CA-125 As a Screen for Ovarian Cancer in the Asymptomatic, Average-Risk Population

    Science.gov (United States)

    Stewart, Sherri L.; Rim, Sun Hee; Gelb, Cynthia A.

    2012-01-01

    Effective early detection strategies for ovarian cancer do not exist. Current screening guidelines recommend against routine screening using CA-125 alone or in combination with transvaginal ultrasonography (TVS). In this study, the authors used the 2008 "DocStyles" survey to measure clinician beliefs about the effectiveness of CA-125 and…

  10. PGC-1α accelerates cytosolic Ca2+ clearance without disturbing Ca2+ homeostasis in cardiac myocytes

    International Nuclear Information System (INIS)

    Chen, Min; Wang, Yanru; Qu, Aijuan

    2010-01-01

    Energy metabolism and Ca 2+ handling serve critical roles in cardiac physiology and pathophysiology. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) is a multi-functional coactivator that is involved in the regulation of cardiac mitochondrial functional capacity and cellular energy metabolism. However, the regulation of PGC-1α in cardiac Ca 2+ signaling has not been fully elucidated. To address this issue, we combined confocal line-scan imaging with off-line imaging processing to characterize calcium signaling in cultured adult rat ventricular myocytes expressing PGC-1α via adenoviral transduction. Our data shows that overexpressing PGC-1α improved myocyte contractility without increasing the amplitude of Ca 2+ transients, suggesting that myofilament sensitivity to Ca 2+ increased. Interestingly, the decay kinetics of global Ca 2+ transients and Ca 2+ waves accelerated in PGC-1α-expressing cells, but the decay rate of caffeine-elicited Ca 2+ transients showed no significant change. This suggests that sarcoplasmic reticulum (SR) Ca 2+ -ATPase (SERCA2a), but not Na + /Ca 2+ exchange (NCX) contribute to PGC-1α-induced cytosolic Ca 2+ clearance. Furthermore, PGC-1α induced the expression of SERCA2a in cultured cardiac myocytes. Importantly, overexpressing PGC-1α did not disturb cardiac Ca 2+ homeostasis, because SR Ca 2+ load and the propensity for Ca 2+ waves remained unchanged. These data suggest that PGC-1α can ameliorate cardiac Ca 2+ cycling and improve cardiac work output in response to physiological stress. Unraveling the PGC-1α-calcium handing pathway sheds new light on the role of PGC-1α in the therapy of cardiac diseases.

  11. Size and receptor density of glutamatergic synapses: a viewpoint from left-right asymmetry of CA3-CA1 connections

    Directory of Open Access Journals (Sweden)

    Yoshiaki Shinohara

    2009-07-01

    Full Text Available Synaptic plasticity is considered to be the main mechanism for learning and memory. Excitatory synapses in the cerebral cortex and hippocampus undergo plastic changes during development and in response to electric stimulation. It is widely accepted that this process is mediated by insertion and elimination of various glutamate receptors. In a series of recent investigations on left-right asymmetry of hippocampal CA3-CA1 synapses, glutamate receptor subunits have been found to have distinctive expression patterns that depend on the postsynaptic density (PSD area. Particularly notable are the GluR1 AMPA receptor subunit and NR2B NMDA receptor subunit, where receptor density has either a supra-linear (GluR1 AMPA or inverse (NR2B NMDAR relationship to the PSD area. We review current understanding of structural and physiological synaptic plasticity and propose a scheme to classify receptor subtypes by their expression pattern with respect to PSD area.

  12. Intercellular communication within the rat anterior pituitary gland. XV. Properties of spontaneous and LHRH-induced Ca2+ transients in the transitional zone of the rat anterior pituitary in situ.

    Science.gov (United States)

    Hattori, Kazuki; Shirasawa, Nobuyuki; Suzuki, Hikaru; Otsuka, Takanobu; Wada, Ikuo; Yashiro, Takashi; Herbert, Damon C; Soji, Tsuyoshi; Hashitani, Hikaru

    2013-01-01

    In the transitional zone of the rat anterior pituitary, spontaneous and LHRH-induced Ca(2+) dynamics were visualized using fluo-4 fluorescence Ca(2+) imaging. A majority of cells exhibited spontaneous Ca(2+) transients, while small populations of cells remained quiescent. Approximately 70% of spontaneously active cells generated fast, oscillatory Ca(2+) transients that were inhibited by cyclopiazonic acid (10 μm) but not nicardipine (1 μm), suggesting that Ca(2+) handling by endoplasmic reticulum, but not Ca(2+) influx through voltage-dependent L-type Ca(2+) channels, plays a fundamental role in their generation. In the adult rat anterior pituitary, LHRH (100 μg/ml) caused a transient increase in the Ca(2+) level in a majority of preparations taken from the morning group rats killed between 0930 h and 1030 h. However, the second application of LHRH invariably failed to elevate Ca(2+) levels, suggesting that the long-lasting refractoriness to LHRH stimulation was developed upon the first challenge of LHRH. In contrast, LHRH had no effect in most preparations taken from the afternoon group rats euthanized between 1200 h and 1400 h. In the neonatal rat anterior pituitary, LHRH caused a suppression of spontaneous Ca(2+) transients. Strikingly, the second application of LHRH was capable of reproducing the suppression of Ca(2+) signals, indicating that the refractoriness to LHRH had not been established in neonatal rats. These results suggest that responsiveness to LHRH has a long-term refractoriness in adult rats, and that the physiological LHRH surge may be clocked in the morning. Moreover, LHRH-induced excitation and associated refractoriness appear to be incomplete in neonatal rats and may be acquired during development.

  13. Evaluation of Serum CEA, CA19-9, CA72-4, CA125 and Ferritin as Diagnostic Markers and Factors of Clinical Parameters for Colorectal Cancer.

    Science.gov (United States)

    Gao, Yanfeng; Wang, Jinping; Zhou, Yue; Sheng, Sen; Qian, Steven Y; Huo, Xiongwei

    2018-02-09

    Blood-based protein biomarkers have recently shown as simpler diagnostic modalities for colorectal cancer, while their association with clinical pathological characteristics is largely unknown. In this study, we not only examined the sensitivity and reliability of single/multiple serum markers for diagnosis, but also assessed their connection with pathological parameters from a total of 279 colorectal cancer patients. Our study shown that glycoprotein carcinoembryonic antigen (CEA) owns the highest sensitivity among single marker in the order of CEA > cancer antigen 72-4 (CA72-4) > cancer antigen 19-9 9 (CA19-9) > ferritin > cancer antigen 125 (CA125), while the most sensitive combined-markers for two to five were: CEA + CA72-4; CEA + CA72-4 + CA125; CEA + CA19-9 + CA72-4 + CA125; and CEA + CA19-9 + CA72-4 + CA125 + ferritin, respectively. We also demonstrated that patients who had positive preoperative serum CEA, CA19-9, or CA72-4 were more likely with lymph node invasion, positive CA125 were prone to have vascular invasion, and positive CEA or CA125 were correlated with perineural invasion. In addition, positive CA19-9, CA72-4, or CA125 was associated with poorly differentiated tumor, while CEA, CA19-9, CA72-4, CA125 levels were positively correlated with pathological tumor-node-metastasis stages. We here conclude that combined serum markers can be used to not only diagnose colorectal cancer, but also appraise the tumor status for guiding treatment, evaluation of curative effect, and prognosis of patients.

  14. Oncogenicity of L-type amino-acid transporter 1 (LAT1) revealed by targeted gene disruption in chicken DT40 cells: LAT1 is a promising molecular target for human cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Ohkawa, Mayumi [Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai 980-8578 (Japan); Ohno, Yoshiya [Laboratory of Immunobiology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe-shi, Hyogo 650-8530 (Japan); Masuko, Kazue; Takeuchi, Akiko; Suda, Kentaro; Kubo, Akihiro; Kawahara, Rieko; Okazaki, Shogo [Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, 4-1 Kowakae 3-chome, Higashiosaka-shi, Osaka 577-8502 (Japan); Tanaka, Toshiyuki [Laboratory of Immunobiology, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe-shi, Hyogo 650-8530 (Japan); Saya, Hideyuki [Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8502 (Japan); Seki, Masayuki; Enomoto, Takemi [Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Aramaki, Aoba-ku, Sendai 980-8578 (Japan); Yagi, Hideki [Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, 4-1 Kowakae 3-chome, Higashiosaka-shi, Osaka 577-8502 (Japan); Hashimoto, Yoshiyuki [Tohoku University, Sendai (Japan); Masuko, Takashi, E-mail: masuko@phar.kindai.ac.jp [Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, 4-1 Kowakae 3-chome, Higashiosaka-shi, Osaka 577-8502 (Japan)

    2011-03-25

    Highlights: {yields} We established LAT1 amino-acid transporter-disrupted DT40 cells. {yields} LAT1-disrupted cells showed slow growth and lost the oncogenicity. {yields} siRNA and mAb inhibited human tumor growth in vitro and in vivo. {yields} LAT1 is a promising target molecule for cancer therapy. -- Abstract: L-type amino-acid transporter 1 (LAT1) is the first identified light chain of CD98 molecule, disulfide-linked to a heavy chain of CD98. Following cDNA cloning of chicken full-length LAT1, we have constructed targeting vectors for the disruption of chicken LAT1 gene from genomic DNA of chicken LAT1 consisting of 5.4 kb. We established five homozygous LAT1-disrupted (LAT1{sup -/-}) cell clones, derived from a heterozygous LAT1{sup +/-} clone of DT40 chicken B cell line. Reactivity of anti-chicken CD98hc monoclonal antibody (mAb) with LAT1{sup -/-} DT40 cells was markedly decreased compared with that of wild-type DT40 cells. All LAT1{sup -/-} cells were deficient in L-type amino-acid transporting activity, although alternative-splice variant but not full-length mRNA of LAT1 was detected in these cells. LAT1{sup -/-} DT40 clones showed outstandingly slow growth in liquid culture and decreased colony-formation capacity in soft agar compared with wild-type DT40 cells. Cell-cycle analyses indicated that LAT1{sup -/-} DT40 clones have prolonged cell-cycle phases compared with wild-type or LAT1{sup +/-} DT40 cells. Knockdown of human LAT1 by small interfering RNAs resulted in marked in vitro cell-growth inhibition of human cancer cells, and in vivo tumor growth of HeLa cells in athymic mice was significantly inhibited by anti-human LAT1 mAb. All these results indicate essential roles of LAT1 in the cell proliferation and occurrence of malignant phenotypes and that LAT1 is a promising candidate as a molecular target of human cancer therapy.

  15. Oncogenicity of L-type amino-acid transporter 1 (LAT1) revealed by targeted gene disruption in chicken DT40 cells: LAT1 is a promising molecular target for human cancer therapy

    International Nuclear Information System (INIS)

    Ohkawa, Mayumi; Ohno, Yoshiya; Masuko, Kazue; Takeuchi, Akiko; Suda, Kentaro; Kubo, Akihiro; Kawahara, Rieko; Okazaki, Shogo; Tanaka, Toshiyuki; Saya, Hideyuki; Seki, Masayuki; Enomoto, Takemi; Yagi, Hideki; Hashimoto, Yoshiyuki; Masuko, Takashi

    2011-01-01

    Highlights: → We established LAT1 amino-acid transporter-disrupted DT40 cells. → LAT1-disrupted cells showed slow growth and lost the oncogenicity. → siRNA and mAb inhibited human tumor growth in vitro and in vivo. → LAT1 is a promising target molecule for cancer therapy. -- Abstract: L-type amino-acid transporter 1 (LAT1) is the first identified light chain of CD98 molecule, disulfide-linked to a heavy chain of CD98. Following cDNA cloning of chicken full-length LAT1, we have constructed targeting vectors for the disruption of chicken LAT1 gene from genomic DNA of chicken LAT1 consisting of 5.4 kb. We established five homozygous LAT1-disrupted (LAT1 -/- ) cell clones, derived from a heterozygous LAT1 +/- clone of DT40 chicken B cell line. Reactivity of anti-chicken CD98hc monoclonal antibody (mAb) with LAT1 -/- DT40 cells was markedly decreased compared with that of wild-type DT40 cells. All LAT1 -/- cells were deficient in L-type amino-acid transporting activity, although alternative-splice variant but not full-length mRNA of LAT1 was detected in these cells. LAT1 -/- DT40 clones showed outstandingly slow growth in liquid culture and decreased colony-formation capacity in soft agar compared with wild-type DT40 cells. Cell-cycle analyses indicated that LAT1 -/- DT40 clones have prolonged cell-cycle phases compared with wild-type or LAT1 +/- DT40 cells. Knockdown of human LAT1 by small interfering RNAs resulted in marked in vitro cell-growth inhibition of human cancer cells, and in vivo tumor growth of HeLa cells in athymic mice was significantly inhibited by anti-human LAT1 mAb. All these results indicate essential roles of LAT1 in the cell proliferation and occurrence of malignant phenotypes and that LAT1 is a promising candidate as a molecular target of human cancer therapy.

  16. Reverse mode Na+/Ca2+ exchange mediated by STIM1 contributes to Ca2+ influx in airway smooth muscle following agonist stimulation

    Directory of Open Access Journals (Sweden)

    Fox Jane

    2010-12-01

    Full Text Available Abstract Background Agonist stimulation of airway smooth muscle (ASM results in IP3 mediated Ca2+ release from the sarcoplasmic reticulum followed by the activation of store operated and receptor operated non-selective cation channels. Activation of these non-selective channels also results in a Na+ influx. This localised increase in Na+ levels can potentially switch the Na+/Ca2+ exchanger into reverse mode and so result in a further influx of Ca2+. The aim of this study was to characterise the expression and physiological function of the Na+/Ca2+ exchanger in cultured human bronchial smooth muscle cells and determine its contribution to agonist induced Ca2+ influx into these cells. Methods The expression profile of NCX (which encodes the Na+/Ca2+ exchanger homologues in cultured human bronchial smooth muscle cells was determined by reverse transcriptase PCR. The functional activity of reverse mode NCX was investigated using a combination of whole cell patch clamp, intracellular Ca2+ measurements and porcine airway contractile analyses. KB-R7943 (an antagonist for reverse mode NCX and target specific siRNA were utilised as tools to inhibit NCX function. Results NCX1 protein was detected in cultured human bronchial smooth muscle cells (HBSMC cells and NCX1.3 was the only mRNA transcript variant detected. A combination of intracellular Na+ loading and addition of extracellular Ca2+ induced an outwardly rectifying current which was augmented following stimulation with histamine. This outwardly rectifying current was inhibited by 10 μM KB-R7943 (an antagonist of reverse mode NCX1 and was reduced in cells incubated with siRNA against NCX1. Interestingly, this outwardly rectifying current was also inhibited following knockdown of STIM1, suggesting for the first time a link between store operated cation entry and NCX1 activation. In addition, 10 μM KB-R7943 inhibited agonist induced changes in cytosolic Ca2+ and induced relaxation of porcine

  17. Regulated release of Ca2+ from respiring mitochondria by Ca2+/2H+ antiport.

    Science.gov (United States)

    Fiskum, G; Lehninger, A L

    1979-07-25

    Simultaneous measurements of oxygen consumption and transmembrane transport of Ca2+, H+, and phosphate show that the efflux of Ca2+ from respiring tightly coupled rat liver mitochondria takes place by an electroneutral Ca2+/2H+ antiport process that is ruthenium red-insensitive and that is regulated by the oxidation-reduction state of the mitochondrial pyridine nucleotides. When mitochondrial pyridine nucleotides are kept in a reduced steady state, the efflux of Ca2+ is inhibited; when they are in an oxidized state, Ca2+ efflux is activated. These processes were demonstrated by allowing phosphate-depleted mitochondria respiring on succinate in the presence of rotenone to take up Ca2+ from the medium. Upon subsequent addition of ruthenium red to block Ca2+ transport via the electrophoretic influx pathway, and acetoacetate, to bring mitochondrial pyridine nucleotides into the oxidized state, Ca2+ efflux and H+ influx ensued. The observed H+ influx/Ca2+ efflux ratio was close to the value 2.0 predicted for the operation of an electrically neutral Ca2+/2H+ antiport process.

  18. Reduced endogenous Ca2+ buffering speeds active zone Ca2+ signaling.

    Science.gov (United States)

    Delvendahl, Igor; Jablonski, Lukasz; Baade, Carolin; Matveev, Victor; Neher, Erwin; Hallermann, Stefan

    2015-06-09

    Fast synchronous neurotransmitter release at the presynaptic active zone is triggered by local Ca(2+) signals, which are confined in their spatiotemporal extent by endogenous Ca(2+) buffers. However, it remains elusive how rapid and reliable Ca(2+) signaling can be sustained during repetitive release. Here, we established quantitative two-photon Ca(2+) imaging in cerebellar mossy fiber boutons, which fire at exceptionally high rates. We show that endogenous fixed buffers have a surprisingly low Ca(2+)-binding ratio (∼ 15) and low affinity, whereas mobile buffers have high affinity. Experimentally constrained modeling revealed that the low endogenous buffering promotes fast clearance of Ca(2+) from the active zone during repetitive firing. Measuring Ca(2+) signals at different distances from active zones with ultra-high-resolution confirmed our model predictions. Our results lead to the concept that reduced Ca(2+) buffering enables fast active zone Ca(2+) signaling, suggesting that the strength of endogenous Ca(2+) buffering limits the rate of synchronous synaptic transmission.

  19. Extremely Elevated CA 125 and CA 19-9 in Endometrioma; A Case Series

    Directory of Open Access Journals (Sweden)

    Vugar Bayramov

    2010-03-01

    Full Text Available Although endometriosis is a benign condition, increased levels of the tumor markers CA 125 and CA 19-9 may be seen. However, these tumor markers reach to very high levels, rarely. In this report, 4 patients between 20 and 43 year-old with extremely elevated CA 125, CA 19-9 and CA 15-3 levels are discussed. In endometriosis extremely increased tumor markers are determined in the case of ruptured endometrioma cyst. There are two mechanisms to clarify extremely elevated levels of CA 125 in endometriosis. First, the peritoneal irritation of CA 125 molecule after the rupture of endometioma cyst and CA 125 secretion from the periton. And the second is penetration of the CA 125 moecule easily to the circulation through the peritoneal endothelial surface after the cyst rupture. In conclusion, the diagnosis of ruptured endometrioma cyst should be kept in mind especially in young patients with extremely elevated serum CA 125 levels with regard to the history and ultrasonographical signs and invasive procedures should be avoided.

  20. EnviroAtlas - Fresno, CA - Block Groups

    Data.gov (United States)

    U.S. Environmental Protection Agency — This EnviroAtlas dataset is the base layer for the Fresno, CA EnviroAtlas area. The block groups are from the US Census Bureau and are included/excluded based on...

  1. Preparation and Properties of Nanoparticles of Calcium Phosphates With Various Ca/P Ratios.

    Science.gov (United States)

    Sun, Limin; Chow, Laurence C; Frukhtbeyn, Stanislav A; Bonevich, John E

    2010-01-01

    This study aimed at preparing and studying the properties of nanoparticles of calcium phosphate (nCaP) with Ca/P ratios ranging from 1.0 to 1.67 using a spray-drying technique. Micro-structural analyses suggested that the nCaPs with Ca/P ratios of 1.67 to 1.33 were nano-sized amorphous calcium phosphate (ACP) containing varying amounts of acid phosphate and carbonate. The nCaP with Ca/P ratio of 1 contained only nano-sized low crystalline dicalcium phosphate (DCP). BET measurements of the nCaPs showed specific surface areas of (12 ± 2 to 50 ± 1) m(2)/g, corresponding to estimated equivalent spherical diameters of (38 to 172) nm. However, dynamic light scattering measurements revealed much larger particles of (380 ± 49 to 768 ± 111) nm, owing to agglomeration of the smaller primary nano particles as revealed by Scanning Electron Microscopy (SEM). Thermodynamic solubility measurements showed that the nCaPs with Ca/P ratio of 1.33 - 1.67 all have similar solubility behavior. The materials were more soluble than the crystalline hydroxyapatite (HA) at pH greater than about 4.7, and more soluble than β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP) and DCP at pH above 5.5. Their solubility approached that of α-tricalcium phosphate (α-TCP) at about pH 7. These nCaPs, which cannot be readily prepared by other currently available methods for nanoparticle preparation, have potential biomedical applications.

  2. The Pr and Ca substitution in GdBa2Cu3O7-8

    International Nuclear Information System (INIS)

    Shakeri, H.; Akhavan, M.

    2002-01-01

    The granular Gd 1 -x-zPr x Ca z Ba 2 Cu 3 O 7 -8 (Gd Pr Ca-123) high-temperature cuprate samples with 0.0≤x≤0.3 and 0.0≤z≤0.35 are prepared by standard solid state reaction and characterized by XRD and SEM techniques. The BaCuO 2 and impurity phases are less than 1% in the samples having high levels of Pr and Ca concentrations. The electrical resistivity measurements show a nonlinear reduction in T c (x,z=etc) versus x. Moreover, the T c (z) curve with x=0 is nonlinear and a plateau appears at z≅0.05-0.015. For Pr-Ca-doped samples with a constant concentration of Pr, T c increases with the increase of Ca up to an optimum value of Ca doping and then in decreases. Based on these observations, we suggest that hole filling and hole localization the main effects of Pr ion substitution. The magnetic measurements indicate that the value of H C 1 is in the order of 10 m T. The magnetoresistance measurements have been measured and analyzed. The superconducting transition region is broadened by the application of magnetic field. The experimental data near the on sen of superconductivity are fitted with the Ambegakor and Halperin (A H) phase-slip model. We observe that the A H parameter, γ(H), depends not only on the temperature and the magnetic field, but also on the Pr and Ca ions concentrations. It is observed that the critical current density increases with Ca substitution and decreases with pr substitution in Gd-123 system. We suggest that the pr ion substitution probably enhances the weak link, but the Ca ion acts as flux pinning center in the Gd Pr Ca-123 system

  3. Ischemic damage in hippocampal CA1 is dependent on glutamate release and intact innervation from CA3

    DEFF Research Database (Denmark)

    Benveniste, H; Jørgensen, M B; Sandberg, M

    1989-01-01

    The removal of glutamatergic afferents to CA1 by destruction of the CA3 region is known to protect CA1 pyramidal cells against 10 min of transient global ischemia. To investigate further the pathogenetic significance of glutamate, we measured the release of glutamate in intact and CA3-lesioned CA...

  4. YouthCaN 2001 / Sirje Janikson

    Index Scriptorium Estoniae

    Janikson, Sirje

    2001-01-01

    Aprillis 2001 toimus keskkonnateemaline õpilaskonverents YouthCaN 2001 Ameerika Loodusajaloo Muuseumis New Yorkìs. 35 seminarist ühe viis läbi Tartu Noorte Loodusmaja geoloogia ja keskkonnaringi esindus, tutvustati loodusmaja keskkonnaprojekte ja räägiti keskkonnaalaste veebilehtede koostamise kogemustest. YouthCaN (Youth Communicating and Networking) on rahvusvaheline noorte organisatsioon, mis vahendab kogemusi ja uusi ideid elukeskkonnast huvitatud noorte hulgas

  5. The caCORE Software Development Kit: Streamlining construction of interoperable biomedical information services

    Directory of Open Access Journals (Sweden)

    Warzel Denise

    2006-01-01

    Full Text Available Abstract Background Robust, programmatically accessible biomedical information services that syntactically and semantically interoperate with other resources are challenging to construct. Such systems require the adoption of common information models, data representations and terminology standards as well as documented application programming interfaces (APIs. The National Cancer Institute (NCI developed the cancer common ontologic representation environment (caCORE to provide the infrastructure necessary to achieve interoperability across the systems it develops or sponsors. The caCORE Software Development Kit (SDK was designed to provide developers both within and outside the NCI with the tools needed to construct such interoperable software systems. Results The caCORE SDK requires a Unified Modeling Language (UML tool to begin the development workflow with the construction of a domain information model in the form of a UML Class Diagram. Models are annotated with concepts and definitions from a description logic terminology source using the Semantic Connector component. The annotated model is registered in the Cancer Data Standards Repository (caDSR using the UML Loader component. System software is automatically generated using the Codegen component, which produces middleware that runs on an application server. The caCORE SDK was initially tested and validated using a seven-class UML model, and has been used to generate the caCORE production system, which includes models with dozens of classes. The deployed system supports access through object-oriented APIs with consistent syntax for retrieval of any type of data object across all classes in the original UML model. The caCORE SDK is currently being used by several development teams, including by participants in the cancer biomedical informatics grid (caBIG program, to create compatible data services. caBIG compatibility standards are based upon caCORE resources, and thus the caCORE SDK has

  6. Endomembrane Ca2+-AtPases play a significant role in virus-induced adaptation to oxidative stress

    DEFF Research Database (Denmark)

    Shabala, Sergey; Bækgaard, Lone; Shabala, Lana

    2011-01-01

    Although the role of Ca2+ influx channels in oxidative stress signaling and cross-tolerance in plants is well established, little is known about the role of active Ca2+ efflux systems in this process. In our recent paper,17 we reported Potato Virus X (PVX)-induced acquired resistance to oxidative...... in adaptive responses to oxidative stress by removing excessive Ca2+ from the cytosol, and that their functional expression is significantly altered in PVX-inoculated plants. These findings highlight the crucial role of Ca2+ efflux systems in acquired tolerance to oxidative stress and open up prospects...... stress in Nicotiana benthamiana and showed the critical role of plasma membrane Ca2+/H+ exchangers in this process. The current study continues this research. Using biochemical and electrophysiological approaches, we reveal that both endomembrane P2A and P2B Ca2+-ATPases play significant roles...

  7. Radiosynthesis of dimethyl-2-[{sup 18}F]-(fluoromethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate for L-type calcium channel imaging

    Energy Technology Data Exchange (ETDEWEB)

    Sadeghpour, H. [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School (AMIRS), Karaj (Iran); Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran Univ. of Medical Sciences, Tehran (Iran); Jalilian, A.R.; Akhlaghi, M.; Mirzaei, M. [Nuclear Medicine Research Group, Agricultural, Medical and Industrial Research School (AMIRS), Karaj (Iran); Shafiee, A. [Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran Univ. of Medical Sciences, Tehran (Iran); Miri, R. [Medicinal and Natural Products Chemistry Research Center, Shiraz Univ. of Medical Sciences, Shiraz (Iran)

    2008-07-01

    Dimethyl 2-(fluoromethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 4a, a fluorinated nifedipine analog, has been shown to elicit significant calcium channel blocker activity using a guinea pig ileal longitudinal smooth muscle model. In order to perform biological studies for detection of L-type calcium channel distribution, we decided to prepare the [{sup 18}F]-labeled compound. The latter compound was prepared in no-carrier-added (n.c.a.) form from dimethyl 2-(bromomethyl)-6-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 2 in one step at 80 C in Kryptofix[222]/K[{sup 18}F]F and acetonitrile as a solvent in 15 min. Column chromatography afforded the radiochemically pure compound in 20 min. Radiochemical purity of the {sup 18}F-nifedipine was determined by RTLC and HPLC (> 98%) and specific activity of 21-48 GBq/{mu}mol (EOB). (orig.)

  8. L-Arginine ethylester enhances in vitro amplification of PrP(Sc) in macaques with atypical L-type bovine spongiform encephalopathy and enables presymptomatic detection of PrP(Sc) in the bodily fluids.

    Science.gov (United States)

    Murayama, Y; Ono, F; Shimozaki, N; Shibata, H

    2016-02-12

    Protease-resistant, misfolded isoforms (PrP(Sc)) of a normal cellular prion protein (PrP(C)) in the bodily fluids, including blood, urine, and saliva, are expected to be useful diagnostic markers of prion diseases, and nonhuman primate models are suited for performing valid diagnostic tests for human Creutzfeldt-Jakob disease (CJD). We developed an effective amplification method for PrP(Sc) derived from macaques infected with the atypical L-type bovine spongiform encephalopathy (L-BSE) prion by using mouse brain homogenate as a substrate in the presence of polyanions and L-arginine ethylester. This method was highly sensitive and detected PrP(Sc) in infected brain homogenate diluted up to 10(10) by sequential amplification. This method in combination with PrP(Sc) precipitation by sodium phosphotungstic acid is capable of amplifying very small amounts of PrP(Sc) contained in the cerebrospinal fluid (CSF), saliva, urine, and plasma of macaques that have been intracerebrally inoculated with the L-BSE prion. Furthermore, PrP(Sc) was detectable in the saliva or urine samples as well as CSF samples obtained at the preclinical phases of the disease. Thus, our novel method may be useful for furthering the understanding of bodily fluid leakage of PrP(Sc) in nonhuman primate models. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Cucumis sativus L-type lectin receptor kinase (CsLecRK) gene family response to Phytophthora melonis, Phytophthora capsici and water immersion in disease resistant and susceptible cucumber cultivars.

    Science.gov (United States)

    Wu, Tingquan; Wang, Rui; Xu, Xiaomei; He, Xiaoming; Sun, Baojuan; Zhong, Yujuan; Liang, Zhaojuan; Luo, Shaobo; Lin, Yu'e

    2014-10-10

    L-type lectin receptor kinase (LecRK) proteins are an important family involved in diverse biological processes such as pollen development, senescence, wounding, salinity and especially in innate immunity in model plants such as Arabidopsis and tobacco. Till date, LecRK proteins or genes of cucumber have not been reported. In this study, a total of 25 LecRK genes were identified in the cucumber genome, unequally distributed across its seven chromosomes. According to similarity comparison of their encoded proteins, the Cucumis sativus LecRK (CsLecRK) genes were classified into six major clades (from Clade I to CladeVI). Expression of CsLecRK genes were tested using QRT-PCR method and the results showed that 25 CsLecRK genes exhibited different responses to abiotic (water immersion) and biotic (Phytophthora melonis and Phytophthora capsici inoculation) stresses, as well as that between disease resistant cultivar (JSH) and disease susceptible cultivar (B80). Among the 25 CsLecRK genes, we found CsLecRK6.1 was especially induced by P. melonis and P. capsici in JSH plants. All these results suggested that CsLecRK genes may play important roles in biotic and abiotic stresses. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters

    Directory of Open Access Journals (Sweden)

    Hüseyin Ilgü

    2018-03-01

    Full Text Available The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures (Tms of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg, agmatine, l-arginine methyl ester, and l-arginine amide. The resulting Tms indicated stabilization of AdiC variants upon ligand binding, in which Tms and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5, an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family.

  11. A 2MASS/AllWISE Search for Extremely Red L Dwarfs: The Discovery of Several Likely L Type Members of β Pic, AB Dor, Tuc-Hor, Argus, and the Hyades

    Energy Technology Data Exchange (ETDEWEB)

    Schneider, Adam C.; Shkolnik, Evgenya L. [School of Earth and Space Exploration, Arizona State University, Tempe, AZ, 85282 (United States); Windsor, James; Cushing, Michael C. [Department of Physics and Astronomy, University of Toledo, 2801 W. Bancroft Street, Toledo, OH 43606 (United States); Kirkpatrick, J. Davy, E-mail: aschneid10@gmail.com [IPAC, Mail Code 100-22, Caltech, 1200 E. California Boulevard, Pasadena, CA 91125 (United States)

    2017-04-01

    Young brown dwarfs share many properties with directly imaged giant extrasolar planets. They therefore provide unique laboratories for investigating the full range of temperature and mass encompassed by the growing collection of planets discovered outside our Solar System. Furthermore, if they can be tied to a particular group of coeval stars, they also provide vital anchor points for low-mass empirical isochrones. We have developed a novel procedure for identifying such objects based on their unique 2MASS and AllWISE colors. Using our search criteria, we have identified 50 new, late-type L dwarf candidates, 47 of which are spectroscopically confirmed as L dwarfs with follow-up near-infrared spectroscopy. We evaluate the potential membership of these objects in nearby, young moving groups using their proper motions, photometric distance estimates, and spectroscopic indicators of youth, and find seven likely L-type members belonging to the β Pictoris moving group, the AB Doradus moving group, the Tucana-Horologium association, or the Argus association, in addition to several lower probability members. Also found are two late-type (L5 and L6) potential members of the nearby Hyades cluster (WISEA J043642.75+190134.8 and WISEA J044105.56+213001.5).

  12. Hexagonal perovskites with cationic vacancies. 17. Structure determination on Ba/sub 9/Nb/sub 6/Wvacant/sub 2/O/sub 27/ - the first stacking polytype of a rhombohedral 27 L-type

    Energy Technology Data Exchange (ETDEWEB)

    Kemmler-Sack, S; Treiber, U [Tuebingen Univ. (Germany, F.R.). Lehrstuhl fuer Anorganische Chemie 2

    1980-03-01

    The hexagonal stacking polytype of rhombohedral 27 L-type, Ba/sub 9/Nb/sub 6/Wvacant/sub 2/O/sub 27/, crystallizes in the space group R3m with the sequence (4)1(3)1 = (hhccchhcc)/sub 3/ and three formula units for the trigonal setting. The refined, intensity, related, R'-value is 9.7%. The octahedral net consists of blocks of three face connected octahedra which are linked to each other alternately through one or two octahedra connected exclusively by common vertices. The cationic vacancies are located in the centers of the groups of three octahedra. With this distribution direct contact between occupied face-sharing octahedra is avoided. The niobium and tungsten atoms are distributed statistically between the remaining octahedral holes. In the blocks of three octahedra they are displaced by approximately 0.29 A from their ideal positions in the direction of the central void. The Ba atoms neighbouring a vacancy (all in hexagonal packed BaO/sub 3/ sheets) are dislocated in the direction of the void, while the cubic packed BaO/sub 3/ sheets maintain nearly regular form.

  13. Effects of Mutations and Ligands on the Thermostability of the l-Arginine/Agmatine Antiporter AdiC and Deduced Insights into Ligand-Binding of Human l-Type Amino Acid Transporters.

    Science.gov (United States)

    Ilgü, Hüseyin; Jeckelmann, Jean-Marc; Colas, Claire; Ucurum, Zöhre; Schlessinger, Avner; Fotiadis, Dimitrios

    2018-03-20

    The l-arginine/agmatine transporter AdiC is a prokaryotic member of the SLC7 family, which enables pathogenic enterobacteria to survive the extremely acidic gastric environment. Wild-type AdiC from Escherichia coli, as well as its previously reported point mutants N22A and S26A, were overexpressed homologously and purified to homogeneity. A size-exclusion chromatography-based thermostability assay was used to determine the melting temperatures ( T m s) of the purified AdiC variants in the absence and presence of the selected ligands l-arginine (Arg), agmatine, l-arginine methyl ester, and l-arginine amide. The resulting T m s indicated stabilization of AdiC variants upon ligand binding, in which T m s and ligand binding affinities correlated positively. Considering results from this and previous studies, we revisited the role of AdiC residue S26 in Arg binding and proposed interactions of the α-carboxylate group of Arg exclusively with amide groups of the AdiC backbone. In the context of substrate binding in the human SLC7 family member l-type amino acid transporter-1 (LAT1; SLC7A5), an analogous role of S66 in LAT1 to S26 in AdiC is discussed based on homology modeling and amino acid sequence analysis. Finally, we propose a binding mechanism for l-amino acid substrates to LATs from the SLC7 family.

  14. Cation-exchange antibody labeling for simultaneous electrochemical detection of tumor markers CA15-3 and CA19-9

    International Nuclear Information System (INIS)

    Wang, Guangjie; Qing, Yi; Shan, Jinlu; Jin, Feng; Wang, Dong; Yuan, Ruo

    2013-01-01

    We report on a new kind of non-covalent multi-label electrochemical immunoassay that was applied to simultaneously quantify the tumor markers CA15-3 and CA19-9. The method employs a nanohybrid composed of an ionomer and conductive titanium dioxide nanoparticles that act as a matrix support for the antibodies. The two antibodies (anti-CA153 and anti-CA199) were labeled (a) with a cobaltous dipyridine complex, and (b) with methylene blue. Labeling is based on cation-exchange interaction rather than on covalent conjugation. The redox potentials of the two labels are separated by an interval of 0.3 V. The resulting sandwich-type immunosensor was read out by differential pulse voltammetry. The potential sites and currents of the two redox probes reflect the concentration of the two analytes. The two analytes were determined with a detection limit of 1.6 U mL −1 for CA19-9, and of 0.3 U mL −1 for CA15-3 (author)

  15. Study on the isospin equilibration phenomenon in nuclear reactions 40Ca + 40Ca , 40Ca + 46Ti , 40Ca + 48Ca , 48Ca + 48Ca at 25 MeV/nucleon by using the CHIMERA multidetector

    Science.gov (United States)

    Martorana, N. S.; Auditore, L.; Berceanu, I.; Cardella, G.; Chatterjee, M. B.; De Luca, S.; De Filippo, E.; Dell'Aquila, D.; Gnoffo, B.; Lanzalone, G.; Lombardo, I.; Maiolino, C.; Norella, S.; Pagano, A.; Pagano, E. V.; Papa, M.; Pirrone, S.; Politi, G.; Porto, F.; Quattrocchi, L.; Rizzo, F.; Russotto, P.; Trifirò, A.; Trimarchi, M.; Verde, G.; Vigilante, M.

    2017-11-01

    We report on the results obtained by studying nuclear reactions between isotopes of Ca and Ti at 25 MeV/nucleon. We used the multidetector CHIMERA to detect charged reaction products. In particular, we studied two main effects: the isospin diffusion and the isospin drift. In order to study these processes we performed a moving-source analysis on kinetic energy spectra of the isobar nuclei ^{3H} and ^{3He} . This method allows to isolate the emission from the typical sources produced in reactions at Fermi energy: projectile like fragment (PLF), target like fragment (TLF), and mid-velocity (MV) emission. The obtained results are compared to previous experimental investigations and to simulations obtained with CoMD-II model.

  16. Transcriptional upregulation of α2δ-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension.

    Science.gov (United States)

    Bannister, John P; Bulley, Simon; Narayanan, Damodaran; Thomas-Gatewood, Candice; Luzny, Patrik; Pachuau, Judith; Jaggar, Jonathan H

    2012-10-01

    A hallmark of hypertension is an increase in arterial myocyte voltage-dependent Ca2+ (CaV1.2) currents that induces pathological vasoconstriction. CaV1.2 channels are heteromeric complexes composed of a pore-forming CaV1.2α1 with auxiliary α2δ and β subunits. Molecular mechanisms that elevate CaV1.2 currents during hypertension and the potential contribution of CaV1.2 auxiliary subunits are unclear. Here, we investigated the pathological significance of α2δ subunits in vasoconstriction associated with hypertension. Age-dependent development of hypertension in spontaneously hypertensive rats was associated with an unequal elevation in α2δ-1 and CaV1.2α1 mRNA and protein in cerebral artery myocytes, with α2δ-1 increasing more than CaV1.2α1. Other α2δ isoforms did not emerge in hypertension. Myocytes and arteries of hypertensive spontaneously hypertensive rats displayed higher surface-localized α2δ-1 and CaV1.2α1 proteins, surface α2δ-1:CaV1.2α1 ratio, CaV1.2 current density and noninactivating current, and pressure- and depolarization-induced vasoconstriction than those of Wistar-Kyoto controls. Pregabalin, an α2δ-1 ligand, did not alter α2δ-1 or CaV1.2α1 total protein but normalized α2δ-1 and CaV1.2α1 surface expression, surface α2δ-1:CaV1.2α1, CaV1.2 current density and inactivation, and vasoconstriction in myocytes and arteries of hypertensive rats to control levels. Genetic hypertension is associated with an elevation in α2δ-1 expression that promotes surface trafficking of CaV1.2 channels in cerebral artery myocytes. This leads to an increase in CaV1.2 current-density and a reduction in current inactivation that induces vasoconstriction. Data also suggest that α2δ-1 targeting is a novel strategy that may be used to reverse pathological CaV1.2 channel trafficking to induce cerebrovascular dilation in hypertension.

  17. Ca(2+-dependent regulation of the Ca(2+ concentration in the myometrium mitochondria. II. Ca(2+ effects on mitochondria membranes polarization and [Ca(2+](m

    Directory of Open Access Journals (Sweden)

    L. G. Babich

    2017-06-01

    Full Text Available It is known that Ca2+ accumulation in the mitochondria undergoes complex regulation by Ca2+ itself. But the mechanisms of such regulation are still discussed. In this paper we have shown that Ca ions directly or indirectly regulate the level of myometrium mitochondria membranes polarization. The additions of 100 µM Ca2+ were accompanied by depolarization of the mitochondria membranes. The following experiments were designed to study the impact of Ca2+ on the myometrium mitochondria [Ca2+]m. Isolated myometrium mitochondria were preincubated without or with 10 μM Са2+ followed by 100 μM Са2+ addition. Experiments were conducted in three mediums: without ATP and Mg2+ (0-medium, in the presence of 3 mM Mg2+ (Mg-medium and 3 mM Mg2+ + 3 mM ATP (Mg,ATP-medium. It was shown that the effects of 10 μM Са2+ addition were different in different mediums, namely in 0- and Mg-medium the [Ca2+]m values increased, whereas in Mg,ATP-medium statistically reliable changes were not registered. Preincubation of mitochondria with 10 μM Са2+ did not affect the [Ca2+]m value after the addition of 100 μM Са2+. The [Ca2+]m values after 100 μM Са2+ addition were the same in 0- and Mg,ATP-mediums and somewhat lower in Mg-medium. Preliminary incubation of mitochondria with 10 μM Са2+ in 0- and Mg-mediums reduced changes of Fluo 4 normalized fluorescence values that were induced by 100 μM Са2+ additions, but in Mg,ATP-medium such differences were not recorded. It is concluded that Са2+ exchange in myometrium mitochondria is regulated by the concentration of Ca ions as in the external medium, so in the matrix of mitochondria. The medium composition had a significant impact on the [Са2+]m values in the absence of exogenous cation. It is suggested that light increase of [Са2+]m before the addition of 100 μM Са2+ may have a positive effect on the functional activity of the mitochondria.

  18. Influence of ER leak on resting cytoplasmic Ca2+ and receptor-mediated Ca2+ signalling in human macrophage.

    Science.gov (United States)

    Layhadi, Janice A; Fountain, Samuel J

    2017-06-03

    Mechanisms controlling endoplasmic reticulum (ER) Ca 2+ homeostasis are important regulators of resting cytoplasmic Ca 2+ concentration ([Ca 2+ ] cyto ) and receptor-mediated Ca 2+ signalling. Here we investigate channels responsible for ER Ca 2+ leak in THP-1 macrophage and human primary macrophage. In the absence of extracellular Ca 2+ we employ ionomycin action at the plasma membrane to stimulate ER Ca 2+ leak. Under these conditions ionomycin elevates [Ca 2+ ] cyto revealing a Ca 2+ leak response which is abolished by thapsigargin. IP 3 receptors (Xestospongin C, 2-APB), ryanodine receptors (dantrolene), and translocon (anisomycin) inhibition facilitated ER Ca 2+ leak in model macrophage, with translocon inhibition also reducing resting [Ca 2+ ] cyto . In primary macrophage, translocon inhibition blocks Ca 2+ leak but does not influence resting [Ca 2+ ] cyto . We identify a role for translocon-mediated ER Ca 2+ leak in receptor-mediated Ca 2+ signalling in both model and primary human macrophage, whereby the Ca 2+ response to ADP (P2Y receptor agonist) is augmented following anisomycin treatment. In conclusion, we demonstrate a role of ER Ca 2+ leak via the translocon in controlling resting cytoplasmic Ca 2+ in model macrophage and receptor-mediated Ca 2+ signalling in model macrophage and primary macrophage. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

    Directory of Open Access Journals (Sweden)

    Carmen Carbone

    2017-06-01

    Full Text Available Differential vulnerability between Substantia Nigra pars compacta (SNpc and Ventral Tegmental Area (VTA dopaminergic (DAergic neurons is a hallmark of Parkinson’s disease (PD. Understanding the molecular bases of this key histopathological aspect would foster the development of much-needed disease-modifying therapies. Non-heterogeneous DAergic degeneration is present in both toxin-based and genetic animal models, suggesting that cellular specificity, rather than causing factors, constitutes the background for differential vulnerability. In this regard, we previously demonstrated that MPP+, a neurotoxin able to cause selective nigrostriatal degeneration in animal rodents and primates, inhibits the Hyperpolarization-activated current (Ih in SNpc DAergic neurons and that pharmacological Ih antagonism causes potentiation of evoked Excitatory post-synaptic potentials (EPSPs. Of note, the magnitude of such potentiation is greater in the SNpc subfield, consistent with higher Ih density. In the present work, we show that Ih block-induced synaptic potentiation leads to the amplification of somatic calcium responses (SCRs in vitro. This effect is specific for the SNpc subfield and largely mediated by L-Type calcium channels, as indicated by sensitivity to the CaV 1 blocker isradipine. Furthermore, Ih is downregulated by low intracellular ATP and determines the efficacy of GABAergic inhibition in SNpc DAergic neurons. Finally, we show that stereotaxic administration of Ih blockers causes SNpc-specific neurodegeneration and hemiparkinsonian motor phenotype in rats. During PD progression, Ih downregulation may result from mitochondrial dysfunction and, in concert with PD-related disinhibition of excitatory inputs, determine a SNpc-specific disease pathway.

  20. Biodegradable Orthopedic Magnesium-Calcium (MgCa Alloys, Processing, and Corrosion Performance

    Directory of Open Access Journals (Sweden)

    Yuebin Guo

    2012-01-01

    Full Text Available Magnesium-Calcium (Mg-Ca alloy has received considerable attention as an emerging biodegradable implant material in orthopedic fixation applications. The biodegradable Mg-Ca alloys avoid stress shielding and secondary surgery inherent with permanent metallic implant materials. They also provide sufficient mechanical strength in load carrying applications as opposed to biopolymers. However, the key issue facing a biodegradable Mg-Ca implant is the fast corrosion in the human body environment. The ability to adjust degradation rate of Mg-Ca alloys is critical for the successful development of biodegradable orthopedic implants. This paper focuses on the functions and requirements of bone implants and critical issues of current implant biomaterials. Microstructures and mechanical properties of Mg-Ca alloys, and the unique properties of novel magnesium-calcium implant materials have been reviewed. Various manufacturing techniques to process Mg-Ca based alloys have been analyzed regarding their impacts on implant performance. Corrosion performance of Mg-Ca alloys processed by different manufacturing techniques was compared. In addition, the societal and economical impacts of developing biodegradable orthopedic implants have been emphasized.

  1. Ca2+ sensitizers: An emerging class of agents for counterbalancing weakness in skeletal muscle diseases?

    Science.gov (United States)

    Ochala, Julien

    2010-02-01

    Ca(2+) ions are key regulators of skeletal muscle contraction. By binding to contractile proteins, they initiate a cascade of molecular events leading to cross-bridge formation and ultimately, muscle shortening and force production. The ability of contractile proteins to respond to Ca(2+) attachment, also known as Ca(2+) sensitivity, is often compromised in acquired and congenital skeletal muscle disorders. It constitutes, undoubtedly, a major physiological cause of weakness for patients. In this review, we discuss recent studies giving strong molecular and cellular evidence that pharmacological modulators of some of the contractile proteins, also termed Ca(2+) sensitizers, are efficient agents to improve Ca(2+) sensitivity and function in diseased skeletal muscle cells. In fact, they compensate for the impaired contractile proteins response to Ca(2+) binding. Currently, such Ca(2+) sensitizing compounds are successfully used for reducing problems in cardiac disorders. Therefore, in the future, under certain conditions, these agents may represent an emerging class of agents to enhance the quality of life of patients suffering from skeletal muscle weakness. Copyright 2009 Elsevier B.V. All rights reserved.

  2. Impacts of CA9 gene polymorphisms on urothelial cell carcinoma susceptibility and clinicopathologic characteristics in Taiwan.

    Directory of Open Access Journals (Sweden)

    Shian-Shiang Wang

    Full Text Available Carbonic anhydrase 9 (CA9 is reportedly overexpressed in several types of carcinomas and is generally considered a marker of malignancy. The current study explored the effect of CA9 gene polymorphisms on the susceptibility of developing urothelial cell carcinoma (UCC and the clinicopathological status.A total of 442 participants, including 221 healthy people and 221 patients with UCC, were recruited for this study. Four single-nucleotide polymorphisms (SNPs of the CA9 gene were assessed by a real-time PCR with the TaqMan assay. After adjusting for other co-variants, the individuals carrying at least one A allele at CA9 rs1048638 had a 2.303-fold risk of developing UCC than did wild-type (CC carriers. Furthermore, UCC patients who carried at least one A allele at rs1048638 had a higher invasive stage risk (p< 0.05 than did patients carrying the wild-type allele. Moreover, among the UCC patients with smoker, people with at least one A allele of CA9 polymorphisms (rs1048638 had a 4.75-fold (95% CI = 1.204-18.746 increased risk of invasive cancer.The rs1048638 polymorphic genotypes of CA9 might contribute to the prediction of susceptibility to and pathological development of UCC. This is the first study to provide insight into risk factors associated with CA9 variants in carcinogenesis of UCC in Taiwan.

  3. Microstructures, mechanical properties and corrosion resistances of extruded Mg-Zn-Ca-xCe/La alloys.

    Science.gov (United States)

    Tong, L B; Zhang, Q X; Jiang, Z H; Zhang, J B; Meng, J; Cheng, L R; Zhang, H J

    2016-09-01

    Magnesium alloys are considered as good candidates for biomedical applications, the influence of Ce/La microalloying on the microstructure, mechanical property and corrosion performance of extruded Mg-5.3Zn-0.6Ca (wt%) alloy has been investigated in the current study. After Ce/La addition, the conventional Ca2Mg6Zn3 phases are gradually replaced by new Mg-Zn-Ce/La-(Ca) phases (T1'), which can effectively divide the Ca2Mg6Zn3 phase. The Ca2Mg6Zn3/T1' structure in Mg-Zn-Ca-0.5Ce/La alloy is favorably broken into small particles during the extrusion, resulting in an obvious refinement of secondary phase. The dynamic recrystallized grain size is dramatically decreased after 0.5Ce/La addition, and the tensile yield strength is improved, while further addition reverses the effect, due to the grain coarsening. However, the corrosion resistance of extruded Mg-Zn-Ca alloy deteriorates after Ce/La addition, because the diameter of secondary phase particle is remarkably decreased, which increases the amount of cathodic sites and accelerates the galvanic corrosion process. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Prognostic significance of preoperative serum CA125, CA19-9 and CEA in gastric carcinoma

    Science.gov (United States)

    Wang, Wei; Chen, Xiao-Long; Zhao, Shen-Yu; Xu, Yu-Hui; Zhang, Wei-Han; Liu, Kai; Chen, Xin-Zu; Yang, Kun; Zhang, Bo; Chen, Zhi-Xin; Chen, Jia-Ping; Zhou, Zong-Guang; Hu, Jian-Kun

    2016-01-01

    The prognostic significance of preoperative serum CA125, CA19-9 and CEA in gastric carcinoma (GC) has been widely reported and is still under debate. Here, we evaluated the prognostic significance of preoperative serum CA125, CA19-9 and CEA in patients with GC. 1692 patients with GC who underwent gastrectomy were divided into the training (from January 2005 to December 2011, n = 1024) and the validation (from January 2012 to December 2013, n = 668) cohorts. Positive groups of CA125 (> 13.72 U/ml), CA19-9 (> 23.36 U/ml) and CEA (> 4.28 ng/ml) were significantly associated with more advanced clinicopathological traits and worse outcomes than that of negative groups (all P tumor size (P tumor markers (NPTM) were more accurate in prognostic prediction than TNM stage alone. Our findings suggested that elevated preoperative serum CA125, CA19-9 and CEA were associated with more advanced clinicopathological traits and less favorable outcomes. In addition, CA125 as an independent prognostic factor should be further investigated. Nomogram based on NPTM could accurately predict the prognosis of GC patients. PMID:27097114

  5. Electronic structures and magnetism of CaFeAsH and CaFeAsF

    International Nuclear Information System (INIS)

    Wang Guangtao; Shi Xianbiao; Liu Haipeng; Liu Qingbo

    2015-01-01

    We studied the electronic structures, magnetism, and Fermi surface (FS) nesting of CaFeAsH and CaFeAsF by first-principles calculations. In the nonmagnetic (NM) states, we found strong FS nesting, which induces magnetic instability and a spin density wave (SDW). Our calculations indicate that the ground state of CaFeAsH and CaFeAsF is the stripe antiferromagnetic state. The calculated bare susceptibility χ 0 (q) peaked at the M-point and was clearly suppressed and became slightly incommensurate with both electron doping and hole doping for both materials. (author)

  6. Study of 40Ca-40Ca elastic scattering at intermediate energy

    International Nuclear Information System (INIS)

    Kumar, Ashok; Srivastava, B.B.

    1980-01-01

    The differential cross sections for 40 Ca- 40 Ca elastic scattering have been calculated at laboratory incident energy of 240 MeV using a sharp cut off of the partial waves below a critical angular momentum, 1sub(c)' to account for absorption. The effective 40 Ca- 40 Ca potential is taken to be the sum of a real nuclear potential and the Coulomb potential. The calculated differential cross sections which are in fair agreement with the experimental data are presented and discussed. (author)

  7. Impact parameter determination for 40Ca + 40Ca reactions using a neural network

    International Nuclear Information System (INIS)

    Haddad, F.; Hagel, K.; Li, J.; Mdeiwayeh, N.; Natowitz, J.B.; Wada, R.; Xiao, B.; David, C.; Freslier, M.; Aichelin, J.

    1995-01-01

    A neural network is used for the impact parameter determination in 40 Ca + 40 Ca reactions at energies between 35 and 70 AMeV. A special attention is devoted to the effect of experimental constraints such as the detection efficiency. An overall improvement of the impact parameter determination of 25% is obtained with the neural network. The neural network technique is then used in the analysis of the Ca+Ca data at 35 AMeV and allows separation of three different class of events among the selected 'complete' events. (authors). 8 refs., 5 figs

  8. Mg/Ca of Continental Ostracode Shells

    Science.gov (United States)

    Ito, E.; Forester, R. M.; Marco-Barba, J.; Mezquita, F.

    2007-12-01

    Marine ionic chemistry is thought to remain constant. This, together with the belief that marine calcifiers partition Mg/Ca in a systematic manner as functions of temperature (and Mg/Ca) of water forms the basis of the Mg/Ca thermometer. In continental settings both of these assumptions are usually not true. Continental waters contain a wide variety of solutes in absolute and relative ion concentrations. Hence, waters with identical Mg/Ca may have very different concentrations of Mg and Ca and very different anions. Here we use two examples to focus on the effects of ion chemistry on Mg/Ca partitioning in continental ostracode shells and we ignore the complexities of solute evolution, which can change Mg/Ca over timescales of minutes to millennia. Palacios-Fest and Dettman (2001) conducted a monthly study of ,Cypridopsis vidua at El Yeso Lake in Sonora, Mexico. They established a relation between temperature and average shell Mg/Ca using regression analyses on averaged data. When their Mg/Ca-temperature relation is applied to monthly ,C. vidua data from Page Pond near Cleveland, Ohio, water temperatures of -8 to -1°C are obtained. The observed Mg/Ca ranges for El Yeso Lake (0.31 to 0.46) and Page Pond (0.33 to 0.46) are similar, as are their specific conductivities (700 to 850μS for El Yeso Lake; 400 to 600μS for Page Pond). However, [Ca] is 140-260 mg/L for El Yeso, but only 70-90 mg/L for Page Pond. Page Pond data, in fact, shows a good temperature shell Mg/Ca relation for .C. vidua, but the relation is different from that at El Yeso. Hence, shell Mg/Ca is a multi-valued, family of curves function of temperature and Mg/Ca of water that depends on the [Mg] and [Ca] values in water and perhaps other factors. Our second example comes from sites near Valencia, Spain and involves shell data for ,Cyprideis torosa, an estuarine ostracode that is tolerant of a wide range of salinity and can live in continental waters as long as the carbonate alkalinity to Ca ratio is

  9. Physical conditions in CaFe interstellar clouds

    OpenAIRE

    Gnacinski, P.; Krogulec, M.

    2007-01-01

    Interstellar clouds that exhibit strong Ca I and Fe I lines were called CaFe clouds. The ionisation equilibrium equations were used to model the column densities of Ca II, Ca I, K I, Na I, Fe I and Ti II in CaFe clouds. The chemical composition of CaFe clouds is that of the Solar System and no depletion of elements onto dust grains is seen. The CaFe clouds have high electron densities n=1 cm^-3 that leads to high column densities of neutral Ca and Fe.

  10. Absolute Ca Isotopic Measurement Using an Improved Double Spike Technique

    Directory of Open Access Journals (Sweden)

    Jason Jiun-San Shen

    2009-01-01

    Full Text Available A new vector analytical method has been developed in order to obtain the true isotopic composition of the 42Ca-48Ca double spike. This is achieved by using two different sample-spike mixtures combined with the double spike and natural Ca data. Be cause the natural sample (two mixtures and the spike should all lie on a single mixing line, we are able to con strain the true isotopic composition of our double spike using this new approach. Once the isotopic composition of the Ca double spike is established, we are able to obtain the true Ca isotopic composition of the NIST Ca standard SRM915a, 40Ca/44Ca = 46.537 ± 2 (2sm, n = 55, 42Ca/44Ca = 0.31031 ± 1, 43Ca/44Ca = 0.06474 ± 1, and 48Ca/44Ca = 0.08956 ± 1. De spite an off set of 1.3% in 40Ca/44Ca between our result and the previously re ported value (Russell et al. 1978, our data indicate an off set of 1.89__in 40Ca/44Ca between SRM915a and seawater, entirely consistent with the published results.

  11. Triton X-100 inhibits agonist-induced currents and suppresses benzodiazepine modulation of GABA(A) receptors in Xenopus oocytes

    DEFF Research Database (Denmark)

    Søgaard, Rikke; Ebert, Bjarke; Klaerke, Dan

    2009-01-01

    Changes in lipid bilayer elastic properties have been proposed to underlie the modulation of voltage-gated Na(+) and L-type Ca(2+) channels and GABA(A) receptors by amphiphiles. The amphiphile Triton X-100 increases the elasticity of lipid bilayers at micromolar concentrations, assessed from its...... by flunitrazepam at alpha(1)beta(3)gamma(2S) receptors. All effects were independent of the presence of a gamma(2S) subunit in the GABA(A) receptor complex. The present study suggests that Triton X-100 may stabilize open and desensitized states of the GABA(A) receptor through changes in lipid bilayer elasticity....

  12. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses

    Directory of Open Access Journals (Sweden)

    Tanaka Mika

    2013-01-01

    Full Text Available Abstract Background Neuronal activity alters calcium ion (Ca2+ dynamics in astrocytes, but the physiologic relevance of these changes is controversial. To examine this issue further, we generated an inducible transgenic mouse model in which the expression of an inositol 1,4,5-trisphosphate absorbent, “IP3 sponge”, attenuates astrocytic Ca2+ signaling. Results Attenuated Ca2+ activity correlated with reduced astrocytic coverage of asymmetric synapses in the hippocampal CA1 region in these animals. The decreased astrocytic ‘protection’ of the synapses facilitated glutamate ‘spillover’, which was reflected by prolonged glutamate transporter currents in stratum radiatum astrocytes and enhanced N-methyl-D-aspartate receptor currents in CA1 pyramidal neurons in response to burst stimulation. These mice also exhibited behavioral impairments in spatial reference memory and remote contextual fear memory, in which hippocampal circuits are involved. Conclusions Our findings suggest that IP3-mediated astrocytic Ca2+ signaling correlates with the formation of functional tripartite synapses in the hippocampus.

  13. Sr/Ca and Mg/Ca in Glycymeris glycymeris (Bivalvia) shells from the Iberian upwelling system: Ontogeny and environmental control

    Science.gov (United States)

    Freitas, Pedro; Richardson, Christopher; Chenery, Simon; Monteiro, Carlos; Butler, Paul; Reynolds, David; Scourse, James; Gaspar, Miguel

    2017-04-01

    Bivalve shells have a great potential as high-resolution geochemical proxy archives of marine environmental conditions. In addition, sclerochronology of long-lived bivalve species (e.g. Arctica islandica) provides a timeline of absolutely dated shell material for geochemical analysis that can extend into the past beyond the lifetime of single individuals through the use of replicated crossmatched centennial to millennial chronologies. However, the interpretation of such records remains extremely challenging and complex, with multiple environmental and biological processes affecting element incorporation in the shell (e.g. crystal fabrics, organic matrix, biomineralization mechanisms and physiological processes). As a result, the effective use of bivalve shell elemental/Ca ratios as palaeoenvironmental proxies has been limited, often to species-specific applications or applications restricted to particular environmental settings. The dog-cockle, Glycymeris glycymeris, is a relatively long-lived bivalve (up to 200 years) that occurs in coarse-grained subtidal sediments of coastal shelf seas of Europe and North West Africa. Glycymeris glycymeris shells provide a valuable, albeit not fully explored, archive to reconstruct past environmental variability in an area lacking sclerochronological studies due to the rarity of long-lived bivalves and lack of coral reefs. In this study, we evaluate the potential of Sr/Ca and Mg/Ca ratios in G. glycymeris shells as geochemical proxies of upwelling conditions in the Iberian Upwelling System, the northern section of the Canary Current Eastern Boundary Upwelling System. Sr/Ca and Mg/Ca generally co-varied significantly and a clear ontogenetic, non-environmental related change in Sr/Ca and Ba/Ca variability was observed. High Sr/Ca and Mg/Ca ratios in older shells (> 10 years old) were found to be associated with the occurrence of growth lines deposited during the winter reduction in shell growth. Nevertheless, Sr/Ca and Mg/Ca

  14. Modulation by endothelin-1 of spontaneous activity and membrane currents of atrioventricular node myocytes from the rabbit heart.

    Directory of Open Access Journals (Sweden)

    Stéphanie C Choisy

    Full Text Available The atrioventricular node (AVN is a key component of the cardiac pacemaker-conduction system. Although it is known that receptors for the peptide hormone endothelin-1 (ET-1 are expressed in the AVN, there is very little information available on the modulatory effects of ET-1 on AVN electrophysiology. This study characterises for the first time acute modulatory effects of ET-1 on AVN cellular electrophysiology.Electrophysiological experiments were conducted in which recordings were made from rabbit isolated AVN cells at 35-37°C using the whole-cell patch clamp recording technique.Application of ET-1 (10 nM to spontaneously active AVN cells led rapidly (within ~13 s to membrane potential hyperpolarisation and cessation of spontaneous action potentials (APs. This effect was prevented by pre-application of the ET(A receptor inhibitor BQ-123 (1 µM and was not mimicked by the ET(B receptor agonist IRL-1620 (300 nM. In whole-cell voltage-clamp experiments, ET-1 partially inhibited L-type calcium current (I(Ca,L and rapid delayed rectifier K(+ current (I(Kr, whilst it transiently activated the hyperpolarisation-activated current (I(f at voltages negative to the pacemaking range, and activated an inwardly rectifying current that was inhibited by both tertiapin-Q (300 nM and Ba(2+ ions (2 mM; each of these effects was sensitive to ET(A receptor inhibition. In cells exposed to tertiapin-Q, ET-1 application did not produce membrane potential hyperpolarisation or immediate cessation of spontaneous activity; instead, there was a progressive decline in AP amplitude and depolarisation of maximum diastolic potential.Acutely applied ET-1 exerts a direct modulatory effect on AVN cell electrophysiology. The dominant effect of ET-1 in this study was activation of a tertiapin-Q sensitive inwardly rectifying K(+ current via ET(A receptors, which led rapidly to cell quiescence.

  15. The destiny of Ca(2+) released by mitochondria.

    Science.gov (United States)

    Takeuchi, Ayako; Kim, Bongju; Matsuoka, Satoshi

    2015-01-01

    Mitochondrial Ca(2+) is known to regulate diverse cellular functions, for example energy production and cell death, by modulating mitochondrial dehydrogenases, inducing production of reactive oxygen species, and opening mitochondrial permeability transition pores. In addition to the action of Ca(2+) within mitochondria, Ca(2+) released from mitochondria is also important in a variety of cellular functions. In the last 5 years, the molecules responsible for mitochondrial Ca(2+) dynamics have been identified: a mitochondrial Ca(2+) uniporter (MCU), a mitochondrial Na(+)-Ca(2+) exchanger (NCLX), and a candidate for a mitochondrial H(+)-Ca(2+) exchanger (Letm1). In this review, we focus on the mitochondrial Ca(2+) release system, and discuss its physiological and pathophysiological significance. Accumulating evidence suggests that the mitochondrial Ca(2+) release system is not only crucial in maintaining mitochondrial Ca(2+) homeostasis but also participates in the Ca(2+) crosstalk between mitochondria and the plasma membrane and between mitochondria and the endoplasmic/sarcoplasmic reticulum.

  16. Changes in the expression of serum markers CA242, CA199, CA125, CEA, TNF-α and TSGF after cryosurgery in pancreatic cancer patients.

    Science.gov (United States)

    Zhou, Gang; Niu, Lizhi; Chiu, David; He, Lihua; Xu, Kecheng

    2012-07-01

    The presence of serum tumor markers, carbohydrate antigen 242 (CA242), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), tumor-supplied group of factors (TSGF) and tumor necrosis factor-α (TNF-α), is closely associated with invasion and metastasis of many malignancies. The expression of these markers were measured in serum taken from 37 pancreatic cancer patients prior to treatment. Levels of CA242, CA199, CA125, CEA and TNF-α expression correlated with tumor size, clinical stage, tumor differentiation, lymph node and liver metastasis (P markers were significantly reduced compared with levels prior to cryosurgery (P 0.05). Thus, cryosurgery is more effective than chemotherapy for decreasing CA242, CA199, CA125, CEA, TSGF and TNF-α serum levels in these patients.

  17. Aconitine-induced Ca{sup 2+} overload causes arrhythmia and triggers apoptosis through p38 MAPK signaling pathway in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Gui-bo; Sun, Hong; Meng, Xiang-bao [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193 (China); Hu, Jin; Zhang, Qiang; Liu, Bo [Academy of Chinese Medical Sciences of Jilin Province, Changchun, Jilin 130021 (China); Wang, Min [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193 (China); Xu, Hui-bo, E-mail: xhb_6505@163.com [Academy of Chinese Medical Sciences of Jilin Province, Changchun, Jilin 130021 (China); Sun, Xiao-bo, E-mail: sun_xiaobo163@163.com [Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193 (China)

    2014-08-15

    {sup 2+} overload causes arrhythmia in rats. • Aconitine induces Ca{sup 2+} overload through the activation of L-type Ca{sup 2+} channels. • Aconitine-induced Ca{sup 2+} overload triggers apoptotic responses in vitro and in vivo. • Aconitine promotes apoptotic development via activation of P38 MAPK.

  18. Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA1.

    Science.gov (United States)

    Planche, Vincent; Koubiyr, Ismail; Romero, José E; Manjon, José V; Coupé, Pierrick; Deloire, Mathilde; Dousset, Vincent; Brochet, Bruno; Ruet, Aurélie; Tourdias, Thomas

    2018-04-01

    Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate. We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3 T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques. At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R 2  = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (ß = 0.87, p < .05). The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance. © 2018 Wiley Periodicals, Inc.

  19. The roles of endogenous CaMKII inhibitors in learning and memory.

    Directory of Open Access Journals (Sweden)

    Fabio Antonio Borges Vigil

    2014-03-01

    Full Text Available Calcium/ Calmodulin-dependent kinase 2 (CaMK2 is a serine/threonine kinase with a wide range of substrates. In the dendrites this kinase is the major post-synaptic density protein. A number of studies have established that CaMK2 is a fundamentally important for various learning and memory processes. Given this importance the activity of CaMK2 must be tightly regulated. Recently two endogenous inhibitor proteins of CaMK2, CaMK2N1 and CaMK2N2, have been identified. During contextual fear memory formation CaMK2N1 and CaMK2N2 increase in brain regions that are related to the task. However, the functions of CaMK2Ns are still unknown. Our aim was to study the physiological roles of these inhibitors in memory and learning process. For that purpose we used adeno-associated virus vector to either knockdown or overexpress one of the inhibitors. Animals were trained in contextual fear conditioning and their memory of the context was tested in two different time points. Treatment knocking down one of the inhibitors had no effect on memory formation but it inhibits memory maintenance. Overexpression of the other inhibitor prior to training blocked memory formation. On the other hand, overexpression of the same inhibitor after training had no effect on learning or memory of the task. We are currently studying the molecular effects of both treatments. We expect to be able to present data obtain with these experiments at the DENDRITES 2014.

  20. Altered myoplasmic Ca(2+) handling in rat fast-twitch skeletal muscle fibres during disuse atrophy.

    Science.gov (United States)

    Weiss, Norbert; Andrianjafiniony, Tina; Dupré-Aucouturier, Sylvie; Pouvreau, Sandrine; Desplanches, Dominique; Jacquemond, Vincent

    2010-03-01

    Calcium-dependent signalling pathways are believed to play an important role in skeletal muscle atrophy, but whether intracellular Ca(2+) homeostasis is affected in that situation remains obscure. We show here that there is a 20% atrophy of the fast-type flexor digitorum brevis (FDB) muscle in rats hind limb unloaded (HU) for 2 weeks, with no change in fibre type distribution. In voltage-clamp experiments, the amplitude of the slow Ca(2+) current was found similar in fibres from control and HU animals. In fibres loaded with the Ca(2+) dye indo-1, the value for the rate of [Ca(2+)] decay after the end of 5-100-ms-long voltage-clamp depolarisations from -80 to +10 mV was found to be 30-50% lower in fibres from HU animals. This effect was consistent with a reduced contribution of both saturable and non-saturable components of myoplasmic Ca(2+) removal. However, there was no change in the relative amount of parvalbumin, and type 1 sarco-endoplasmic reticulum Ca(2+)-ATPase was increased by a factor of three in the atrophied muscles. Confocal imaging of mitochondrial membrane potential showed that atrophied FDB fibres had significantly depolarized mitochondria as compared to control fibres. Depolarization of mitochondria in control fibres with carbonyl cyanide-p-trifluoromethoxyphenylhydrazone induced a slowing of the decay of [Ca(2+)] transients accompanied by an increase in resting [Ca(2+)] and a reduction of the peak amplitude of the transients. Overall results provide the first functional evidence for severely altered intracellular Ca(2+) removal capabilities in atrophied fast-type muscle fibres and highlight the possible contribution of reduced mitochondrial polarisation.

  1. Catalytic properties of inositol trisphosphate kinase: activation by Ca2+ and calmodulin

    International Nuclear Information System (INIS)

    Ryu, S.H.; Lee, S.Y.; Lee, K.Y.; Rhee, S.G.

    1987-01-01

    Inositol 1,4,5-triphosphate (Ins-1,4,5-P 3 ) is an important second-messenger molecule that mobilizes Ca 2+ from intracellular stores in response to the occupancy of receptor by various Ca 2+ -mobilizing agonists. The fate of Ins-1,4,5-P 3 is determined by two enzymes, a 3-kinase and a 5-phosphomonoesterase. The first enzyme converts Ins-1,4,5-P 3 to Ins-1,3,4,5-P 4 , whereas the latter forms Ins-1,4-P 2 . Recent studies suggest that Ins-1,3,4,5-P 4 might modulate the entry of Ca 2+ from an extracellular source. In the current report, the authors describe the partial purification of the 3-kinase from the cytosolic fraction of bovine brain and studies of its catalytic properties. They found that the 3-kinase activity is significantly activated by the Ca 2+ /calmodulin complex. Therefore, they propose that Ca 2+ mobilized from endoplasmic reticulum by the action of Ins-1,4,5-P 3 forms a complex with calmodulin, and that the Ca 2+ /calmodulin complex stimulates the conversion of Ins-1,4,5-P 3 , and intracellular Ca 2+ mobilizer, to Ins-1,3,4,5-P 4 , an extracellular Ca 2+ mobilizer. A rapid assay method for the 3-kinase was developed that is based on the separation of [3- 32 P]Ins-1,3,4,5-P 4 and [γ- 32 P]ATP by thin-layer chromatography. Using this new assay method, they evaluated kinetic parameters (K/sub m/ for ATP = 40 μM, K/sub m/ for Ins-1,4,5-P 3 = 0.7 μM, K/sub i/ for ADP = 12 μM) and divalent cation specificity (Mg 2+ > > Mn 2+ > Ca 2+ ) for the 3-kinase

  2. Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study

    Science.gov (United States)

    Gonzalez, Suzanne; Xu, Chun; Ramirez, Mercedes; Zavala, Juan; Armas, Regina; Contreras, Salvador A; Contreras, Javier; Dassori, Albana; Leach, Robin J; Flores, Deborah; Jerez, Alvaro; Raventós, Henriette; Ontiveros, Alfonso; Nicolini, Humberto; Escamilla, Michael

    2013-01-01

    Objectives Through recent genome-wide association studies (GWAS), several groups have reported significant association between variants in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. Methods This study consisted of 913 individuals from 215 Latino pedigrees recruited from the United States, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9 kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. Results An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). Conclusions Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population. PMID:23437964

  3. Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.

    Science.gov (United States)

    Yamada, Yuko; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakagawa, Yasuaki; Kuwabara, Yoshihiro; Minami, Takeya; Yamada, Chinatsu; Shibata, Junko; Nakao, Kazuhiro; Cho, Kosai; Arai, Yuji; Yasuno, Shinji; Nishikimi, Toshio; Ueshima, Kenji; Kamakura, Shiro; Nishida, Motohiro; Kiyonaka, Shigeki; Mori, Yasuo; Kimura, Takeshi; Kangawa, Kenji; Nakao, Kazuwa

    2014-10-01

    Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B(+/-) mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B(+/+) mice. Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  4. Ventral tegmental area disruption selectively affects CA1/CA2 but not CA3 place fields during a differential reward working memory task.

    Science.gov (United States)

    Martig, Adria K; Mizumori, Sheri J Y

    2011-02-01

    Hippocampus (HPC) receives dopaminergic (DA) projections from the ventral tegmental area (VTA) and substantia nigra. These inputs appear to provide a modulatory signal that influences HPC dependent behaviors and place fields. We examined how efferent projections from VTA to HPC influence spatial working memory and place fields when the reward context changes. CA1 and CA3 process environmental context changes differently and VTA preferentially innervates CA1. Given these anatomical data and electrophysiological evidence that implicate DA in reward processing, we predicted that CA1 place fields would respond more strongly to both VTA disruption and changes in the reward context than CA3 place fields. Rats (N = 9) were implanted with infusion cannula targeting VTA and recording tetrodes aimed at HPC. Then they were tested on a differential reward, win-shift working memory task. One recording session consisted of 5 baseline and 5 manipulation trials during which place cells in CA1/CA2 (N = 167) and CA3 (N = 94) were recorded. Prior to manipulation trials rats were infused with either baclofen or saline and then subjected to control or reward conditions during which the learned locations of large and small reward quantities were reversed. VTA disruption resulted in an increase in errors, and in CA1/CA2 place field reorganization. There were no changes in any measures of CA3 place field stability during VTA disruption. Reward manipulations did not affect performance or place field stability in CA1/CA2 or CA3; however, changes in the reward locations "rescued" performance and place field stability in CA1/CA2 when VTA activity was compromised, perhaps by trigging compensatory mechanisms. These data support the hypothesis that VTA contributes to spatial working memory performance perhaps by maintaining place field stability selectively in CA1/CA2. Copyright © 2009 Wiley-Liss, Inc.

  5. Ca2+ signals, cell membrane disintegration, and activation of TMEM16F during necroptosis.

    Science.gov (United States)

    Ousingsawat, Jiraporn; Cabrita, Inês; Wanitchakool, Podchanart; Sirianant, Lalida; Krautwald, Stefan; Linkermann, Andreas; Schreiber, Rainer; Kunzelmann, Karl

    2017-01-01

    Activated receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain like (MLKL) are essential components of the necroptotic pathway. Phosphorylated MLKL (pMLKL) is thought to induce membrane leakage, leading to cell swelling and disintegration of the cell membrane. However, the molecular identity of the necroptotic membrane pore remains unclear, and the role of pMLKL for membrane permeabilization is currently disputed. We observed earlier that the phospholipid scramblase and ion channel TMEM16F/anoctamin 6 cause large membrane currents, cell swelling, and cell death when activated by a strong increase in intracellular Ca 2+ . We, therefore, asked whether TMEM16F is also central to necroptotic cell death and other cellular events during necroptosis. Necroptosis was induced by TNFα, smac mimetic, and Z-VAD (TSZ) in NIH3T3 fibroblasts and the four additional cell lines HT 29 , 16HBE, H441, and L929. Time-dependent changes in intracellular Ca 2+ , cell morphology, and membrane currents were recorded. TSZ induced a small and only transient oscillatory rise in intracellular Ca 2+ , which was paralleled by the activation of outwardly rectifying Cl - currents, which were typical for TMEM16F/ANO6. Ca 2+ oscillations were due to Ca 2+ release from endoplasmic reticulum, and were independent of extracellular Ca 2+ . The initial TSZ-induced cell swelling was followed by cell shrinkage. Using typical channel blockers and siRNA-knockdown, the Cl - currents were shown to be due to the activation of ANO6. However, the knockdown of ANO6 or inhibitors of ANO6 did not inhibit necroptotic cell death. The present data demonstrate the activation of ANO6 during necroptosis, which, however, is not essential for cell death.

  6. Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+ -induced glucagon exocytosis in pancreas

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Wei, Shun-Hui; Hoang, Dong Nhut

    2009-01-01

    Hormones such as glucagon are secreted by Ca(2+)-induced exocytosis of large dense-core vesicles, but the mechanisms involved have only been partially elucidated. Studies of pancreatic beta-cells secreting insulin revealed that synaptotagmin-7 alone is not sufficient to mediate Ca(2+)-dependent i...

  7. Capture reactions of 40Ca and 48Ca with targets of 197Au and 208Pb

    International Nuclear Information System (INIS)

    Stokstad, R.; Chan, Y.; Chavez, E.

    1988-03-01

    The reactions of 40 Ca and 48 Ca with targets of 197 Au and 208 Pb have been measured in the region from below the interaction barrier to about twice the barrier energy. The fission-like fragments were detected in a pair of position-sensitive, multi-wire proportional counters and were identified from measurements of position and time using two-body kinematics. In the region above the barrier the cross sections for capture are less than those given by the touching condition, indicating that an /open quotes/extra push/close quotes/ is required to induce capture. The observations for 40 Ca and 48 Ca show different fissilities for the onset of the extra push and indicate that charge equilibration may be an important factor governing capture reactions. Below the barrier the cross sections show an enhancement relative to the prediction for a one dimensional barrier. The enhancements are larger for 40 Ca than for 48 Ca (for both targets) and this is in qualitative agreement with predictions based on the coupling of the relative motion to low-lying collective states. Both above and below the barrier, we find that the change in the light partner, from 48 Ca to 40 Ca, has a larger effect on the cross sections than the change from 208 Pb to 197 Au, after correction for the change in the Coulomb barrier. 16 refs., 7 figs

  8. Intercellular Ca2+ Waves: Mechanisms and Function

    Science.gov (United States)

    Sanderson, Michael J.

    2012-01-01

    Intercellular calcium (Ca2+) waves (ICWs) represent the propagation of increases in intracellular Ca2+ through a syncytium of cells and appear to be a fundamental mechanism for coordinating multicellular responses. ICWs occur in a wide diversity of cells and have been extensively studied in vitro. More recent studies focus on ICWs in vivo. ICWs are triggered by a variety of stimuli and involve the release of Ca2+ from internal stores. The propagation of ICWs predominately involves cell communication with internal messengers moving via gap junctions or extracellular messengers mediating paracrine signaling. ICWs appear to be important in both normal physiology as well as pathophysiological processes in a variety of organs and tissues including brain, liver, retina, cochlea, and vascular tissue. We review here the mechanisms of initiation and propagation of ICWs, the key intra- and extracellular messengers (inositol 1,4,5-trisphosphate and ATP) mediating ICWs, and the proposed physiological functions of ICWs. PMID:22811430

  9. Fusion dynamics in 40Ca induced reactions

    International Nuclear Information System (INIS)

    Prasad, E.; Hinde, D.J.; Williams, E.

    2017-01-01

    Synthesis of superheavy elements (SHEs) and investigation of their properties are among the most challenging research topics in modern science. A non-compound nuclear process called quasi fission is partly responsible for the very low production cross sections of SHEs. The formation and survival probabilities of the compound nucleus (CN) strongly depend on the competition between fusion and quasi fission. A clear understanding of these processes and their dynamics is required to make reliable predictions of the best reactions to synthesise new SHEs. All elements beyond Nh are produced using hot fusion reactions and beams of 48 Ca were used in most of these experiments. In this context a series of fission measurements have been carried out at the Australian National University (ANU) using 40;48 Ca beams on various targets ranging from 142 Nd to 249 Cf. Some of the 40 Ca reactions will be discussed in this symposium

  10. Applicative Value of Serum CA19-9, CEA, CA125 and CA242 in Diagnosis and Prognosis for Patients with Pancreatic Cancer Treated by Concurrent Chemoradiotherapy.

    Science.gov (United States)

    Gu, Yu-Lei; Lan, Chao; Pei, Hui; Yang, Shuang-Ning; Liu, Yan-Fen; Xiao, Li-Li

    2015-01-01

    To evaluate the application value of serum CA19-9, CEA, CA125 and CA242 in diagnosis and prognosis of pancreatic cancer cases treated with concurrent chemotherapy. 52 patients with pancreatic cancer, 40 with benign pancreatic diseases and 40 healthy people were selected. The electrochemiluminescence immunoassay method was used for detecting levels of CA19-9, CEA and CA125, and a CanAg CA242 enzyme linked immunoassay kit for assessing the level of CA242. The Kaplan-Meier method was used for analyzing the prognostic factors of patients with pancreatic cancer. The Cox proportional hazard model was applied for analyzing the hazard ratio (HR) and 95% confidential interval (CI) for survival time of patients with pancreatic cancer. The levels of serum CA19-9, CEA, CA125 and CA242 in patients with pancreatic cancer were significantly higher than those in patients with benign pancreatic diseases and healthy people (PCEA. The specificity of CA242 is the highest, followed by CA125, CEA and CA19-9. The sensitivity and specificity of joint detection of serum CA19-9, CEA, CA125and CA242 were 90.4% and 93.8%, obviously higher than single detection of those markers in diagnosis of pancreatic cancer. The median survival time of 52 patients with pancreatic cancer was 10 months (95% CI7.389~12.611).. Patients with the increasing level of serum CA19-9, CEA, CA125, CA242 had shorter survival times (P=0.047. 0.043, 0.0041, 0.029). COX regression analysis showed that CA19-9 was an independent prognostic factor for patients with pancreatic cancer (P=0.001, 95%CI 2.591~38.243). The detection of serum tumor markers (CA19.9, CEA, CA125 and CA242) is conducive to the early diagnosis of pancreatic cancer and joint detection of tumor markers helps improve the diagnostic efficiency. Moreover, CA19-9 is an independent prognostic factor for patients with pancreatic cancer.

  11. Study on Ca2+ antagonistic effect and mechanism of Chinese herbal drugs using 45Ca

    International Nuclear Information System (INIS)

    Yang Yuanyou; Liu Ning; Mo Shangwu; Qiu Mingfeng; Jin Jiannan; Liao Jiali

    2002-01-01

    The Ca 2+ antagonistic effect and mechanism of Chinese herbal drugs are studied by using 45 Ca. The results indicate that potential-dependent Ca 2+ channel (PDC) and receptor-operated Ca 2+ channel (ROC) in cell membranes of smooth muscle can be blocked by several Chinese herbal drugs, including as Crocus sativus L., Carthamus L., Di-ao-xin-xue-kang (DAXXG) and Ginkgo biloba L. leaves. Among them Crocus sativus L. has the strongest antagonistic effect on Ca 2+ channel, while Ginkgo biloba L. leaves has no obvious effect. The whole prescription and the other functional drugs have significant effect on ROC and PDC. The compositions extracted by hexane have the strongest antagonistic. The wrinkled giant hyssop have five active compositions and Pei-lan have two active compositions

  12. Large conductance Ca2+-activated K+ (BK channel: Activation by Ca2+ and voltage

    Directory of Open Access Journals (Sweden)

    RAMÓN LATORRE

    2006-01-01

    Full Text Available Large conductance Ca2+-activated K+ (BK channels belong to the S4 superfamily of K+ channels that include voltage-dependent K+ (Kv channels characterized by having six (S1-S6 transmembrane domains and a positively charged S4 domain. As Kv channels, BK channels contain a S4 domain, but they have an extra (S0 transmembrane domain that leads to an external NH2-terminus. The BK channel is activated by internal Ca2+, and using chimeric channels and mutagenesis, three distinct Ca2+-dependent regulatory mechanisms with different divalent cation selectivity have been identified in its large COOH-terminus. Two of these putative Ca2+-binding domains activate the BK channel when cytoplasmic Ca2+ reaches micromolar concentrations, and a low Ca2+ affinity mechanism may be involved in the physiological regulation by Mg2+. The presence in the BK channel of multiple Ca2+-binding sites explains the huge Ca2+ concentration range (0.1 μM-100 μM in which the divalent cation influences channel gating. BK channels are also voltage-dependent, and all the experimental evidence points toward the S4 domain as the domain in charge of sensing the voltage. Calcium can open BK channels when all the voltage sensors are in their resting configuration, and voltage is able to activate channels in the complete absence of Ca2+. Therefore, Ca2+ and voltage act independently to enhance channel opening, and this behavior can be explained using a two-tiered allosteric gating mechanism.

  13. Cardiac microvascular endothelial cells express a functional Ca+ -sensing receptor.

    Science.gov (United States)

    Berra Romani, Roberto; Raqeeb, Abdul; Laforenza, Umberto; Scaffino, Manuela Federica; Moccia, Francesco; Avelino-Cruz, Josè Everardo; Oldani, Amanda; Coltrini, Daniela; Milesi, Veronica; Taglietti, Vanni; Tanzi, Franco

    2009-01-01

    The mechanism whereby extracellular Ca(2+) exerts the endothelium-dependent control of vascular tone is still unclear. In this study, we assessed whether cardiac microvascular endothelial cells (CMEC) express a functional extracellular Ca(2+)-sensing receptor (CaSR) using a variety of techniques. CaSR mRNA was detected using RT-PCR, and CaSR protein was identified by immunocytochemical analysis. In order to assess the functionality of the receptor, CMEC were loaded with the Ca(2+)-sensitive fluorochrome, Fura-2/AM. A number of CaSR agonists, such as spermine, Gd(3+), La(3+) and neomycin, elicited a heterogeneous intracellular Ca(2+) signal, which was abolished by disruption of inositol 1,4,5-trisphosphate (InsP(3)) signaling and by depletion of intracellular stores with cyclopiazonic acid. The inhibition of the Na(+)/Ca(2+) exchanger upon substitution of extracellular Na(+) unmasked the Ca(2+) signal triggered by an increase in extracellular Ca(2+) levels. Finally, aromatic amino acids, which function as allosteric activators of CaSR, potentiated the Ca(2+) response to the CaSR agonist La(3+). These data provide evidence that CMEC express CaSR, which is able to respond to physiological agonists by mobilizing Ca(2+) from intracellular InsP(3)-sensitive stores. Copyright 2008 S. Karger AG, Basel.

  14. Herpesvirus-Mediated Delivery of a Genetically Encoded Fluorescent Ca2+ Sensor to Canine Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    János Prorok

    2009-01-01

    Full Text Available We report the development and application of a pseudorabies virus-based system for delivery of troponeon, a fluorescent Ca2+ sensor to adult canine cardiomyocytes. The efficacy of transduction was assessed by calculating the ratio of fluorescently labelled and nonlabelled cells in cell culture. Interaction of the virus vector with electrophysiological properties of cardiomyocytes was evaluated by the analysis of transient outward current (Ito, kinetics of the intracellular Ca2+ transients, and cell shortening. Functionality of transferred troponeon was verified by FRET analysis. We demonstrated that the transfer efficiency of troponeon to cultured adult cardiac myocytes was virtually 100%. We showed that even after four days neither the amplitude nor the kinetics of the Ito current was significantly changed and no major shifts occurred in parameters of [Ca2+]i transients. Furthermore, we demonstrated that infection of cardiomyocytes with the virus did not affect the morphology, viability, and physiological attributes of cells.

  15. Value of Combined Detection of Serum CEA, CA72-4, CA19-9, CA15-3 and CA12-5 in the Diagnosis of Gastric Cancer.

    Science.gov (United States)

    Chen, Changguo; Chen, Qiuyuan; Zhao, Qiangyuan; Liu, Min; Guo, Jianwei

    2017-05-01

    To examine whether the combined detection of serum tumor markers (CEA, CA72-4, CA19-9, CA15-3 and CA12-5) improves the sensitivity and accuracy in the diagnosis of gastric cancer (GC). An automatic chemiluminescence immune analyzer with matched kits was used to determine the levels of serum CEA, CA72-4, CA19-9, CA15-3, and CA12-5 in 87 patients with gastric cancer (GC group), 60 patients with gastric benign diseases (GBD group) who were hospitalized during the same period, and 40 healthy subjects undergoing a physical examination. The values of these 5 tumor markers in the diagnosis of gastric cancer were analyzed. The levels of serum CEA, CA72-4, CA19-9, and CA12-5 were higher in the GC group than in the GBD group and healthy subjects, and these differences were significant ( P 0.05). The combined detection of CEA, CA72-4, CA19-9, and CA12-5 had a higher diagnostic value for gastric cancer than did single detection, and the positive detection rate of the combined detection of the four tumor markers was 60.9%. The diagnostic power when using the combined detection of CA72-4, CEA, CA19-9, and CA12-5 was the best. The combined detection of serum CA72-4, CEA, CA19-9 and CA12-5 increases the sensitivity and accuracy in the diagnosis of GC and can thus be considered an important tool for early diagnosis. © 2017 by the Association of Clinical Scientists, Inc.

  16. Exchange stiffness of Ca-doped YIG

    Science.gov (United States)

    Avgin, I.; Huber, D. L.

    1994-05-01

    An effective medium theory for the zero-temperature exchange stiffness of uncompensated Ca-doped YIG is presented. The theory is based on the assumption that the effect of the Ca impurities is to produce strong, random ferromagnetic interactions between spins on the a and d sublattices. In the simplest version of the theory, a fraction, x, of the ad exchange integrals are large and positive, x being related to the Ca concentration. The stiffness is calculated as function of x for arbitrary perturbed ad exchange integral, Jxad. For Jxad≳(1/5)‖8Jaa+3Jdd‖, with Jaa and Jdd denoting the aa and dd exchange integrals, respectively, there is a critical concentration, Xc, such that when x≳Xc, the stiffness is complex. It is suggested that Xc delineates the region where there are significant departures from colinearity in the ground state of the Fe spins. Extension of the theory to a model where the Ca doping is assumed to generate Fe4+ ions on the tetrahedral sites is discussed. Possible experimental tests of the theory are mentioned.

  17. Ca teos report in register N 13377

    International Nuclear Information System (INIS)

    Pena, S; Arrighetti, R.

    2011-01-01

    This work is about a report about ca teos carried out in register N 13377 in the department of Canelones to know the depth of the field. The drilling done allowed to identify granite and clay. This granite outcrops are developed in the east of the middle course of the stream Pando

  18. literacy.ca EXPRESS. April 2010

    Science.gov (United States)

    Movement for Canadian Literacy, 2010

    2010-01-01

    This issue of "literacy.ca EXPRESS" focuses on poverty. The articles included in this issue are: (1) Poverty Overview; (2) Tony's Story; (3) LAN (Learner Advisory Network) Member's Story (Dianne Smith); (4) Linking Adult Literacy to Poverty Reduction; (5) MCL (Movement for Canadian Literacy) Update; (6) Highlights from the LAN; (7) Good…

  19. Inflammatory mediator bradykinin increases population of sensory neurons expressing functional T-type Ca(2+) channels.

    Science.gov (United States)

    Huang, Dongyang; Liang, Ce; Zhang, Fan; Men, Hongchao; Du, Xiaona; Gamper, Nikita; Zhang, Hailin

    2016-04-29

    T-type Ca(2+) channels are important regulators of peripheral sensory neuron excitability. Accordingly, T-type Ca(2+) currents are often increased in various pathological pain conditions, such as inflammation or nerve injury. Here we investigated effects of inflammation on functional expression of T-type Ca(2+) channels in small-diameter cultured dorsal root ganglion (DRG) neurons. We found that overnight treatment of DRG cultures with a cocktail of inflammatory mediators bradykinin (BK), adenosine triphosphate (ATP), norepinephrine (NE) and prostaglandin E2 (PGE2) strongly increased the population size of the small-diameter neurons displaying low-voltage activated (LVA, T-type) Ca(2+) currents while having no effect on the peak LVA current amplitude. When applied individually, BK and ATP also increased the population size of LVA-positive neurons while NE and PGE2 had no effect. The PLC inhibitor U-73122 and B2 receptor antagonist, Hoe-140, both abolished the increase of the population of LVA-positive DRG neurons. Inflammatory treatment did not affect CaV3.2 mRNA or protein levels in DRG cultures. Furthermore, an ubiquitination inhibitor, MG132, did not increase the population of LVA-positive neurons. Our data suggest that inflammatory mediators BK and ATP increase the abundance of LVA-positive DRG neurons in total neuronal population by stimulating the recruitment of a 'reserve pool' of CaV3.2 channels, particularly in neurons that do not display measurable LVA currents under control conditions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Effect of Nd substitution for Ca on crystal structure, optical and magnetic properties of multiferroic Bi0.9Ca0.1FeO3

    International Nuclear Information System (INIS)

    Quan, Chuye; Ma, Yuhui; Han, Yumin; Tang, Xingxing; Lu, Mengjia; Mao, Weiwei; Zhang, Jian; Yang, Jianping; Li, Xing’ao

    2015-01-01

    Highlights: • Crystal structure of doped samples transform to two phase coexistence. • The crystal size decreased to ∼50 nm after doping. • Ultraviolet absorption peak demonstrates apparent blue shift for doped sample. • The ratio of Fe 2+ increased by merging Nd. • Ca, Nd co-doped can promote the ferromagnetism obviously. - Abstract: Pure and co-doped BiFeO 3 (Ca, Nd) nanoparticles with diameter in the range of 50–250 nm were synthesized through a sol–gel method. X-ray diffraction (XRD) and Raman results show that Bi-site co-doped with Ca, Nd could result in a transition of crystal structure (from single phase rhombohedral (R3c) to two phase coexistence). An apparent blue shift can be observed in the co-doped samples along with a decrease of the direct optical band gap. Moreover, the leakage current was decreased due to the introduction of nonvolatile Ca and Nd at Bi 3+ site. Analysis of MPMS-VSM magnetic hysteresis data reveals a further enhancement in magnetism in the Nd doped Bi 0.9 Ca 0.1 FeO 3, which is further explained by XPS characterization

  1. Non-Dioxin-Like Polychlorinated Biphenyls Inhibit G-Protein Coupled Receptor-Mediated Ca2+ Signaling by Blocking Store-Operated Ca2+ Entry.

    Directory of Open Access Journals (Sweden)

    Se-Young Choi

    Full Text Available Polychlorinated biphenyls (PCBs are ubiquitous pollutants which accumulate in the food chain. Recently, several molecular mechanisms by which non-dioxin-like (NDL PCBs mediate neurodevelopmental and neurobehavioral toxicity have been elucidated. However, although the G-protein coupled receptor (GPCR is a significant target for neurobehavioral disturbance, our understanding of the effects of PCBs on GPCR signaling remains unclear. In this study, we investigated the effects of NDL-PCBs on GPCR-mediated Ca2+ signaling in PC12 cells. We found that ortho-substituted 2,2',6-trichlorinated biphenyl (PCB19 caused a rapid decline in the Ca2+ signaling of bradykinin, a typical Gq- and phospholipase Cβ-coupled GPCR, without any effect on its inositol 1,4,5-trisphosphate production. PCB19 reduced thapsigargin-induced sustained cytosolic Ca2+ levels, suggesting that PCB19 inhibits SOCE. The abilities of other NDL-PCBs to inhibit store-operated Ca2+ entry (SOCE were also examined and found to be of similar potencies to that of PCB19. PCB19 also showed a manner equivalent to that of known SOCE inhibitors. PCB19-mediated SOCE inhibition was confirmed by demonstrating the ability of PCB19 to inhibit the SOCE current and thapsigargin-induced Mn2+ influx. These results imply that one of the molecular mechanism by which NDL-PCBs cause neurobehavioral disturbances involves NDL-PCB-mediated inhibition of SOCE, thereby interfering with GPCR-mediated Ca2+ signaling.

  2. The study of skeletal calcium metabolism with 41Ca and 45Ca

    Science.gov (United States)

    Freeman, Stewart P. H. T.; Beck, Belinda; Bierman, June M.; Caffee, Marc W.; Heaney, Robert P.; Holloway, Leah; Marcus, Robert; Southon, John R.; Vogel, John S.

    2000-10-01

    The living skeleton can be labeled for life by the administration of radiologically trivial amounts of 41Ca tracer. After initial elimination of tracer from the readily exchangeable calcium pools subsequent skeletal calcium turnover maintains and modulates the urine 41Ca content. Uniquely, bone calcium metabolism may then be studied with tracer in near equilibrium with the body's calcium and resorbing calcium directly measured by accelerator mass spectrometry (AMS) of excreta. Our experiments with 25 41Ca labeled subjects demonstrate excellent diurnal stability and remarkable response to intervention of the urine signal. Thus the tracer method may prove a competitive means of measuring the effects of antiresorptive osteoporosis treatments, for therapy development or even clinical monitoring. Novel studies of long-term skeletal evolution are also possible. We realize that routinely administered short-lived calcium radiotracers contain 41Ca impurities and that thousands of experimental participants have been historically inadvertently 41Ca labeled. The 41Ca urine index might now rapidly further be characterized by contemporary measurements of these one-time subjects, and with their by now thoroughly skeleton-equilibrated tracer they might be ideal participants in other new experiments. We are also investigating 45Ca AMS. It may prove preferable to label the skeleton with this radiotracer already familiar to bioscientists, but new to AMS.

  3. Mg-Ca Alloys Produced by Reduction of CaO: Understanding of ECO-Mg Alloy Production

    Science.gov (United States)

    Jung, In-Ho; Lee, Jin Kyu; Kim, Shae K.

    2017-04-01

    There have been long debates about the environment conscious (ECO) Mg technology which utilizes CaO to produce Ca-containing Mg alloys. Two key process technologies of the ECO-Mg process are the chemical reduction of CaO by liquid Mg and the maintenance of melt cleanliness during the alloying of Ca. Thermodynamic calculations using FactSage software were performed to explain these two key issues. In addition, an experimental study was performed to compare the melt cleanliness of the Ca-containing Mg alloys produced by the conventional route with metallic Ca and the ECO-Mg route with CaO.

  4. DA-6034 Induces [Ca(2+)]i Increase in Epithelial Cells.

    Science.gov (United States)

    Yang, Yu-Mi; Park, Soonhong; Ji, Hyewon; Kim, Tae-Im; Kim, Eung Kweon; Kang, Kyung Koo; Shin, Dong Min

    2014-04-01

    DA-6034, a eupatilin derivative of flavonoid, has shown potent effects on the protection of gastric mucosa and induced the increases in fluid and glycoprotein secretion in human and rat corneal and conjunctival cells, suggesting that it might be considered as a drug for the treatment of dry eye. However, whether DA-6034 induces Ca(2+) signaling and its underlying mechanism in epithelial cells are not known. In the present study, we investigated the mechanism for actions of DA-6034 in Ca(2+) signaling pathways of the epithelial cells (conjunctival and corneal cells) from human donor eyes and mouse salivary gland epithelial cells. DA-6034 activated Ca(2+)-activated Cl(-) channels (CaCCs) and increased intracellular calcium concentrations ([Ca(2+)]i) in primary cultured human conjunctival cells. DA-6034 also increased [Ca(2+)]i in mouse salivary gland cells and human corneal epithelial cells. [Ca(2+)]i increase of DA-6034 was dependent on the Ca(2+) entry from extracellular and Ca(2+) release from internal Ca(2+) stores. Interestingly, these effects of DA-6034 were related to ryanodine receptors (RyRs) but not phospholipase C/inositol 1,4,5-triphosphate (IP3) pathway and lysosomal Ca(2+) stores. These results suggest that DA-6034 induces Ca(2+) signaling via extracellular Ca(2+) entry and RyRs-sensitive Ca(2+) release from internal Ca(2+) stores in epithelial cells.

  5. New limits on 2β processes in 40Ca and 46Ca by using low radioactive CaF2(Eu) crystal scintillators

    International Nuclear Information System (INIS)

    Belli, P.; Bernabei, R.; Dai, C.J.

    2001-01-01

    The development of highly radiopure CaF 2 (Eu) crystal scintillators has been performed aiming at a substantial sensitivity enhancement of the 2β decay investigation and of the search for dark matter particles with spin-dependent (SD) interaction. The results of CaF 2 (Eu) background measurements and simulation are presented. New and highly improved T 1/2 limits on the 2β decay of 46 Ca and the double electron capture of 40 Ca are obtained

  6. Biomarkers in pancreatic adenocarcinoma: current perspectives.

    Science.gov (United States)

    Swords, Douglas S; Firpo, Matthew A; Scaife, Courtney L; Mulvihill, Sean J

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year survival rate of 7.7%. Most patients are diagnosed at an advanced stage not amenable to potentially curative resection. A substantial portion of this review is dedicated to reviewing the current literature on carbohydrate antigen (CA 19-9), which is currently the only guideline-recommended biomarker for PDAC. It provides valuable prognostic information, can predict resectability, and is useful in decision making about neoadjuvant therapy. We also discuss carcinoembryonic antigen (CEA), CA 125, serum biomarker panels, circulating tumor cells, and cell-free nucleic acids. Although many biomarkers have now been studied in relation to PDAC, significant work still needs to be done to validate their usefulness in the early detection of PDAC and management of patients with PDAC.

  7. Aging-related impairments of hippocampal mossy fibers synapses on CA3 pyramidal cells.

    Science.gov (United States)

    Villanueva-Castillo, Cindy; Tecuatl, Carolina; Herrera-López, Gabriel; Galván, Emilio J

    2017-01-01

    The network interaction between the dentate gyrus and area CA3 of the hippocampus is responsible for pattern separation, a process that underlies the formation of new memories, and which is naturally diminished in the aged brain. At the cellular level, aging is accompanied by a progression of biochemical modifications that ultimately affects its ability to generate and consolidate long-term potentiation. Although the synapse between dentate gyrus via the mossy fibers (MFs) onto CA3 neurons has been subject of extensive studies, the question of how aging affects the MF-CA3 synapse is still unsolved. Extracellular and whole-cell recordings from acute hippocampal slices of aged Wistar rats (34 ± 2 months old) show that aging is accompanied by a reduction in the interneuron-mediated inhibitory mechanisms of area CA3. Several MF-mediated forms of short-term plasticity, MF long-term potentiation and at least one of the critical signaling cascades necessary for potentiation are also compromised in the aged brain. An analysis of the spontaneous glutamatergic and gamma-aminobutyric acid-mediated currents on CA3 cells reveal a dramatic alteration in amplitude and frequency of the nonevoked events. CA3 cells also exhibited increased intrinsic excitability. Together, these results demonstrate that aging is accompanied by a decrease in the GABAergic inhibition, reduced expression of short- and long-term forms of synaptic plasticity, and increased intrinsic excitability. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Effects of Ca on microstructure, mechanical and corrosion properties and biocompatibility of Mg-Zn-Ca alloys.

    Science.gov (United States)

    Yin, Ping; Li, Nian Feng; Lei, Ting; Liu, Lin; Ouyang, Chun

    2013-06-01

    Zn and Ca were selected as alloying elements to develop an Mg-Zn-Ca alloy system for biomedical application due to their good biocompatibility. The effects of Ca on the microstructure, mechanical and corrosion properties as well as the biocompatibility of the as-cast Mg-Zn-Ca alloys were studied. Results indicate that the microstructure of Mg-Zn-Ca alloys typically consists of primary α-Mg matrix and Ca₂Mg₆Zn₃/Mg₂Ca intermetallic phase mainly distributed along grain boundary. The yield strength of Mg-Zn-Ca alloy increased slightly with the increase of Ca content, whilst its tensile strength increased at first and then decreased. Corrosion tests in the simulated body fluid revealed that the addition of Ca is detrimental to corrosion resistance due to the micro-galvanic corrosion acceleration. In vitro hemolysis and cytotoxicity assessment disclose that Mg-5Zn-1.0Ca alloy has suitable biocompatibility.

  9. Reassigning the CaH+ 11Σ → 21Σ vibronic transition with CaD+

    Science.gov (United States)

    Condoluci, J.; Janardan, S.; Calvin, A. T.; Rugango, R.; Shu, G.; Sherrill, C. D.; Brown, K. R.

    2017-12-01

    We observe vibronic transitions in CaD+ between the 11Σ and 21Σ electronic states by resonance enhanced multiphoton photodissociation spectroscopy in a Coulomb crystal. The vibronic transitions are compared with previous measurements on CaH+. The result is a revised assignment of the CaH+ vibronic levels and a disagreement with multi-state-complete-active-space second-order perturbation theory theoretical calculations by approximately 700 cm-1. Updated high-level coupled-cluster calculations that include core-valence correlations reduce the disagreement between theory and experiment to 300 cm-1.

  10. Mg and Ca isotope fractionation during CaCO3 biomineralisation

    International Nuclear Information System (INIS)

    Chang, Veronica T.-C.; Williams, R.J.P.; Makishima, Akio; Belshawl, Nick S.; O'Nions, R. Keith

    2004-01-01

    The natural variation of Mg and Ca stable isotopes of carbonates has been determined in carbonate skeletons of perforate foraminifera and reef coral together with Mg/Ca ratios to assess the influence of biomineralisation processes. The results for coral aragonite suggest its formation, in terms of stable isotope behaviour, approximates to inorganic precipitation from a seawater reservoir. In contrast, results for foraminifera calcite suggest a marked biological control on Mg isotope ratios presumably related to its low Mg content compared with seawater. The bearing of these observations on the use of Mg and Ca isotopes as proxies in paleoceanography is considered

  11. Thermoluminescence of CaCO3:Dy and CaCO3:Mn

    International Nuclear Information System (INIS)

    Bapat, V.N.; Nambi, K.S.V.

    1976-01-01

    CaCO 3 samples doped with Dy and Mn were prepared in the laboratory by co-precipitation techniques. Thermoluminescence and emission spectra of these phosphors were studied and were compared with those of the naturally occuring calcite and undoped CaCO 3 samples. Dy-doping seems to give a more efficient phosphor and indicates a possibility of getting a better phosphor by a judicious choice of a rare earth doping of CaCO 3 . Interesting result have been obtained on the TL glow curve variations of these phosphors with different temperature treatments prior to irradiation. (author)

  12. Inhibition of T cell proliferation by selective block of Ca(2+)-activated K(+) channels

    DEFF Research Database (Denmark)

    Jensen, B S; Odum, Niels; Jorgensen, N K

    1999-01-01

    cell activation and proliferation has been investigated by using various blockers of IK channels. The Ca(2+)-activated K(+) current in human T cells is shown by the whole-cell voltage-clamp technique to be highly sensitive to clotrimazole, charybdotoxin, and nitrendipine, but not to ketoconazole...

  13. Effects of electron-irradiation on electrical properties of AgCa/Si Schottky diodes

    International Nuclear Information System (INIS)

    Harmatha, L.; Zizka, M.; Sagatova, A.; Nemec, M.; Hybler, P.

    2013-01-01

    This contribution presents the results of the current-voltage I-V and the capacitance-voltage C-V measurement on the Schottky diodes with the AgCa gate on the silicon n-type substrate. The Si substrate was irradiated by 5 MeV electrons with a different dose value before the Schottky diode preparation. (authors)

  14. Dark matter search with CaF sub 2 scintillators in Osaka

    CERN Document Server

    Ogawa, I; Hazama, R; Ajimura, S; Matsuoka, K; Suzuki, N; Nitta, T; Miyawaki, H; Shiomi, S; Tanaka, Y; Ejiri, H; Kudomi, N; Kume, K; Ohsumi, H; Fushimi, K

    2000-01-01

    A detector system which consists of CaF sub 2 scintillators surrounded by active and passive shields, is developed to search for spin coupled dark matter. The whole system is in operation at the underground laboratory located in Nara (Oto Cosmo Observatory) which has effectively 1.2 km water equivalent shield. In this article our current status of the investigation is described.

  15. Superconductivity in volumetric and film ceramics Bi-Sr-Ca-Cu-O

    International Nuclear Information System (INIS)

    Sukhanov, A.A.; Ozmanyan, Kh.R.; Sandomirskij, B.B.

    1988-01-01

    A superconducting transition with T c0 =82-95 K and T c (R=0)=82-72 K was observed in volumetric and film Bi(Sr 1-x Ca x ) 2 Cu 3 O y samples obtained by solid-phase reaction. Temperature dependences of resistance critical current and magnetic susceptibility are measured

  16. Superconductivity in Bi-Sr-Ca-Cu-O bulk and film ceramics

    Energy Technology Data Exchange (ETDEWEB)

    Sukhanov, A A; Ozmanian, KH R; Sandomirskii, B B

    1988-07-01

    A superconducting transition with Tc0 = 82-95 K and Tc(R = 0) = 82-72 K was observed in Bi(Sr/1-x/Ca/x/)2Cu3O(y) bulk and film specimens obtained via a solid-phase reaction. Temperature dependences of the resistance, critical current, and magnetic susceptibility were measured.

  17. The Pr and Ca Substitution in GdBa2Cu3O7- & delta

    Directory of Open Access Journals (Sweden)

    H. S. H.

    2001-12-01

    Full Text Available   The granular Gd1-x-zPrxCazBa2Cu3O7-δ high-temperature cuprate samples with 0.0 ≤ x ≤ 0.3 and 0.0≤ x ≤ 0.35 are prepared by standard solid state reaction and characterized by XRD and SEM techniques. The BaCuO2 and impurity phases are less than 1% in the samples having high levels of pr and Ca concentrations. The electrical resistivity measurements show a nonlinear reduction in Tc(x,z=etc versus x. Moreover, the Tc(z curve with x=0 is nonlinear and aplateau appears at z≈ 0.05-0.015. For Pr-Ca-doped samples with a constant concentration of Pr, Tc increases with the increase of Ca up to an optimum value of Ca doping and then in decreases. Based on these observations, we suggest that hole filling and hole localization the main effects of Pr ion substiution. The magnetic measurements indicate that the value of Hc1 is in the order of 10 mT. The mangetoresistance measurements have been measured and analyzed. The superconducting transition region is broadened by the application of magnetic field. The experimental data near the onsen of superconductivity are fitted with the Ambegakor and Halperin (AH phase-slip model. We observe that the AH parameter,γ (H, depends not only on the temperature and the magnetic field, but also on the Pr and Ca ions concentrations. It is observed that the critical current density increases with Ca substitution and decreases with Pr substitution in Gd-123 system. We suggest that the Pr ion substitution probably enhances the weak link, but the Ca ion acts as flux pinning center in the GdPrCa-123 system.

  18. Teratogenic effect of calcium edetate (CaEDTA) in rats and the protective effect of zinc.

    Science.gov (United States)

    Brownie, C F; Brownie, C; Noden, D; Krook, L; Haluska, M; Aronson, A L

    1986-03-15

    The calcium chelate of EDTA (CaEDTA) currently is the drug of choice in the treatment of lead intoxication. This study investigated the teratogenic potential of CaEDTA, administered parenterally during periods of organogenesis and determined if incorporating zinc into EDTA would protect against teratogenic effects. Four doses (2, 4, 6, and 8 mmol/m2/day) of CaEDTA, two concentrations (8 and 20 mmol/m2/day) of ZnEDTA and ZnCaEDTA (molar ratio 0.5:0.5:1) were used, and a saline control (0.9% NaCl). Timed-pregnant Long-Evans rats were assigned at random to the treatment groups, 20 per dose for each chelate and 30 to the saline control. Rats were injected with the chelate or saline solution sc, twice daily during the 11th through 15th days of gestation. Pups removed by cesarean section on the 21st day were processed for osseous and visceral examination. Additional animals per treatment group were used for maternal plasma and liver and fetal zinc determinations. Results showed increases in several abnormalities (submucous cleft, cleft palate, adactyly-syndactyly, curly tail, abnormal rib and vertebrae) with increasing amounts of CaEDTA. No malformations were seen with ZnEDTA at either dose or with ZnCaEDTA at 8 mmol/m2/day. However, submucous cleft was seen in 6 of 20 litters from the dams receiving the higher dose of ZnCaEDTA. It was concluded that CaEDTA is teratogenic in rats at concentrations which, except for decreased weight gain, produce no discernible toxicity to the dam, and which are comparable to the recommended therapeutic dosage in humans (1500 mg/m2/day corresponding to 4 mmol/m2/day). Protection is afforded by incorpora