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Sample records for gene herg channels

  1. Rab11-dependent Recycling of the Human Ether-a-go-go-related Gene (hERG) Channel*

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    Chen, Jeffery; Guo, Jun; Yang, Tonghua; Li, Wentao; Lamothe, Shawn M.; Kang, Yudi; Szendrey, John A.; Zhang, Shetuan

    2015-01-01

    The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr). A reduction in the hERG current causes long QT syndrome, which predisposes affected individuals to ventricular arrhythmias and sudden death. We reported previously that hERG channels in the plasma membrane undergo vigorous internalization under low K+ conditions. In the present study, we addressed whether hERG internalization occurs under normal K+ conditions and whether/how internalized channels are recycled back to the plasma membrane. Using patch clamp, Western blot, and confocal imaging analyses, we demonstrated that internalized hERG channels can effectively recycle back to the plasma membrane. Low K+-enhanced hERG internalization is accompanied by an increased rate of hERG recovery in the plasma membrane upon reculture following proteinase K-mediated clearance of cell-surface proteins. The increased recovery rate is not due to enhanced protein synthesis, as hERG mRNA expression was not altered by low K+ exposure, and the increased recovery was observed in the presence of the protein biosynthesis inhibitor cycloheximide. GTPase Rab11, but not Rab4, is involved in the recycling of hERG channels. Interfering with Rab11 function not only delayed hERG recovery in cells after exposure to low K+ medium but also decreased hERG expression and function in cells under normal culture conditions. We concluded that the recycling pathway plays an important role in the homeostasis of plasma membrane-bound hERG channels. PMID:26152716

  2. The effects of deoxyelephantopin on the cardiac delayed rectifier potassium channel current (IKr) and human ether-a-go-go-related gene (hERG) expression.

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    Teah, Yi Fan; Abduraman, Muhammad Asyraf; Amanah, Azimah; Adenan, Mohd Ilham; Sulaiman, Shaida Fariza; Tan, Mei Lan

    2017-09-01

    Elephantopus scaber Linn and its major bioactive component, deoxyelephantopin are known for their medicinal properties and are often reported to have various cytotoxic and antitumor activities. This plant is widely used as folk medicine for a plethora of indications although its safety profile remains unknown. Human ether-a-go-go-related gene (hERG) encodes the cardiac I Kr current which is a determinant of the duration of ventricular action potentials and QT interval. The hERG potassium channel is an important antitarget in cardiotoxicity evaluation. This study investigated the effects of deoxyelephantopin on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells. The hERG tail currents following depolarization pulses were insignificantly affected by deoxyelephantopin in the transfected cell line. Current reduction was less than 40% as compared with baseline at the highest concentration of 50 μM. The results were consistent with the molecular docking simulation and hERG surface protein expression. Interestingly, it does not affect the hERG expression at both transcriptional and translational level at most concentrations, although higher concentration at 10 μM caused protein accumulation. In conclusion, deoxyelephantopin is unlikely a clinically significant hERG channel and I kr blocker. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Escitalopram block of hERG potassium channels.

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    Chae, Yun Ju; Jeon, Ji Hyun; Lee, Hong Joon; Kim, In-Beom; Choi, Jin-Sung; Sung, Ki-Wug; Hahn, Sang June

    2014-01-01

    Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active S-enantiomer of the racemic mixture of RS-citalopram and is widely used in the treatment of depression. The effects of escitalopram and citalopram on the human ether-a-go-go-related gene (hERG) channels expressed in human embryonic kidney cells were investigated using voltage-clamp and Western blot analyses. Both drugs blocked hERG currents in a concentration-dependent manner with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a steep increase across the voltage range of channel activation. However, voltage independence was observed over the full range of activation. The blocking by escitalopram was frequency dependent. A rapid application of escitalopram induced a rapid and reversible blocking of the tail current of hERG. The extent of the blocking by escitalopram during the depolarizing pulse was less than that during the repolarizing pulse, suggesting that escitalopram has a high affinity for the open state of the hERG channel, with a relatively lower affinity for the inactivated state. Both escitalopram and citalopram produced a reduction of hERG channel protein trafficking to the plasma membrane but did not affect the short-term internalization of the hERG channel. These results suggest that escitalopram blocked hERG currents at a supratherapeutic concentration and that it did so by preferentially binding to both the open and the inactivated states of the channels and by inhibiting the trafficking of hERG channel protein to the plasma membrane.

  4. Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels

    DEFF Research Database (Denmark)

    Dupuis, Delphine S; Klaerke, Dan A; Olesen, Søren-Peter

    2005-01-01

    Patients with congenital long QT syndrome may develop arrhythmias under conditions of increased sympathetic tone. We have addressed whether some of the beta-adrenoceptor blockers commonly used to prevent the development of these arrhythmias could per se block the cardiac HERG (Human Ether....... These data showed that HERG blockade by beta-adrenoceptor blockers occurred only at high micromolar concentrations, which are significantly above the recently established safe margin of 100 (Redfern et al., 2003).......-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride) blocked the HERG channel with similar affinity, whereas the beta1-receptor antagonists metoprolol and atenolol showed weak effects. Further, the four compounds blocked HERG channels expressed in a mammalian HEK293 cell line...

  5. Inhibitory effects and mechanism of dihydroberberine on hERG channels expressed in HEK293 cells.

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    Dahai Yu

    Full Text Available The human ether-a-go-go-related gene (hERG potassium channel conducts rapid delayed rectifier potassium currents (IKr and contributes to phase III cardiac action potential repolarization. Drugs inhibit hERG channels by binding to aromatic residues in hERG helixes. Berberine (BBR has multiple actions, and its hydrogenated derivative dihydroberberine (DHB is a potential candidate for developing new drugs. Previous studies have demonstrated that BBR blocks hERG channels and prolongs action potential duration (APD. Our present study aimed to investigate the effects and mechanism of DHB on hERG channels. Protein expression and the hERG current were analyzed using western blotting and patch-clamp, respectively. DHB inhibited the hERG current concentration-dependently after instantaneous perfusion, accelerated channel inactivation by directly binding tyrosine (Tyr652 and phenylalanine (Phe656, and decreased mature (155-kDa and simultaneously increased immature (135-kDa hERG expression, respectively. This suggests disruption of forward trafficking of hERG channels. Besides, DHB remarkably reduced heat shock protein 90 (Hsp90 expression and its interaction with hERG, indicating that DHB disrupted hERG trafficking by impairing channel folding. Meanwhie, DHB enhanced the expression of cleaved activating transcription factor-6 (ATF-6, a biomarker of unfolded protein response (UPR. Expression of calnexin and calreticulin, chaperones activated by ATF-6 to facilitate channel folding, were also increased, which indicating UPR activation. Additionally, the degradation rate of mature 155-kDa hERG increased following DHB exposure. In conclusion, we demonstrated that DHB acutely blocked hERG channels by binding the aromatic Tyr652 and Phe656. DHB may decrease hERG plasma membrane expression through two pathways involving disruption of forward trafficking of immature hERG channels and enhanced degradation of mature hERG channels. Furthermore, forward trafficking was

  6. Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels.

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    Hantouche, Christine; Williamson, Brittany; Valinsky, William C; Solomon, Joshua; Shrier, Alvin; Young, Jason C

    2017-02-10

    Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. Voltage-Dependent Gating of hERG Potassium Channels

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    Cheng, Yen May; Claydon, Tom W.

    2012-01-01

    The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv) channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4–S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-à-go-go related gene, hERG), which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure–function relationships underlying activation and deactivation gating in Shaker and hERG channels, with a focus on the roles of the voltage-sensing domain and the S4–S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter-charge interactions. More recent data suggest that key amino acid differences in the hERG voltage-sensing unit and S4–S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor. PMID:22586397

  8. Voltage-dependent gating of hERG potassium channels

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    Yen May eCheng

    2012-05-01

    Full Text Available The mechanisms by which voltage-gated channels sense changes in membrane voltage and energetically couple this with opening of the ion conducting pore has been the source of significant interest. In voltage-gated potassium (Kv channels, much of our knowledge in this area comes from Shaker-type channels, for which voltage-dependent gating is quite rapid. In these channels, activation and deactivation are associated with rapid reconfiguration of the voltage-sensing domain unit that is electromechanically coupled, via the S4-S5 linker helix, to the rate-limiting opening of an intracellular pore gate. However, fast voltage-dependent gating kinetics are not typical of all Kv channels, such as Kv11.1 (human ether-a-go-go related gene, hERG, which activates and deactivates very slowly. Compared to Shaker channels, our understanding of the mechanisms underlying slow hERG gating is much poorer. Here, we present a comparative review of the structure-function relationships underlying voltage-dependent gating in Shaker and hERG channels, with a focus on the roles of the voltage sensing domain and the S4-S5 linker that couples voltage sensor movements to the pore. Measurements of gating current kinetics and fluorimetric analysis of voltage sensor movement are consistent with models suggesting that the hERG activation pathway contains a voltage independent step, which limits voltage sensor transitions. Constraints upon hERG voltage sensor movement may result from loose packing of the S4 helices and additional intra-voltage sensor counter charge interactions. More recent data suggest that key amino acid differences in the hERG voltage sensing unit and S4-S5 linker, relative to fast activating Shaker-type Kv channels, may also contribute to the increased stability of the resting state of the voltage sensor.

  9. Channel sialic acids limit hERG channel activity during the ventricular action potential.

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    Norring, Sarah A; Ednie, Andrew R; Schwetz, Tara A; Du, Dongping; Yang, Hui; Bennett, Eric S

    2013-02-01

    Activity of human ether-a-go-go-related gene (hERG) 1 voltage-gated K(+) channels is responsible for portions of phase 2 and phase 3 repolarization of the human ventricular action potential. Here, we questioned whether and how physiologically and pathophysiologically relevant changes in surface N-glycosylation modified hERG channel function. Voltage-dependent hERG channel gating and activity were evaluated as expressed in a set of Chinese hamster ovary (CHO) cell lines under conditions of full glycosylation, no sialylation, no complex N-glycans, and following enzymatic deglycosylation of surface N-glycans. For each condition of reduced glycosylation, hERG channel steady-state activation and inactivation relationships were shifted linearly by significant depolarizing ∼9 and ∼18 mV, respectively. The hERG window current increased significantly by 50-150%, and the peak shifted by a depolarizing ∼10 mV. There was no significant change in maximum hERG current density. Deglycosylated channels were significantly more active (20-80%) than glycosylated controls during phases 2 and 3 of action potential clamp protocols. Simulations of hERG current and ventricular action potentials corroborated experimental data and predicted reduced sialylation leads to a 50-70-ms decrease in action potential duration. The data describe a novel mechanism by which hERG channel gating is modulated through physiologically and pathophysiologically relevant changes in N-glycosylation; reduced channel sialylation increases hERG channel activity during the action potential, thereby increasing the rate of action potential repolarization.

  10. High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

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    Yuan-Qi Shi

    2015-08-01

    Full Text Available Background/Aims: Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM. It is well known that the human ether-ago-go-related gene (hERG controls the rapid delayed rectifier K+ current (IKr in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown. Methods: The expression of the hERG channel was assessed via western blot analysis, and the hERG current was detected with a patch-clamp technique. Results: The results of our study revealed that the expression of the hERG protein and the hERG current were substantially decreased in high-glucose-treated hERG-HEK cells. Moreover, we demonstrated that the high-glucose-mediated damage to the hERG channel depended on the down-regulation of protein levels but not the alteration of channel kinetics. These discoveries indicated that high glucose likely disrupted hERG channel trafficking. From the western blot and immunoprecipitation analyses, we found that high glucose induced trafficking inhibition through an effect on the expression of Hsp90 and its interaction with hERG. Furthermore, the high-glucose-induced inhibition of hERG channel trafficking could activate the unfolded protein response (UPR by up-regulating the expression levels of activating transcription factor-6 (ATF-6 and the ER chaperone protein calnexin. In addition, we demonstrated that 100 nM insulin up-regulated the expression of the hERG channel and rescued the hERG channel repression caused by high glucose. Conclusion: The results of our study provide the first evidence of a high-glucose-induced hERG channel deficiency resulting from the inhibition of channel trafficking. Furthermore, insulin promotes the expression of the hERG channel

  11. Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

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    Yan, Meng; Zhang, Kaiping; Shi, Yanhui; Feng, Lifang; Lv, Lin; Li, Baoxin

    2015-01-01

    Berberine (BBR), an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG) potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293) cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652) and phenylalanine (Phe656) in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR. PMID:26543354

  12. Towards a Structural View of Drug Binding to hERG K+ Channels.

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    Vandenberg, Jamie I; Perozo, Eduardo; Allen, Toby W

    2017-10-01

    The human ether-a-go-go-related gene (hERG) K + channel is of great medical and pharmaceutical relevance. Inherited mutations in hERG result in congenital long-QT syndrome which is associated with a markedly increased risk of cardiac arrhythmia and sudden death. hERG K + channels are also remarkably susceptible to block by a wide range of drugs, which in turn can cause drug-induced long-QT syndrome and an increased risk of sudden death. The recent determination of the near-atomic resolution structure of the hERG K + channel, using single-particle cryo-electron microscopy (cryo-EM), provides tremendous insights into how these channels work. It also suggests a way forward in our quest to understand why these channels are so promiscuous with respect to drug binding. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Cholesterol regulates HERG K+ channel activation by increasing phospholipase C β1 expression.

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    Chun, Yoon Sun; Oh, Hyun Geun; Park, Myoung Kyu; Cho, Hana; Chung, Sungkwon

    2013-01-01

    Human ether-a-go-go-related gene (HERG) K(+) channel underlies the rapidly activating delayed rectifier K(+) conductance (IKr) during normal cardiac repolarization. Also, it may regulate excitability in many neuronal cells. Recently, we showed that enrichment of cell membrane with cholesterol inhibits HERG channels by reducing the levels of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] due to the activation of phospholipase C (PLC). In this study, we further explored the effect of cholesterol enrichment on HERG channel kinetics. When membrane cholesterol level was mildly increased in human embryonic kidney (HEK) 293 cells expressing HERG channel, the inactivation and deactivation kinetics of HERG current were not affected, but the activation rate was significantly decelerated at all voltages tested. The application of PtdIns(4,5)P2 or inhibitor for PLC prevented the effect of cholesterol enrichment, while the presence of antibody against PtdIns(4,5)P2 in pipette solution mimicked the effect of cholesterol enrichment. These results indicate that the effect of cholesterol enrichment on HERG channel is due to the depletion of PtdIns(4,5)P2. We also found that cholesterol enrichment significantly increases the expression of β1 and β3 isoforms of PLC (PLCβ1, PLCβ3) in the membrane. Since the effects of cholesterol enrichment on HERG channel were prevented by inhibiting transcription or by inhibiting PLCβ1 expression, we conclude that increased PLCβ1 expression leads to the deceleration of HERG channel activation rate via downregulation of PtdIns(4,5)P2. These results confirm a crosstalk between two plasma membrane-enriched lipids, cholesterol and PtdIns(4,5)P2, in the regulation of HERG channels.

  14. Mechanism and pharmacological rescue of berberine-induced hERG channel deficiency

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    Yan M

    2015-10-01

    Full Text Available Meng Yan,1 Kaiping Zhang,1 Yanhui Shi,1 Lifang Feng,1 Lin Lv,1 Baoxin Li1,2 1Department of Pharmacology, Harbin Medical University, 2State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People’s Republic of China Abstract: Berberine (BBR, an isoquinoline alkaloid mainly isolated from plants of Berberidaceae family, is extensively used to treat gastrointestinal infections in clinics. It has been reported that BBR can block human ether-a-go-go-related gene (hERG potassium channel and inhibit its membrane expression. The hERG channel plays crucial role in cardiac repolarization and is the target of diverse proarrhythmic drugs. Dysfunction of hERG channel can cause long QT syndrome. However, the regulatory mechanisms of BBR effects on hERG at cell membrane level remain unknown. This study was designed to investigate in detail how BBR decreased hERG expression on cell surface and further explore its pharmacological rescue strategies. In this study, BBR decreases caveolin-1 expression in a concentration-dependent manner in human embryonic kidney 293 (HEK293 cells stably expressing hERG channel. Knocking down the basal expression of caveolin-1 alleviates BBR-induced hERG reduction. In addition, we found that aromatic tyrosine (Tyr652 and phenylalanine (Phe656 in S6 domain mediate the long-term effect of BBR on hERG by using mutation techniques. Considering both our previous and present work, we propose that BBR reduces hERG membrane stability with multiple mechanisms. Furthermore, we found that fexofenadine and resveratrol shorten action potential duration prolongated by BBR, thus having the potential effects of alleviating the cardiotoxicity of BBR. Keywords: berberine, hERG, cavoline-1, cardiotoxicity, LQTS, pharmacological rescue

  15. Local anesthetic interaction with human ether-a-go-go-related gene (HERG) channels: role of aromatic amino acids Y652 and F656

    DEFF Research Database (Denmark)

    Siebrands, Cornelia C; Schmitt, Nicole; Friederich, Patrick

    2005-01-01

    was to determine the effect of the mutations Y652A and F656A in the putative drug binding region of HERG on the inhibition by bupivacaine, ropivacaine, and mepivacaine. METHODS: The authors examined the inhibition of wild-type and mutant HERG channels, transiently expressed in Chinese hamster ovary cells...... by bupivacaine, ropivacaine, and mepivacaine. Whole cell patch clamp recordings were performed at room temperature. RESULTS: Inhibition of HERG wild-type and mutant channels by the different local anesthetics was concentration dependent, stereoselective, and reversible. The sensitivity decreased in the order...... bupivacaine > ropivacaine > mepivacaine for wild-type and mutant channels. The mutant channels were approximately 4-30 times less sensitive to the inhibitory action of the different local anesthetics than the wild-type channel. The concentration-response data were described by Hill functions (bupivacaine...

  16. Stereoselective inhibition of the hERG1 potassium channel

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    Liliana eSintra Grilo

    2010-11-01

    Full Text Available A growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1 channel, whose current is one of the main determinants of action potential duration. Prolonged repolarization is reflected by lengthening of the QT interval of the electrocardiogram, as seen in the suitably named drug-induced long QT syndrome. Chirality (presence of an asymmetric atom is a common feature of marketed drugs, which can therefore exist in at least two enantiomers with distinct three-dimensional structures and possibly distinct biological fates. Both the pharmacokinetic and pharmacodynamic properties can differ between enantiomers, as well as also between individuals who take the drug due to metabolic polymorphisms. Despite the large number of reports about drugs reducing the hERG1 current, potential stereoselective contributions have only been scarcely investigated. In this review, we present a non-exhaustive list of clinically important molecules which display chiral toxicity that may be related to hERG1-blocking properties. We particularly focus on methadone cardiotoxicity, which illustrates the importance of the stereoselective effect of drug chirality as well as individual variations resulting from pharmacogenetics. Furthermore, it seems likely that, during drug development, consideration of chirality in lead optimization and systematic assessment of the hERG1 current block with all enantiomers could contribute to the reduction of the risk of drug-induced LQTS.

  17. Inhibition of HERG potassium channels by celecoxib and its mechanism.

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    Roman V Frolov

    Full Text Available Celecoxib (Celebrex, a widely prescribed selective inhibitor of cyclooxygenase-2, can modulate ion channels independently of cyclooxygenase inhibition. Clinically relevant concentrations of celecoxib can affect ionic currents and alter functioning of neurons and myocytes. In particular, inhibition of Kv2.1 channels by celecoxib leads to arrhythmic beating of Drosophila heart and of rat heart cells in culture. However, the spectrum of ion channels involved in human cardiac excitability differs from that in animal models, including mammalian models, making it difficult to evaluate the relevance of these observations to humans. Our aim was to examine the effects of celecoxib on hERG and other human channels critically involved in regulating human cardiac rhythm, and to explore the mechanisms of any observed effect on the hERG channels.Celecoxib inhibited the hERG, SCN5A, KCNQ1 and KCNQ1/MinK channels expressed in HEK-293 cells with IC(50s of 6.0 µM, 7.5 µM, 3.5 µM and 3.7 µM respectively, and the KCND3/KChiP2 channels expressed in CHO cells with an IC(50 of 10.6 µM. Analysis of celecoxib's effects on hERG channels suggested gating modification as the mechanism of drug action.The above channels play a significant role in drug-induced long QT syndrome (LQTS and short QT syndrome (SQTS. Regulatory guidelines require that all new drugs under development be tested for effects on the hERG channel prior to first administration in humans. Our observations raise the question of celecoxib's potential to induce cardiac arrhythmias or other channel related adverse effects, and make a case for examining such possibilities.

  18. In Silico Predictions of hERG Channel Blockers in Drug Discovery

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    Taboureau, Olivier; Sørensen, Flemming Steen

    2011-01-01

    The risk for cardiotoxic side effects represents a major problem in clinical studies of drug candidates and regulatory agencies have explicitly recommended that all new drug candidates should be tested for blockage of the human Ether-a-go-go Related-Gene (hERG) potassium channel. Indeed, several ...

  19. Interaction between the cardiac rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels revealed by low K+-induced hERG endocytic degradation.

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    Guo, Jun; Wang, Tingzhong; Yang, Tonghua; Xu, Jianmin; Li, Wentao; Fridman, Michael D; Fisher, John T; Zhang, Shetuan

    2011-10-07

    Cardiac repolarization is controlled by the rapidly (I(Kr)) and slowly (I(Ks)) activating delayed rectifier potassium channels. The human ether-a-go-go-related gene (hERG) encodes I(Kr), whereas KCNQ1 and KCNE1 together encode I(Ks). Decreases in I(Kr) or I(Ks) cause long QT syndrome (LQTS), a cardiac disorder with a high risk of sudden death. A reduction in extracellular K(+) concentration ([K(+)](o)) induces LQTS and selectively causes endocytic degradation of mature hERG channels from the plasma membrane. In the present study, we investigated whether I(Ks) compensates for the reduced I(Kr) under low K(+) conditions. Our data show that when hERG and KCNQ1 were expressed separately in human embryonic kidney (HEK) cells, exposure to 0 mM K(+) for 6 h completely eliminated the mature hERG channel expression but had no effect on KCNQ1. When hERG and KCNQ1 were co-expressed, KCNQ1 significantly delayed 0 mM K(+)-induced hERG reduction. Also, hERG degradation led to a significant reduction in KCNQ1 in 0 mM K(+) conditions. An interaction between hERG and KCNQ1 was identified in hERG+KCNQ1-expressing HEK cells. Furthermore, KCNQ1 preferentially co-immunoprecipitated with mature hERG channels that are localized in the plasma membrane. Biophysical and pharmacological analyses indicate that although hERG and KCNQ1 closely interact with each other, they form distinct hERG and KCNQ1 channels. These data extend our understanding of delayed rectifier potassium channel trafficking and regulation, as well as the pathology of LQTS.

  20. Characterization of hERG1a and hERG1b potassium channels-a possible role for hERG1b in the I (Kr) current

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    Larsen, Anders Peter; Olesen, Søren-Peter; Grunnet, Morten

    2008-01-01

    I (Kr) is the fast component of the delayed rectifier potassium currents responsible for the repolarization of the cardiac muscle. The molecular correlate underlying the I (Kr) current has been identified as the hERG1 channel. Recently, two splice variants of the hERG1 alpha-subunit, hERG1a and hERG......1b, have been shown to be co-expressed in human cardiomyocytes. In this paper, we present the electrophysiological characterization of hERG1a, hERG1b, and co-expressed hERG1a/b channels in a mammalian expression system using the whole-cell patch clamp technique. We also quantified the messenger RNA...... (mRNA) levels of hERG1a and hERG1b in human cardiac tissue, and based on the expressed ratios, we evaluated the resulting currents in Xenopus laevis oocytes. Compared to hERG1a channels, activation was faster for both hERG1b and hERG1a/b channels. The deactivation kinetics was greatly accelerated...

  1. In vitro chronic effects on hERG channel caused by the marine biotoxin Yessotoxin.

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    Sara Fernández Ferreiro

    2014-06-01

    Currently, published evidence indicates that hERG channel dysfunction can be due to more than one mechanism for many drugs (Guth, 2007. Alterations of hERG channel trafficking are considered an important factor in hERG-related cardiotoxicity. Actually, a screening study revealed that almost 40% of the drugs that block Ikr have also trafficking effects (Wible et al., 2005. Although YTX does not block hERG channels, it has been historically described as cardiotoxic due to in vivo damage to cardiomyocytes. Our results show that YTX induces a significant increase of hERG channel levels on the extracellular side of the plasma membrane in vitro. YTX causes cell death in many cell lines (Korsnes and Espenes, 2011 and the alterations of surface hERG levels might be related to the apoptotic process. However, annexin-V, a relatively early marker of apoptosis (Vermes et al., 1995, occurs later than the increase of surface hERG. Additionally, staurosporine triggered apoptosis without a simultaneous increase of surface hERG, so events are not necessarily related. Therefore YTX-induced elevated hERG in the plasma membrane seem to be independent of apoptosis. Functional implications of hERG currents have been described after alterations of cell surface hERG density (Guth, 2007. YTX did not cause significant alterations of hERG currents. Furthermore the hERG levels after YTX treatment were duplicated, so the effect on currents should be clearly evidenced if these channels were functional. The hERG channels on the cell surface are regulated by its production, translocation to the plasma membrane and degradation. The increase of extracellular channel could be a consequence of a higher production and externalization or a slower degradation. Higher synthesis in our cell model would not be physiologically relevant but our results demonstrated that the amount of immature hERG is reduced instead of increased. Fully glycosylated hERG seems slightly increased in these conditions but it is

  2. A novel hypothesis for the binding mode of HERG channel blockers

    International Nuclear Information System (INIS)

    Choe, Han; Nah, Kwang Hoon; Lee, Soo Nam; Lee, Han Sam; Lee, Hui Sun; Jo, Su Hyun; Leem, Chae Hun; Jang, Yeon Jin

    2006-01-01

    We present a new docking model for HERG channel blockade. Our new model suggests three key interactions such that (1) a protonated nitrogen of the channel blocker forms a hydrogen bond with the carbonyl oxygen of HERG residue T623; (2) an aromatic moiety of the channel blocker makes a π-π interaction with the aromatic ring of HERG residue Y652; and (3) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. The previous model assumes two interactions such that (1) a protonated nitrogen of the channel blocker forms a cation-π interaction with the aromatic ring of HERG residue Y652; and (2) a hydrophobic group of the channel blocker forms a hydrophobic interaction with the benzene ring of HERG residue F656. To test these models, we classified 69 known HERG channel blockers into eight binding types based on their plausible binding modes, and further categorized them into two groups based on the number of interactions our model would predict with the HERG channel (two or three). We then compared the pIC 5 value distributions between these two groups. If the old hypothesis is correct, the distributions should not differ between the two groups (i.e., both groups show only two binding interactions). If our novel hypothesis is correct, the distributions should differ between Groups 1 and 2. Consistent with our hypothesis, the two groups differed with regard to pIC 5 , and the group having more predicted interactions with the HERG channel had a higher mean pIC 5 value. Although additional work will be required to further validate our hypothesis, this improved understanding of the HERG channel blocker binding mode may help promote the development of in silico predictions methods for identifying potential HERG channel blockers

  3. Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker

    Science.gov (United States)

    Helliwell, Matthew V.; Zhang, Yihong; El Harchi, Aziza; Du, Chunyun; Hancox, Jules C.; Dempsey, Christopher E.

    2018-01-01

    Cardiac potassium channels encoded by human ether-à-go-go–related gene (hERG) are major targets for structurally diverse drugs associated with acquired long QT syndrome. This study characterized hERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-affinity drug-binding site of the hERG pore. hERG current (IhERG) recorded at physiological temperature from HEK293 cells was inhibited with an IC50 of 35.6 nm with time and voltage dependence characteristic of blockade contingent upon channel gating. Potency of Cavalli-2 action was markedly reduced for attenuated inactivation mutants located near (S620T; 54-fold) and remote from (N588K; 15-fold) the channel pore. The S6 Y652A and F656A mutations decreased inhibitory potency 17- and 75-fold, respectively, whereas T623A and S624A at the base of the selectivity filter also decreased potency (16- and 7-fold, respectively). The S5 helix F557L mutation decreased potency 10-fold, and both F557L and Y652A mutations eliminated voltage dependence of inhibition. Computational docking using the recent cryo-EM structure of an open channel hERG construct could only partially recapitulate experimental data, and the high dependence of Cavalli-2 block on Phe-656 is not readily explainable in that structure. A small clockwise rotation of the inner (S6) helix of the hERG pore from its configuration in the cryo-EM structure may be required to optimize Phe-656 side chain orientations compatible with high-affinity block. PMID:29545312

  4. Effects of Tannic Acid, Green Tea and Red Wine on hERG Channels Expressed in HEK293 Cells.

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    Xi Chu

    Full Text Available Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-à-go-go-related gene (hERG channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells, and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 μM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Δ23.2 mV. Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Δ30.8 mV and Δ26.0 mV, respectively. Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities.

  5. Effects of Tannic Acid, Green Tea and Red Wine on hERG Channels Expressed in HEK293 Cells

    Science.gov (United States)

    Xu, Bingyuan; Li, Wenya; Lin, Yue; Sun, Xiaorun; Ding, Chunhua; Zhang, Xuan

    2015-01-01

    Tannic acid presents in varying concentrations in plant foods, and in relatively high concentrations in green teas and red wines. Human ether-à-go-go-related gene (hERG) channels expressed in multiple tissues (e.g. heart, neurons, smooth muscle and cancer cells), and play important roles in modulating cardiac action potential repolarization and tumor cell biology. The present study investigated the effects of tannic acid, green teas and red wines on hERG currents. The effects of tannic acid, teas and red wines on hERG currents stably transfected in HEK293 cells were studied with a perforated patch clamp technique. In this study, we demonstrated that tannic acid inhibited hERG currents with an IC50 of 3.4 μM and ~100% inhibition at higher concentrations, and significantly shifted the voltage dependent activation to more positive potentials (Δ23.2 mV). Remarkably, a 100-fold dilution of multiple types of tea (green tea, oolong tea and black tea) or red wine inhibited hERG currents by ~90%, and significantly shifted the voltage dependent activation to more positive potentials (Δ30.8 mV and Δ26.0 mV, respectively). Green tea Lung Ching and red wine inhibited hERG currents, with IC50 of 0.04% and 0.19%, respectively. The effects of tannic acid, teas and red wine on hERG currents were irreversible. These results suggest tannic acid is a novel hERG channel blocker and consequently provide a new mechanistic evidence for understanding the effects of tannic acid. They also revealed the potential pharmacological basis of tea- and red wine-induced biology activities. PMID:26625122

  6. Data on the construction of a recombinant HEK293 cell line overexpressing hERG potassium channel and examining the presence of hERG mRNA and protein expression

    Directory of Open Access Journals (Sweden)

    Yi Fan Teah

    2017-10-01

    Full Text Available The data presented in this article are related to the research article entitled “The effects of deoxyelephantopin on the cardiac delayed rectifier potassium channel current (IKr and human ether-a-go-go-related gene (hERG expression” (Y.F. Teah, M.A. Abduraman, A. Amanah, M.I. Adenan, S.F. Sulaiman, M.L. Tan [1], which the possible hERG blocking properties of deoxyelephantopin were investigated. This article describes the construction of human embryonic kidney 293 (HEK293 cells overexpressing HERG potassium channel and verification of the presence of hERG mRNA and protein expression in this recombinant cell line.

  7. Modeling of the hERG K+ Channel Blockage Using Online Chemical Database and Modeling Environment (OCHEM).

    Science.gov (United States)

    Li, Xiao; Zhang, Yuan; Li, Huanhuan; Zhao, Yong

    2017-12-01

    Human ether-a-go-go related gene (hERG) K+ channel plays an important role in cardiac action potential. Blockage of hERG channel may result in long QT syndrome (LQTS), even cause sudden cardiac death. Many drugs have been withdrawn from the market because of the serious hERG-related cardiotoxicity. Therefore, it is quite essential to estimate the chemical blockage of hERG in the early stage of drug discovery. In this study, a diverse set of 3721 compounds with hERG inhibition data was assembled from literature. Then, we make full use of the Online Chemical Modeling Environment (OCHEM), which supplies rich machine learning methods and descriptor sets, to build a series of classification models for hERG blockage. We also generated two consensus models based on the top-performing individual models. The consensus models performed much better than the individual models both on 5-fold cross validation and external validation. Especially, consensus model II yielded the prediction accuracy of 89.5 % and MCC of 0.670 on external validation. This result indicated that the predictive power of consensus model II should be stronger than most of the previously reported models. The 17 top-performing individual models and the consensus models and the data sets used for model development are available at https://ochem.eu/article/103592. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride

    International Nuclear Information System (INIS)

    Long, Yan; Lin, Zuoxian; Xia, Menghang; Zheng, Wei; Li, Zhiyuan

    2013-01-01

    Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC 50 values of 4 nM and 17 nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I–V curves in a hyperpolarized direction for 10–15 mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I–V curve in a hyperpolarized direction for 24.4 mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners. - Highlights: ► Tetra-n-octylammonium and benzethonium are potent HERG channel inhibitors. ► Channel activation and inactivation processes are accelerated by the two compounds. ► Both compounds are the open-channel blockers to HERG channels. ► HERG channel inhibition by both compounds is use-, voltage- and state dependent. ► The in vivo risk of QT prolongation needs to be studied for the two compounds

  9. Mechanism of HERG potassium channel inhibition by tetra-n-octylammonium bromide and benzethonium chloride

    Energy Technology Data Exchange (ETDEWEB)

    Long, Yan; Lin, Zuoxian [Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 (China); Xia, Menghang; Zheng, Wei [National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892 (United States); Li, Zhiyuan, E-mail: li_zhiyuan@gibh.ac.cn [Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530 (China)

    2013-03-01

    Tetra-n-octylammonium bromide and benzethonium chloride are synthetic quaternary ammonium salts that are widely used in hospitals and industries for the disinfection and surface treatment and as the preservative agent. Recently, the activities of HERG channel inhibition by these compounds have been found to have potential risks to induce the long QT syndrome and cardiac arrhythmia, although the mechanism of action is still elusive. This study was conducted to investigate the mechanism of HERG channel inhibition by these compounds by using whole-cell patch clamp experiments in a CHO cell line stably expressing HERG channels. Tetra-n-octylammonium bromide and benzethonium chloride exhibited concentration-dependent inhibitions of HERG channel currents with IC{sub 50} values of 4 nM and 17 nM, respectively, which were also voltage-dependent and use-dependent. Both compounds shifted the channel activation I–V curves in a hyperpolarized direction for 10–15 mV and accelerated channel activation and inactivation processes by 2-fold. In addition, tetra-n-octylammonium bromide shifted the inactivation I–V curve in a hyperpolarized direction for 24.4 mV and slowed the rate of channel deactivation by 2-fold, whereas benzethonium chloride did not. The results indicate that tetra-n-octylammonium bromide and benzethonium chloride are open-channel blockers that inhibit HERG channels in the voltage-dependent, use-dependent and state-dependent manners. - Highlights: ► Tetra-n-octylammonium and benzethonium are potent HERG channel inhibitors. ► Channel activation and inactivation processes are accelerated by the two compounds. ► Both compounds are the open-channel blockers to HERG channels. ► HERG channel inhibition by both compounds is use-, voltage- and state dependent. ► The in vivo risk of QT prolongation needs to be studied for the two compounds.

  10. High potency inhibition of hERG potassium channels by the sodium–calcium exchange inhibitor KB-R7943

    Science.gov (United States)

    Cheng, Hongwei; Zhang, Yihong; Du, Chunyun; Dempsey, Christopher E; Hancox, Jules C

    2012-01-01

    BACKGROUND AND PURPOSE KB-R7943 is an isothiourea derivative that is used widely as a pharmacological inhibitor of sodium–calcium exchange (NCX) in experiments on cardiac and other tissue types. This study investigated KB-R7943 inhibition of hERG (human ether-à-go-go-related gene) K+ channels that underpin the cardiac rapid delayed rectifier potassium current, IKr. EXPERIMENTAL APPROACH Whole-cell patch-clamp measurements were made of hERG current (IhERG) carried by wild-type or mutant hERG channels and of native rabbit ventricular IKr. Docking simulations utilized a hERG homology model built on a MthK-based template. KEY RESULTS KB-R7943 inhibited both IhERG and native IKr rapidly on membrane depolarization with IC50 values of ∼89 and ∼120 nM, respectively, for current tails at −40 mV following depolarizing voltage commands to +20 mV. Marked IhERG inhibition also occurred under ventricular action potential voltage clamp. IhERG inhibition by KB-R7943 exhibited both time- and voltage-dependence but showed no preference for inactivated over activated channels. Results of alanine mutagenesis and docking simulations indicate that KB-R7943 can bind to a pocket formed of the side chains of aromatic residues Y652 and F656, with the compound's nitrobenzyl group orientated towards the cytoplasmic side of the channel pore. The structurally related NCX inhibitor SN-6 also inhibited IhERG, but with a markedly reduced potency. CONCLUSIONS AND IMPLICATIONS KB-R7943 inhibits IhERG/IKr with a potency that exceeds that reported previously for acute cardiac NCX inhibition. Our results also support the feasibility of benzyloxyphenyl-containing NCX inhibitors with reduced potential, in comparison with KB-R7943, to inhibit hERG. PMID:21950687

  11. Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels.

    Science.gov (United States)

    Tan, Peter S; Perry, Matthew D; Ng, Chai Ann; Vandenberg, Jamie I; Hill, Adam P

    2012-09-01

    Human ether-a-go-go-related gene (hERG) potassium channels exhibit unique gating kinetics characterized by unusually slow activation and deactivation. The N terminus of the channel, which contains an amphipathic helix and an unstructured tail, has been shown to be involved in regulation of this slow deactivation. However, the mechanism of how this occurs and the connection between voltage-sensing domain (VSD) return and closing of the gate are unclear. To examine this relationship, we have used voltage-clamp fluorometry to simultaneously measure VSD motion and gate closure in N-terminally truncated constructs. We report that mode shifting of the hERG VSD results in a corresponding shift in the voltage-dependent equilibrium of channel closing and that at negative potentials, coupling of the mode-shifted VSD to the gate defines the rate of channel closure. Deletion of the first 25 aa from the N terminus of hERG does not alter mode shifting of the VSD but uncouples the shift from closure of the cytoplasmic gate. Based on these observations, we propose the N-terminal tail as an adaptor that couples voltage sensor return to gate closure to define slow deactivation gating in hERG channels. Furthermore, because the mode shift occurs on a time scale relevant to the cardiac action potential, we suggest a physiological role for this phenomenon in maximizing current flow through hERG channels during repolarization.

  12. Common variants in the hERG (KCNH2) voltage-gated potassium channel are associated with altered fasting and glucose-stimulated plasma incretin and glucagon responses

    DEFF Research Database (Denmark)

    Engelbrechtsen, Line; Mahendran, Yuvaraj; Jonsson, Anna

    2018-01-01

    BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused by a dysfun......BACKGROUND: Patients with long QT syndrome due to rare loss-of-function mutations in the human ether-á-go-go-related gene (hERG) have prolonged QT interval, risk of arrhythmias, increased secretion of insulin and incretins and impaired glucagon response to hypoglycemia. This is caused...... by a dysfunctional Kv11.1 voltage-gated potassium channel. Based on these findings in patients with rare variants in hERG, we hypothesized that common variants in hERG may also lead to alterations in glucose homeostasis. Subsequently, we aimed to evaluate the effect of two common gain-of-function variants in hERG...... in hERG on QT-interval and circulation levels of incretins, insulin and glucagon. The Danish population-based Inter99 cohort (n = 5895) was used to assess the effect of common variants on QT-interval. The Danish ADDITION-PRO cohort was used (n = 1329) to study genetic associations with levels of GLP-1...

  13. New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1

    DEFF Research Database (Denmark)

    Korolkova, Yuliya V; Bocharov, Eduard V; Angelo, Kamilla

    2002-01-01

    The scorpion toxin BeKm-1 is unique among a variety of known short scorpion toxins affecting potassium channels in its selective action on ether-a-go-go-related gene (ERG)-type channels. BeKm-1 shares the common molecular scaffold with other short scorpion toxins. The toxin spatial structure...... resolved by NMR consists of a short alpha-helix and a triple-stranded antiparallel beta-sheet. By toxin mutagenesis study we identified the residues that are important for the binding of BeKm-1 to the human ERG K+ (HERG) channel. The most critical residues (Tyr-11, Lys-18, Arg-20, Lys-23) are located...

  14. New aspects of HERG K⁺ channel function depending upon cardiac spatial heterogeneity.

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    Pen Zhang

    Full Text Available HERG K(+ channel, the genetic counterpart of rapid delayed rectifier K(+ current in cardiac cells, is responsible for many cases of inherited and drug-induced long QT syndromes. HERG has unusual biophysical properties distinct from those of other K(+ channels. While the conventional pulse protocols in patch-clamp studies have helped us elucidate these properties, their limitations in assessing HERG function have also been progressively noticed. We employed AP-clamp techniques using physiological action potential waveforms recorded from various regions of canine heart to study HERG function in HEK293 cells and identified several novel aspects of HERG function. We showed that under AP-clamp IHERG increased gradually with membrane repolarization, peaked at potentials around 20-30 mV more negative than revealed by pulse protocols and at action potential duration (APD to 60%-70% full repolarization, and fell rapidly at the terminal phase of repolarization. We found that the rising phase of IHERG was conferred by removal of inactivation and the decaying phase resulted from a fall in driving force, which were all determined by the rate of membrane repolarization. We identified regional heterogeneity and transmural gradient of IHERG when quantified with the area covered by IHERG trace. In addition, we observed regional and transmural differences of IHERG in response to dofetilide blockade. Finally, we characterized the influence of HERG function by selective inhibition of other ion currents. Based on our results, we conclude that the distinct biophysical properties of HERG reported by AP-clamp confer its unique function in cardiac repolarization thereby in antiarrhythmia and arrhythmogenesis.

  15. The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.

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    Chai Ann Ng

    Full Text Available Human ether-à-go-go-related gene (hERG K(+ channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.

  16. A radiolabeled peptide ligand of the hERG channel, [125I]-BeKm-1

    DEFF Research Database (Denmark)

    Angelo, Kamilla; Korolkova, Yuliya V; Grunnet, Morten

    2003-01-01

    The wild-type scorpion toxin BeKm-1, which selectively blocks human ether-a-go-go related (hERG) channels, was radiolabeled with iodine at tyrosine 11. Both the mono- and di-iodinated derivatives were found to be biologically active. In electrophysiological patch-clamp recordings mono-[127I]-BeKm-1...... had a concentration of half-maximal inhibition (IC50 value) of 27 nM, while wild-type BeKm-1 inhibited hERG channels with an IC50 value of 7 nM. Mono-[125I]-BeKm-1 was found to bind in a concentration-dependent manner and with picomolar affinity to hERG channel protein in purified membrane vesicles...... of [125I]-BeKm-1 to the hERG channel to an IC50 of 7 nM. In autoradiographic studies on rat hearts, binding of [125I]-BeKm-1 was dose-dependent and could partially be displaced by the addition of excess amounts of non-radioactive BeKm-1. The density of the radioactive signal was equally distributed...

  17. Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study

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    Laura L. Perissinotti

    2018-04-01

    Full Text Available IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS (Lees-Miller et al., 1997 in humans are linked to functional modifications in the Kv11.1 (hERG ion channel and potentially life threatening arrhythmias. There is little doubt now that hERG-related component of IKr in the heart depends on the tetrameric (homo- or hetero- channels formed by two alternatively processed isoforms of hERG, termed hERG1a and hERG1b. Isoform composition (hERG1a- vs. the b-isoform has recently been reported to alter pharmacologic responses to some hERG blockers and was proposed to be an essential factor pre-disposing patients for drug-induced QT prolongation. Very little is known about the gating and pharmacological properties of two isoforms in heart membranes. For example, how gating mechanisms of the hERG1a channels differ from that of hERG1b is still unknown. The mechanisms by which hERG 1a/1b hetero-tetramers contribute to function in the heart, or what role hERG1b might play in disease are all questions to be answered. Structurally, the two isoforms differ only in the N-terminal region located in the cytoplasm: hERG1b is 340 residues shorter than hERG1a and the initial 36 residues of hERG1b are unique to this isoform. In this study, we combined electrophysiological measurements for HEK cells, kinetics and structural modeling to tease out the individual contributions of each isoform to Action Potential formation and then make predictions about the effects of having various mixture ratios of the two isoforms. By coupling electrophysiological data with computational kinetic modeling, two proposed mechanisms of hERG gating in two homo-tetramers were examined. Sets of data from various experimental stimulation protocols (HEK cells were analyzed simultaneously and fitted to Markov-chain models (M

  18. A molecular switch driving inactivation in the cardiac K+ channel HERG.

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    David A Köpfer

    Full Text Available K(+ channels control transmembrane action potentials by gating open or closed in response to external stimuli. Inactivation gating, involving a conformational change at the K(+ selectivity filter, has recently been recognized as a major K(+ channel regulatory mechanism. In the K(+ channel hERG, inactivation controls the length of the human cardiac action potential. Mutations impairing hERG inactivation cause life-threatening cardiac arrhythmia, which also occur as undesired side effects of drugs. In this paper, we report atomistic molecular dynamics simulations, complemented by mutational and electrophysiological studies, which suggest that the selectivity filter adopts a collapsed conformation in the inactivated state of hERG. The selectivity filter is gated by an intricate hydrogen bond network around residues S620 and N629. Mutations of this hydrogen bond network are shown to cause inactivation deficiency in electrophysiological measurements. In addition, drug-related conformational changes around the central cavity and pore helix provide a functional mechanism for newly discovered hERG activators.

  19. The N-terminal tail of hERG contains an amphipathic α-helix that regulates channel deactivation.

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    Chai Ann Ng

    Full Text Available The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N-terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS domain (residues 26-135 as well as an amphipathic α-helix (residues 13-23 and an initial unstructured segment (residues 2-9. Deletion of residues 2-25, only the unstructured segment (residues 2-9 or replacement of the α-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the α-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal α-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel.

  20. Acute alteration of cardiac ECG, action potential, I{sub Kr} and the human ether-a-go-go-related gene (hERG) K{sup +} channel by PCB 126 and PCB 77

    Energy Technology Data Exchange (ETDEWEB)

    Park, Mi-Hyeong; Park, Won Sun; Jo, Su-Hyun, E-mail: suhyunjo@kangwon.ac.kr

    2012-07-01

    Polychlorinated biphenyls (PCBs) have been known as serious persistent organic pollutants (POPs), causing developmental delays and motor dysfunction. We have investigated the effects of two PCB congeners, 3,3′,4,4′-tetrachlorobiphenyl (PCB 77) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) on ECG, action potential, and the rapidly activating delayed rectifier K{sup +} current (I{sub Kr}) of guinea pigs' hearts, and hERG K{sup +} current expressed in Xenopus oocytes. PCB 126 shortened the corrected QT interval (QTc) of ECG and decreased the action potential duration at 90% (APD{sub 90}), and 50% of repolarization (APD{sub 50}) (P < 0.05) without changing the action potential duration at 20% (APD{sub 20}). PCB 77 decreased APD{sub 20} (P < 0.05) without affecting QTc, APD{sub 90}, and APD{sub 50}. The PCB 126 increased the I{sub Kr} in guinea-pig ventricular myocytes held at 36 °C and hERG K{sup +} current amplitude at the end of the voltage steps in voltage-dependent mode (P < 0.05); however, PCB 77 did not change the hERG K{sup +} current amplitude. The PCB 77 increased the diastolic Ca{sup 2+} and decreased Ca{sup 2+} transient amplitude (P < 0.05), however PCB 126 did not change. The results suggest that PCB 126 shortened the QTc and decreased the APD{sub 90} possibly by increasing I{sub Kr}, while PCB 77 decreased the APD{sub 20} possibly by other modulation related with intracellular Ca{sup 2+}. The present data indicate that the environmental toxicants, PCBs, can acutely affect cardiac electrophysiology including ECG, action potential, intracellular Ca{sup 2+}, and channel activity, resulting in toxic effects on the cardiac function in view of the possible accumulation of the PCBs in human body. -- Highlights: ► PCBs are known as serious environmental pollutants and developmental disruptors. ► PCB 126 shortened QT interval of ECG and action potential duration. ► PCB 126 increased human ether-a-go-go-related K{sup +} current and I{sub Kr}.

  1. An NMR investigation of the structure, function and role of the hERG channel selectivity filter in the long QT syndrome.

    Science.gov (United States)

    Gravel, Andrée E; Arnold, Alexandre A; Dufourc, Erick J; Marcotte, Isabelle

    2013-06-01

    The human ether-a-go-go-related gene (hERG) voltage-gated K(+) channels are located in heart cell membranes and hold a unique selectivity filter (SF) amino acid sequence (SVGFG) as compared to other K(+) channels (TVGYG). The hERG provokes the acquired long QT syndrome (ALQTS) when blocked, as a side effect of drugs, leading to arrhythmia or heart failure. Its pore domain - including the SF - is believed to be a cardiotoxic drug target. In this study combining solution and solid-state NMR experiments we examine the structure and function of hERG's L(622)-K(638) segment which comprises the SF, as well as its role in the ALQTS using reported active drugs. We first show that the SF segment is unstructured in solution with and without K(+) ions in its surroundings, consistent with the expected flexibility required for the change between the different channel conductive states predicted by computational studies. We also show that the SF segment has the potential to perturb the membrane, but that the presence of K(+) ions cancels this interaction. The SF moiety appears to be a possible target for promethazine in the ALQTS mechanism, but not as much for bepridil, cetirizine, diphenhydramine and fluvoxamine. The membrane affinity of the SF is also affected by the presence of drugs which also perturb model DMPC-based membranes. These results thus suggest that the membrane could play a role in the ALQTS by promoting the access to transmembrane or intracellular targets on the hERG channel, or perturbing the lipid-protein synergy. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

    Science.gov (United States)

    Masi, A; Becchetti, A; Restano-Cassulini, R; Polvani, S; Hofmann, G; Buccoliero, A M; Paglierani, M; Pollo, B; Taddei, G L; Gallina, P; Di Lorenzo, N; Franceschetti, S; Wanke, E; Arcangeli, A

    2005-01-01

    Recent studies have led to considerable advancement in our understanding of the molecular mechanisms that underlie the relentless cell growth and invasiveness of human gliomas. Partial understanding of these mechanisms has (1) improved the classification for gliomas, by identifying prognostic subgroups, and (2) pointed to novel potential therapeutic targets. Some classes of ion channels have turned out to be involved in the pathogenesis and malignancy of gliomas. We studied the expression and properties of K+ channels in primary cultures obtained from surgical specimens: human ether a gò-gò related (hERG)1 voltage-dependent K+ channels, which have been found to be overexpressed in various human cancers, and human ether a gò-gò-like 2 channels, that share many of hERG1's biophysical features. The expression pattern of these two channels was compared to that of the classical inward rectifying K+ channels, IRK, that are widely expressed in astrocytic cells and classically considered a marker of astrocytic differentiation. In our study, hERG1 was found to be specifically overexpressed in high-grade astrocytomas, that is, glioblastoma multiforme (GBM). In addition, we present evidence that, in GBM cell lines, hERG1 channel activity actively contributes to malignancy by promoting vascular endothelial growth factor secretion, thus stimulating the neoangiogenesis typical of high-grade gliomas. Our data provide important confirmation for studies proposing the hERG1 channel as a molecular marker of tumour progression and a possible target for novel anticancer therapies. PMID:16175187

  3. Computational analysis of the effects of the hERG channel opener NS1643 in a human ventricular cell model

    DEFF Research Database (Denmark)

    Peitersen, Torben; Grunnet, Morten; Benson, Alan P

    2008-01-01

    BACKGROUND: Dysfunction or pharmacologic inhibition of repolarizing cardiac ionic currents can lead to fatal arrhythmias. The hERG potassium channel underlies the repolarizing current I(Kr), and mutations therein can produce both long and short QT syndromes (LQT2 and SQT1). We previously reported...

  4. Role of the activation gate in determining the extracellular potassium dependency of block of HERG by trapped drugs.

    Science.gov (United States)

    Pareja, Kristeen; Chu, Elaine; Dodyk, Katrina; Richter, Kristofer; Miller, Alan

    2013-01-01

    Drug induced long QT syndrome (diLQTS) results primarily from block of the cardiac potassium channel HERG (human-ether-a-go-go related gene). In some cases long QT syndrome can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with serum potassium abnormalities due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, and aging. Extracellular potassium influences HERG channel inactivation and can alter block of HERG by some drugs. However, block of HERG by a number of drugs is not sensitive to extracellular potassium. In this study, we show that block of WT HERG by bepridil and terfenadine, two drugs previously shown to be trapped inside the HERG channel after the channel closes, is insensitive to extracellular potassium over the range of 0 mM to 20 mM. We also show that bepridil block of the HERG mutant D540K, a mutant channel that is unable to trap drugs, is dependent on extracellular potassium, correlates with the permeant ion, and is independent of HERG inactivation. These results suggest that the lack of extracellular potassium dependency of block of HERG by some drugs may in part be related to the ability of these drugs to be trapped inside the channel after the channel closes.

  5. Indexing molecules for their hERG liability.

    Science.gov (United States)

    Rayan, Anwar; Falah, Mizied; Raiyn, Jamal; Da'adoosh, Beny; Kadan, Sleman; Zaid, Hilal; Goldblum, Amiram

    2013-07-01

    The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  6. Homozygous premature truncation of the HERG protein : the human HERG knockout

    NARCIS (Netherlands)

    Hoorntje, T.; Alders, M.; van Tintelen, P.; van der Lip, K.; Sreeram, N.; van der Wal, A.; Mannens, M.; Wilde, A.

    1999-01-01

    Background-In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K(+) channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits "loss of function." HERG, which is involved in LQT2, is the gene encoding the rapid component of the

  7. Effects of the small molecule HERG activator NS1643 on Kv11.3 channels.

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    Arne Bilet

    Full Text Available NS1643 is one of the small molecule HERG (Kv11.1 channel activators and has also been found to increase erg2 (Kv11.2 currents. We now investigated whether NS1643 is also able to act as an activator of Kv11.3 (erg3 channels expressed in CHO cells. Activation of rat Kv11.3 current occurred in a dose-dependent manner and maximal current increasing effects were obtained with 10 µM NS1643. At this concentration, steady-state outward current increased by about 80% and the current increase was associated with a significant shift in the voltage dependence of activation to more negative potentials by about 15 mV. In addition, activation kinetics were accelerated, whereas deactivation was slowed. There was no significant effect on the kinetics of inactivation and recovery from inactivation. The strong current-activating agonistic effect of NS1643 did not result from a shift in the voltage dependence of Kv11.3 channel inactivation and was independent from external Na(+ or Ca(2+. At the higher concentration of 20 µM, NS1643 induced clearly less current increase. The left shift in the voltage dependence of activation reversed and the voltage sensitivity of activation dramatically decreased along with a slowing of Kv11.3 channel activation. These data show that, in comparison to other Kv11 family members, NS1643 exerts distinct effects on Kv11.3 channels with especially pronounced partial antagonistic effects at higher concentration.

  8. Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

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    La Torre Agostino

    2010-09-01

    Full Text Available Abstract Background Treatment strategies for Retinoblastoma (RB, the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K+ channels. Case presentation Two patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the vegf-a, flt-1, kdr, and hif1-α transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K+ channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue. Conclusions We provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the vegf-a, flt-1, kdr and hif1-α transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the herg1 gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress

  9. hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.

    Science.gov (United States)

    Nogawa, Hisashi; Kawai, Tomoyuki

    2014-10-15

    Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Interactions between charged residues in the transmembrane segments of the voltage-sensing domain in the hERG channel.

    Science.gov (United States)

    Zhang, M; Liu, J; Jiang, M; Wu, D-M; Sonawane, K; Guy, H R; Tseng, G-N

    2005-10-01

    Studies on voltage-gated K channels such as Shaker have shown that positive charges in the voltage-sensor (S4) can form salt bridges with negative charges in the surrounding transmembrane segments in a state-dependent manner, and different charge pairings can stabilize the channels in closed or open states. The goal of this study is to identify such charge interactions in the hERG channel. This knowledge can provide constraints on the spatial relationship among transmembrane segments in the channel's voltage-sensing domain, which are necessary for modeling its structure. We first study the effects of reversing S4's positive charges on channel activation. Reversing positive charges at the outer (K525D) and inner (K538D) ends of S4 markedly accelerates hERG activation, whereas reversing the 4 positive charges in between either has no effect or slows activation. We then use the 'mutant cycle analysis' to test whether D456 (outer end of S2) and D411 (inner end of S1) can pair with K525 and K538, respectively. Other positive charges predicted to be able, or unable, to interact with D456 or D411 are also included in the analysis. The results are consistent with predictions based on the distribution of these charged residues, and confirm that there is functional coupling between D456 and K525 and between D411 and K538.

  11. Performance of Machine Learning Algorithms for Qualitative and Quantitative Prediction Drug Blockade of hERG1 channel.

    Science.gov (United States)

    Wacker, Soren; Noskov, Sergei Yu

    2018-05-01

    Drug-induced abnormal heart rhythm known as Torsades de Pointes (TdP) is a potential lethal ventricular tachycardia found in many patients. Even newly released anti-arrhythmic drugs, like ivabradine with HCN channel as a primary target, block the hERG potassium current in overlapping concentration interval. Promiscuous drug block to hERG channel may potentially lead to perturbation of the action potential duration (APD) and TdP, especially when with combined with polypharmacy and/or electrolyte disturbances. The example of novel anti-arrhythmic ivabradine illustrates clinically important and ongoing deficit in drug design and warrants for better screening methods. There is an urgent need to develop new approaches for rapid and accurate assessment of how drugs with complex interactions and multiple subcellular targets can predispose or protect from drug-induced TdP. One of the unexpected outcomes of compulsory hERG screening implemented in USA and European Union resulted in large datasets of IC 50 values for various molecules entering the market. The abundant data allows now to construct predictive machine-learning (ML) models. Novel ML algorithms and techniques promise better accuracy in determining IC 50 values of hERG blockade that is comparable or surpassing that of the earlier QSAR or molecular modeling technique. To test the performance of modern ML techniques, we have developed a computational platform integrating various workflows for quantitative structure activity relationship (QSAR) models using data from the ChEMBL database. To establish predictive powers of ML-based algorithms we computed IC 50 values for large dataset of molecules and compared it to automated patch clamp system for a large dataset of hERG blocking and non-blocking drugs, an industry gold standard in studies of cardiotoxicity. The optimal protocol with high sensitivity and predictive power is based on the novel eXtreme gradient boosting (XGBoost) algorithm. The ML-platform with XGBoost

  12. High yield purification of full-length functional hERG K+ channels produced in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Molbaek, Karen; Scharff-Poulsen, Peter; Hélix-Nielsen, Claus

    2015-01-01

    knowledge this is the first reported high-yield production and purification of full length, tetrameric and functional hERG. This significant breakthrough will be paramount in obtaining hERG crystal structures, and in establishment of new high-throughput hERG drug safety screening assays....

  13. Improved functional expression of recombinant human ether-a-go-go (hERG K+ channels by cultivation at reduced temperature

    Directory of Open Access Journals (Sweden)

    Hamilton Bruce

    2007-12-01

    Full Text Available Abstract Background HERG potassium channel blockade is the major cause for drug-induced long QT syndrome, which sometimes cause cardiac disrhythmias and sudden death. There is a strong interest in the pharmaceutical industry to develop high quality medium to high-throughput assays for detecting compounds with potential cardiac liability at the earliest stages of drug development. Cultivation of cells at lower temperature has been used to improve the folding and membrane localization of trafficking defective hERG mutant proteins. The objective of this study was to investigate the effect of lower temperature maintenance on wild type hERG expression and assay performance. Results Wild type hERG was stably expressed in CHO-K1 cells, with the majority of channel protein being located in the cytoplasm, but relatively little on the cell surface. Expression at both locations was increased several-fold by cultivation at lower growth temperatures. Intracellular hERG protein levels were highest at 27°C and this correlated with maximal 3H-dofetilide binding activity. In contrast, the expression of functionally active cell surface-associated hERG measured by patch clamp electrophysiology was optimal at 30°C. The majority of the cytoplasmic hERG protein was associated with the membranes of cytoplasmic vesicles, which markedly increased in quantity and size at lower temperatures or in the presence of the Ca2+-ATPase inhibitor, thapsigargin. Incubation with the endocytic trafficking blocker, nocodazole, led to an increase in hERG activity at 37°C, but not at 30°C. Conclusion Our results are consistent with the concept that maintenance of cells at reduced temperature can be used to boost the functional expression of difficult-to-express membrane proteins and improve the quality of assays for medium to high-throughput compound screening. In addition, these results shed some light on the trafficking of hERG protein under these growth conditions.

  14. MiR-17-5p impairs trafficking of H-ERG K+ channel protein by targeting multiple er stress-related chaperones during chronic oxidative stress.

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    Qi Wang

    Full Text Available BACKGROUND: To investigate if microRNAs (miRNAs play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. METHODS: We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K(+ current. RESULTS: H-ERG trafficking was impaired by H2O2 after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2, with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H2O2-induced impairment of h-ERG trafficking. Upregulation of endogenous by H2O2 or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking. CONCLUSIONS: Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.

  15. MiR-17-5p impairs trafficking of H-ERG K+ channel protein by targeting multiple er stress-related chaperones during chronic oxidative stress.

    Science.gov (United States)

    Wang, Qi; Hu, Weina; Lei, Mingming; Wang, Yong; Yan, Bing; Liu, Jun; Zhang, Ren; Jin, Yuanzhe

    2013-01-01

    To investigate if microRNAs (miRNAs) play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Luciferase reporter gene assay was used to study miRNA and target interactions. Whole-cell patch-clamp techniques were employed to record h-ERG K(+) current. H-ERG trafficking was impaired by H2O2 after 48 h treatment, accompanied by reciprocal changes of expression between miR-17-5p seed miRNAs and several chaperones (Hsp70, Hsc70, CANX, and Golga2), with the former upregulated and the latter downregulated. We established these chaperones as targets for miR-17-5p. Application miR-17-5p inhibitor rescued H2O2-induced impairment of h-ERG trafficking. Upregulation of endogenous by H2O2 or forced miR-17-5p expression either reduced h-ERG current. Sequestration of AP1 by its decoy molecule eliminated the upregulation of miR-17-5p, and ameliorated impairment of h-ERG trafficking. Collectively, deregulation of the miR-17-5p seed family miRNAs can cause severe impairment of h-ERG trafficking through targeting multiple ER stress-related chaperones, and activation of AP1 likely accounts for the deleterious upregulation of these miRNAs, in the setting of prolonged duration of oxidative stress. These findings revealed the role of miRNAs in h-ERG trafficking, which may contribute to the cardiac electrical disturbances associated with oxidative stress.

  16. The role of hERG1 ion channels in epithelial-mesenchymal transition and the capacity of riluzole to reduce cisplatin resistance in colorectal cancer cells.

    Science.gov (United States)

    Fortunato, Angelo

    2017-08-01

    The transition of cells from the epithelial to the mesenchymal state (EMT) plays an important role in tumor progression. EMT allows cells to acquire mobility, stem-like behavior and resistance to apoptosis and drug treatment. These features turn EMT into a central process in tumor biology. Ion channels are attractive targets for the treatment of cancer since they play critical roles in controlling a wide range of physiological processes that are frequently deregulated in cancer. Here, we investigated the role of ether-a-go-go-related 1 (hERG1) ion channels in the EMT of colorectal cancer cells. We studied the epithelial-mesenchymal profile of different colorectal cancer-derived cell lines and the expression of hERG1 potassium channels in these cell lines using real-time PCR. Next, we knocked down hERG1 expression in HCT116 cells using lentivirus mediated RNA interference and characterized the hERG1 silenced cells in vitro and in vivo. Finally, we investigated the capacity of riluzole, an ion channel-modulating drug used in humans to treat amyotrophic lateral sclerosis, to reduce the resistance of the respective colorectal cancer cells to the chemotherapeutic drug cisplatin. We found that of the colorectal cancer-derived cell lines tested, HCT116 showed the highest mesenchymal profile and a high hERG1 expression. Subsequent hERG1 expression knockdown induced a change in cell morphology, which was accompanied by a reduction in the proliferative and tumorigenic capacities of the cells. Notably, we found that hERG1expression knockdown elicited a reversion of the EMT profile in HCT116 cells with a reacquisition of the epithelial-like profile. We also found that riluzole increased the sensitivity of HCT116 cisplatin-resistant cells to cisplatin. Our data indicate that hERG1 plays a role in the EMT of colorectal cancer cells and that its knockdown reduces the proliferative and tumorigenic capacities of these cells. In addition, we conclude that riluzole may be used in

  17. Molecular determinants of interactions between the N-terminal domain and the transmembrane core that modulate hERG K+ channel gating.

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    Jorge Fernández-Trillo

    Full Text Available A conserved eag domain in the cytoplasmic amino terminus of the human ether-a-go-go-related gene (hERG potassium channel is critical for its slow deactivation gating. Introduction of gene fragments encoding the eag domain are able to restore normal deactivation properties of channels from which most of the amino terminus has been deleted, and also those lacking exclusively the eag domain or carrying a single point mutation in the initial residues of the N-terminus. Deactivation slowing in the presence of the recombinant domain is not observed with channels carrying a specific Y542C point mutation in the S4-S5 linker. On the other hand, mutations in some initial positions of the recombinant fragment also impair its ability to restore normal deactivation. Fluorescence resonance energy transfer (FRET analysis of fluorophore-tagged proteins under total internal reflection fluorescence (TIRF conditions revealed a substantial level of FRET between the introduced N-terminal eag fragments and the eag domain-deleted channels expressed at the membrane, but not between the recombinant eag domain and full-length channels with an intact amino terminus. The FRET signals were also minimized when the recombinant eag fragments carried single point mutations in the initial portion of their amino end, and when Y542C mutated channels were used. These data suggest that the restoration of normal deactivation gating by the N-terminal recombinant eag fragment is an intrinsic effect of this domain directed by the interaction of its N-terminal segment with the gating machinery, likely at the level of the S4-S5 linker.

  18. Functional characterization of Kv11.1 (hERG) potassium channels split in the voltage-sensing domain.

    Science.gov (United States)

    de la Peña, Pilar; Domínguez, Pedro; Barros, Francisco

    2018-03-23

    Voltage-dependent KCNH family potassium channel functionality can be reconstructed using non-covalently linked voltage-sensing domain (VSD) and pore modules (split channels). However, the necessity of a covalent continuity for channel function has not been evaluated at other points within the two functionally independent channel modules. We find here that by cutting Kv11.1 (hERG, KCNH2) channels at the different loops linking the transmembrane spans of the channel core, not only channels split at the S4-S5 linker level, but also those split at the intracellular S2-S3 and the extracellular S3-S4 loops, yield fully functional channel proteins. Our data indicate that albeit less markedly, channels split after residue 482 in the S2-S3 linker resemble the uncoupled gating phenotype of those split at the C-terminal end of the VSD S4 transmembrane segment. Channels split after residues 514 and 518 in the S3-S4 linker show gating characteristics similar to those of the continuous wild-type channel. However, breaking the covalent link at this level strongly accelerates the voltage-dependent accessibility of a membrane impermeable methanethiosulfonate reagent to an engineered cysteine at the N-terminal region of the S4 transmembrane helix. Thus, besides that of the S4-S5 linker, structural integrity of the intracellular S2-S3 linker seems to constitute an important factor for proper transduction of VSD rearrangements to opening and closing the cytoplasmic gate. Furthermore, our data suggest that the short and probably rigid characteristics of the extracellular S3-S4 linker are not an essential component of the Kv11.1 voltage sensing machinery.

  19. In silico analysis of conformational changes induced by mutation of aromatic binding residues: consequences for drug binding in the hERG K+ channel.

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    Kirsten Knape

    Full Text Available Pharmacological inhibition of cardiac hERG K(+ channels is associated with increased risk of lethal arrhythmias. Many drugs reduce hERG current by directly binding to the channel, thereby blocking ion conduction. Mutation of two aromatic residues (F656 and Y652 substantially decreases the potency of numerous structurally diverse compounds. Nevertheless, some drugs are only weakly affected by mutation Y652A. In this study we utilize molecular dynamics simulations and docking studies to analyze the different effects of mutation Y652A on a selected number of hERG blockers. MD simulations reveal conformational changes in the binding site induced by mutation Y652A. Loss of π-π-stacking between the two aromatic residues induces a conformational change of the F656 side chain from a cavity facing to cavity lining orientation. Docking studies and MD simulations qualitatively reproduce the diverse experimentally observed modulatory effects of mutation Y652A and provide a new structural interpretation for the sensitivity differences.

  20. Dynamics of hERG closure allow novel insights into hERG blocking by small molecules.

    Science.gov (United States)

    Schmidtke, Peter; Ciantar, Marine; Theret, Isabelle; Ducrot, Pierre

    2014-08-25

    Today, drug discovery routinely uses experimental assays to determine very early if a lead compound can yield certain types of off-target activity. Among such off targets is hERG. The ion channel plays a primordial role in membrane repolarization and altering its activity can cause severe heart arrhythmia and sudden death. Despite routine tests for hERG activity, rather little information is available for helping medicinal chemists and molecular modelers to rationally circumvent hERG activity. In this article novel insights into the dynamics of hERG channel closure are described. Notably, helical pairwise closure movements have been observed. Implications and relations to hERG inactivation are presented. Based on these dynamics novel insights on hERG blocker placement are presented, compared to literature, and discussed. Last, new evidence for horizontal ligand positioning is shown in light of former studies on hERG blockers.

  1. The human ether-a-go-go-related gene (hERG) current inhibition selectively prolongs action potential of midmyocardial cells to augment transmural dispersion.

    Science.gov (United States)

    Yasuda, C; Yasuda, S; Yamashita, H; Okada, J; Hisada, T; Sugiura, S

    2015-08-01

    The majority of drug induced arrhythmias are related to the prolongation of action potential duration following inhibition of rapidly activating delayed rectifier potassium current (I(Kr)) mediated by the hERG channel. However, for arrhythmias to develop and be sustained, not only the prolongation of action potential duration but also its transmural dispersion are required. Herein, we evaluated the effect of hERG inhibition on transmural dispersion of action potential duration using the action potential clamp technique that combined an in silico myocyte model with the actual I(Kr) measurement. Whole cell I(Kr) current was measured in Chinese hamster ovary cells stably expressing the hERG channel. The measured current was coupled with models of ventricular endocardial, M-, and epicardial cells to calculate the action potentials. Action potentials were evaluated under control condition and in the presence of 1, 10, or 100 μM disopyramide, an hERG inhibitor. Disopyramide dose-dependently increased the action potential durations of the three cell types. However, action potential duration of M-cells increased disproportionately at higher doses, and was significantly different from that of epicardial and endocardial cells (dispersion of repolarization). By contrast, the effects of disopyramide on peak I(Kr) and instantaneous current-voltage relation were similar in all cell types. Simulation study suggested that the reduced repolarization reserve of M-cell with smaller amount of slowly activating delayed rectifier potassium current levels off at longer action potential duration to make such differences. The action potential clamp technique is useful for studying the mechanism of arrhythmogenesis by hERG inhibition through the transmural dispersion of repolarization.

  2. Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains.

    Science.gov (United States)

    de la Peña, Pilar; Domínguez, Pedro; Barros, Francisco

    2018-03-01

    Kv11.1 (hERG, KCNH2) is a voltage-gated potassium channel crucial in setting the cardiac rhythm and the electrical behaviour of several non-cardiac cell types. Voltage-dependent gating of Kv11.1 can be reconstructed from non-covalently linked voltage sensing and pore modules (split channels), challenging classical views of voltage-dependent channel activation based on a S4-S5 linker acting as a rigid mechanical lever to open the gate. Progressive displacement of the split position from the end to the beginning of the S4-S5 linker induces an increasing negative shift in activation voltage dependence, a reduced z g value and a more negative ΔG 0 for current activation, an almost complete abolition of the activation time course sigmoid shape and a slowing of the voltage-dependent deactivation. Channels disconnected at the S4-S5 linker near the S4 helix show a destabilization of the closed state(s). Furthermore, the isochronal ion current mode shift magnitude is clearly reduced in the different splits. Interestingly, the progressive modifications of voltage dependence activation gating by changing the split position are accompanied by a shift in the voltage-dependent availability to a methanethiosulfonate reagent of a Cys introduced at the upper S4 helix. Our data demonstrate for the first time that alterations in the covalent connection between the voltage sensor and the pore domains impact on the structural reorganizations of the voltage sensor domain. Also, they support the hypothesis that the S4-S5 linker integrates signals coming from other cytoplasmic domains that constitute either an important component or a crucial regulator of the gating machinery in Kv11.1 and other KCNH channels.

  3. MiR-17-5p Impairs Trafficking of H-ERG K+ Channel Protein by Targeting Multiple ER Stress-Related Chaperones during Chronic Oxidative Stress

    OpenAIRE

    Wang, Qi; Hu, Weina; Lei, Mingming; Wang, Yong; Yan, Bing; Liu, Jun; Zhang, Ren; Jin, Yuanzhe

    2013-01-01

    BACKGROUND: To investigate if microRNAs (miRNAs) play a role in regulating h-ERG trafficking in the setting of chronic oxidative stress as a common deleterious factor for many cardiac disorders. METHODS: We treated neonatal rat ventricular myocytes and HEK293 cells with stable expression of h-ERG with H2O2 for 12 h and 48 h. Expression of miR-17-5p seed miRNAs was quantified by real-time RT-PCR. Protein levels of chaperones and h-ERG trafficking were measured by Western blot analysis. Lucifer...

  4. Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc.

    Science.gov (United States)

    Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

    2006-09-01

    The discovery of maraviroc 17 is described with particular reference to the generation of high selectivity over affinity for the HERG potassium channel. This was achieved through the use of a high throughput binding assay for the HERG channel that is known to show an excellent correlation with functional effects.

  5. Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia.

    Science.gov (United States)

    Wang, N; Kang, H S; Ahmmed, G; Khan, S A; Makarenko, V V; Prabhakar, N R; Nanduri, J

    2016-03-01

    Human ether-a-go-go-related gene (hERG) channels conduct delayed rectifier K(+) current. However, little information is available on physiological situations affecting hERG channel protein and function. In the present study we examined the effects of intermittent hypoxia (IH), which is a hallmark manifestation of sleep apnea, on hERG channel protein and function. Experiments were performed on SH-SY5Y neuroblastoma cells, which express hERG protein. Cells were exposed to IH consisting of alternating cycles of 30 s of hypoxia (1.5% O2) and 5 min of 20% O2. IH decreased hERG protein expression in a stimulus-dependent manner. A similar reduction in hERG protein was also seen in adrenal medullary chromaffin cells from IH-exposed neonatal rats. The decreased hERG protein was associated with attenuated hERG K(+) current. IH-evoked hERG protein degradation was not due to reduced transcription or increased proteosome/lysomal degradation. Rather it was mediated by calcium-activated calpain proteases. Both COOH- and NH2-terminal sequences of the hERG protein were the targets of calpain-dependent degradation. IH increased reactive oxygen species (ROS) levels, intracellular Ca(2+) concentration ([Ca(2+)]i), calpain enzyme activity, and hERG protein degradation, and all these effects were prevented by manganese-(111)-tetrakis-(1-methyl-4-pyridyl)-porphyrin pentachloride, a membrane-permeable ROS scavenger. These results demonstrate that activation of calpains by ROS-dependent elevation of [Ca(2+)]i mediates hERG protein degradation by IH. Copyright © 2016 the American Physiological Society.

  6. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death

    DEFF Research Database (Denmark)

    De Bruin, M L; Pettersson, M; Meyboom, R H B

    2005-01-01

    AIMS: Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. METHODS...... defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value......, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. CONCLUSION: Anti-HERG activity is associated...

  7. Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.

    Science.gov (United States)

    Subbotina, Julia; Yarov-Yarovoy, Vladimir; Lees-Miller, James; Durdagi, Serdar; Guo, Jiqing; Duff, Henry J; Noskov, Sergei Yu

    2010-11-01

    The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene lead to one form of the Long QT Syndrome (LQTS) in humans. Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel have been a key target in molecular cardiology and pharmacology for the last decade. Although many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all transmembrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2-Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared with that established by toxin foot-printing and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed. © 2010 Wiley-Liss, Inc.

  8. Mitragynine and its potential blocking effects on specific cardiac potassium channels

    Energy Technology Data Exchange (ETDEWEB)

    Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min [Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang (Malaysia); Jamil, Mohd Fadzly Amar [Clinical Research Center, Hospital Seberang Jaya, Kementerian Kesihatan Malaysia, Pulau Pinang (Malaysia); Kollert, Sina [Institute of Physiology, University of Wurzburg, Wurzburg (Germany); Adenan, Mohd Ilham [Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Selangor Darul Ehsan (Malaysia); Wahab, Habibah Abdul [Pharmaceutical Design & Simulation (PhDS) Laboratory, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Pulau Pinang (Malaysia); Döring, Frank; Wischmeyer, Erhard [Institute of Physiology, University of Wurzburg, Wurzburg (Germany); Tan, Mei Lan, E-mail: tanml@usm.my [Malaysian Institute of Pharmaceuticals & Nutraceuticals, NIBM, Ministry of Science, Technology & Innovation (MOSTI), Pulau Pinang (Malaysia); Advanced Medical and Dental Institute, Universiti Sains Malaysia, Pulau Pinang (Malaysia)

    2016-08-15

    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac I{sub Kr} current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, I{sub K1}, a Kir current mediated by Kir2.1 channel and I{sub KACh}, a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC{sub 50} value of 1.62 μM and 1.15 μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit I{sub KACh} current with an IC{sub 50} value of 3.32 μM but has no significant effects on I{sub K1}. Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks. - Highlights: • The potential cardiac potassium channel blocking properties of mitragynine were investigated. • Mitragynine blocks hERG channel and I{sub Kr} in hERG-transfected HEK293 cells and hERG cRNA-injected Xenopus oocytes. • Mitragynine inhibits the hERG protein but not the mRNA expression. • Mitragynine

  9. Mitragynine and its potential blocking effects on specific cardiac potassium channels

    International Nuclear Information System (INIS)

    Tay, Yea Lu; Teah, Yi Fan; Chong, Yoong Min; Jamil, Mohd Fadzly Amar; Kollert, Sina; Adenan, Mohd Ilham; Wahab, Habibah Abdul; Döring, Frank; Wischmeyer, Erhard; Tan, Mei Lan

    2016-01-01

    Mitragyna speciosa Korth is known for its euphoric properties and is frequently used for recreational purposes. Several poisoning and fatal cases involving mitragynine have been reported but the underlying causes remain unclear. Human ether-a-go-go-related gene (hERG) encodes the cardiac I Kr current which is a determinant of the duration of ventricular action potentials and QT interval. On the other hand, I K1 , a Kir current mediated by Kir2.1 channel and I KACh , a receptor-activated Kir current mediated by GIRK channel are also known to be important in maintaining the cardiac function. This study investigated the effects of mitragynine on the current, mRNA and protein expression of hERG channel in hERG-transfected HEK293 cells and Xenopus oocytes. The effects on Kir2.1 and GIRK channels currents were also determined in the oocytes. The hERG tail currents following depolarization pulses were inhibited by mitragynine with an IC 50 value of 1.62 μM and 1.15 μM in the transfected cell line and Xenopus oocytes, respectively. The S6 point mutations of Y652A and F656A attenuated the inhibitor effects of mitragynine, indicating that mitragynine interacts with these high affinity drug-binding sites in the hERG channel pore cavity which was consistent with the molecular docking simulation. Interestingly, mitragynine does not affect the hERG expression at the transcriptional level but inhibits the protein expression. Mitragynine is also found to inhibit I KACh current with an IC 50 value of 3.32 μM but has no significant effects on I K1 . Blocking of both hERG and GIRK channels may cause additive cardiotoxicity risks. - Highlights: • The potential cardiac potassium channel blocking properties of mitragynine were investigated. • Mitragynine blocks hERG channel and I Kr in hERG-transfected HEK293 cells and hERG cRNA-injected Xenopus oocytes. • Mitragynine inhibits the hERG protein but not the mRNA expression. • Mitragynine inhibits GIRK channel. • Simultaneous

  10. Acute and Chronic Toxicity, Cytochrome P450 Enzyme Inhibition, and hERG Channel Blockade Studies with a Polyherbal, Ayurvedic Formulation for Inflammation

    Directory of Open Access Journals (Sweden)

    Debendranath Dey

    2015-01-01

    Full Text Available Ayurvedic plants are known for thousands of years to have anti-inflammatory and antiarthritic effect. We have recently shown that BV-9238, a proprietary formulation of Withania somnifera, Boswellia serrata, Zingiber officinale, and Curcuma longa, inhibits LPS-induced TNF-alpha and nitric oxide production from mouse macrophage and reduces inflammation in different animal models. To evaluate the safety parameters of BV-9238, we conducted a cytotoxicity study in RAW 264.7 cells (0.005–1 mg/mL by MTT/formazan method, an acute single dose (2–10 g/kg bodyweight toxicity study and a 180-day chronic study with 1 g and 2 g/kg bodyweight in Sprague Dawley rats. Some sedation, ptosis, and ataxia were observed for first 15–20 min in very high acute doses and hence not used for further chronic studies. At the end of 180 days, gross and histopathology, blood cell counts, liver and renal functions were all at normal levels. Further, a modest attempt was made to assess the effects of BV-9238 (0.5 µg/mL on six major human cytochrome P450 enzymes and 3H radioligand binding assay with human hERG receptors. BV-9238 did not show any significant inhibition of these enzymes at the tested dose. All these suggest that BV-9238 has potential as a safe and well tolerated anti-inflammatory formulation for future use.

  11. Early identification of hERG liability in drug discovery programs by automated patch clamp

    Directory of Open Access Journals (Sweden)

    Timm eDanker

    2014-09-01

    Full Text Available Blockade of the cardiac ion channel coded by hERG can lead to cardiac arrhythmia, which has become a major concern in drug discovery and development. Automated electrophysiological patch clamp allows assessment of hERG channel effects early in drug development to aid medicinal chemistry programs and has become routine in pharmaceutical companies. However, a number of potential sources of errors in setting up hERG channel assays by automated patch clamp can lead to misinterpretation of data or false effects being reported. This article describes protocols for automated electrophysiology screening of compound effects on the hERG channel current. Protocol details and the translation of criteria known from manual patch clamp experiments to automated patch clamp experiments to achieve good quality data are emphasized. Typical pitfalls and artifacts that may lead to misinterpretation of data are discussed. While this article focuses on hERG channel recordings using the QPatch (Sophion A/S, Copenhagen, Denmark technology, many of the assay and protocol details given in this article can be transferred for setting up different ion channel assays by automated patch clamp and are similar on other planar patch clamp platforms.

  12. Mechanisms underlying probucol-induced hERG-channel deficiency

    Directory of Open Access Journals (Sweden)

    Shi YQ

    2015-07-01

    Full Text Available Yuan-Qi Shi,1,* Cai-Chuan Yan,1,* Xiao Zhang,1 Meng Yan,1 Li-Rong Liu,1 Huai-Ze Geng,1 Lin Lv,1 Bao-Xin Li1,21Department of Pharmacology, Harbin Medical University, 2State-Province Key Laboratory of Biopharmaceutical Engineering, Harbin, Heilongjiang, People’s Republic of China*These authors contributed equally to this workAbstract: The hERG gene encodes the pore-forming α-subunit of the rapidly activating delayed rectifier potassium channel (IKr, which is important for cardiac repolarization. Reduction of IhERG due to genetic mutations or drug interferences causes long QT syndrome, leading to life-threatening cardiac arrhythmias (torsades de pointes or sudden death. Probucol is a cholesterol-lowering drug that could reduce hERG current by decreasing plasma membrane hERG protein expression and eventually cause long QT syndrome. Here, we investigated the mechanisms of probucol effects on IhERG and hERG-channel expression. Our data demonstrated that probucol reduces SGK1 expression, known as SGK isoform, in a concentration-dependent manner, resulting in downregulation of phosphorylated E3 ubiquitin ligase Nedd4-2 expression, but not the total level of Nedd4-2. As a result, the hERG protein reduces, due to the enhanced ubiquitination level. On the contrary, carbachol could enhance the phosphorylation level of Nedd4-2 as an alternative to SGK1, and thus rescue the ubiquitin-mediated degradation of hERG channels caused by probucol. These discoveries provide a novel mechanism of probucol-induced hERG-channel deficiency, and imply that carbachol or its analog may serve as potential therapeutic compounds for the handling of probucol cardiotoxicity.Keywords: long QT, hERG potassium channels, probucol, SGK1, Nedd4-2

  13. BmTx3, a scorpion toxin with two putative functional faces separately active on A-type K+ and HERG currents.

    OpenAIRE

    Huys, Isabelle; Xu, Chen-Qi; Wang, Cheng-Zhong; Vacher, Hélène; Martin-Eauclaire, Marie-France; Chi, Cheng-Wu; Tytgat, Jan

    2004-01-01

    A novel HERG channel blocker was isolated from the venom of the scorpion Buthus martensi Karsch, sequenced and characterized at the pharmacological level after chemical synthesis. According to the determined amino acid sequence, the cDNA and genomic genes were then cloned. The genomic gene consists of two exons interrupted by an intron of 65 bp at position -6 upstream from the mature toxin. The protein sequence of this toxin was completely identical with that of a known A-type K+ current bloc...

  14. A novel assessment of nefazodone-induced hERG inhibition by electrophysiological and stereochemical method

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Dae-Seop; Park, Myoung Joo [Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of); Lee, Hyang-Ae [Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of); Lee, Joo Yun; Chung, Hee-Chung; Yoo, Dae Seok; Chae, Chong Hak [Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of); Park, Sang-Joon [College of Veterinary Medicine, Kyungpook National University, Daegu (Korea, Republic of); Kim, Ki-Suk [Korea Institute of Toxicology, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of); Bae, Myung Ae, E-mail: mbae@krict.re.kr [Drug Discovery Platform Technology Research Group, Korea Research Institute of Chemical Technology, Daejeon (Korea, Republic of)

    2014-02-01

    Nefazodone was used widely as an antidepressant until it was withdrawn from the U.S. market in 2004 due to hepatotoxicity. We have investigated methods to predict various toxic effects of drug candidates to reduce the failure rate of drug discovery. An electrophysiological method was used to assess the cardiotoxicity of drug candidates. Small molecules, including withdrawn drugs, were evaluated using a patch-clamp method to establish a database of hERG inhibition. Nefazodone inhibited hERG channel activity in our system. However, nefazodone-induced hERG inhibition indicated only a theoretical risk of cardiotoxicity. Nefazodone inhibited the hERG channel in a concentration-dependent manner with an IC{sub 50} of 45.3 nM in HEK-293 cells. Nefazodone accelerated both the recovery from inactivation and its onset. Nefazodone also accelerated steady-state inactivation, although it did not modify the voltage-dependent character. Alanine mutants of hERG S6 and pore region residues were used to identify the nefazodone-binding site on hERG. The hERG S6 point mutants Y652A and F656A largely abolished the inhibition by nefazodone. The pore region mutant S624A mildly reduced the inhibition by nefazodone but T623A had little effect. A docking study showed that the aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions, while an amine interacted with the S624 residue in the pore region. In conclusion, Y652 and F656 in the S6 domain play critical roles in nefazodone binding. - Highlights: • Nefazodone inhibits hERG channels with an IC{sub 50} of 45.3 nM in HEK-293 cells. • Nefazodone blocks hERG channels by binding to the open channels. • Y652 and F656 are important for binding of nefazodone. • The aromatic rings of nefazodone interact with Y652 and F656 via π–π interactions.

  15. Endocytosis of HERG is clathrin-independent and involves arf6.

    Directory of Open Access Journals (Sweden)

    Rucha Karnik

    Full Text Available The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression of hERG at the plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases the risk of ventricular arrhythmias. Thus, it is of fundamental importance to understand how the density of this channel at the plasma membrane is regulated. We used antibodies to an extracellular native or engineered epitope, in conjunction with immunofluorescence and ELISA, to investigate the mechanism of hERG endocytosis in recombinant cells and validated the findings in rat neonatal cardiac myocytes. The data reveal that this channel undergoes rapid internalisation, which is inhibited by neither dynasore, an inhibitor of dynamin, nor a dominant negative construct of Rab5a, into endosomes that are largely devoid of the transferrin receptor. These results support a clathrin-independent mechanism of endocytosis and exclude involvement of dynamin-dependent caveolin and RhoA mechanisms. In agreement, internalised hERG displayed marked overlap with glycosylphosphatidylinositol-anchored GFP, a clathrin-independent cargo. Endocytosis was significantly affected by cholesterol extraction with methyl-β-cyclodextrin and inhibition of Arf6 function with dominant negative Arf6-T27N-eGFP. Taken together, we conclude that hERG undergoes clathrin-independent endocytosis via a mechanism involving Arf6.

  16. Endocytosis of hERG Is Clathrin-Independent and Involves Arf6

    Science.gov (United States)

    Abuarab, Nada; Smith, Andrew J.; Hardy, Matthew E. L.; Elliott, David J. S.; Sivaprasadarao, Asipu

    2013-01-01

    The hERG potassium channel is critical for repolarisation of the cardiac action potential. Reduced expression of hERG at the plasma membrane, whether caused by hereditary mutations or drugs, results in long QT syndrome and increases the risk of ventricular arrhythmias. Thus, it is of fundamental importance to understand how the density of this channel at the plasma membrane is regulated. We used antibodies to an extracellular native or engineered epitope, in conjunction with immunofluorescence and ELISA, to investigate the mechanism of hERG endocytosis in recombinant cells and validated the findings in rat neonatal cardiac myocytes. The data reveal that this channel undergoes rapid internalisation, which is inhibited by neither dynasore, an inhibitor of dynamin, nor a dominant negative construct of Rab5a, into endosomes that are largely devoid of the transferrin receptor. These results support a clathrin-independent mechanism of endocytosis and exclude involvement of dynamin-dependent caveolin and RhoA mechanisms. In agreement, internalised hERG displayed marked overlap with glycosylphosphatidylinositol-anchored GFP, a clathrin-independent cargo. Endocytosis was significantly affected by cholesterol extraction with methyl-β-cyclodextrin and inhibition of Arf6 function with dominant negative Arf6-T27N-eGFP. Taken together, we conclude that hERG undergoes clathrin-independent endocytosis via a mechanism involving Arf6. PMID:24392021

  17. Differential expression of hERG1 channel isoforms reproduces properties of native I(Kr) and modulates cardiac action potential characteristics

    DEFF Research Database (Denmark)

    Larsen, Anders Peter; Olesen, Søren-Peter

    2010-01-01

    The repolarizing cardiac rapid delayed rectifier current, I(Kr), is composed of ERG1 channels. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to I(Kr). Marked heterogeneity in the kinetic properties of native I(Kr) has been described. We hypothesized...

  18. Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

    Science.gov (United States)

    Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

    2008-01-01

    Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

  19. Differential expression of hERG1 channel isoforms reproduces properties of native I(Kr and modulates cardiac action potential characteristics.

    Directory of Open Access Journals (Sweden)

    Anders Peter Larsen

    Full Text Available BACKGROUND: The repolarizing cardiac rapid delayed rectifier current, I(Kr, is composed of ERG1 channels. It has been suggested that two isoforms of the ERG1 protein, ERG1a and ERG1b, both contribute to I(Kr. Marked heterogeneity in the kinetic properties of native I(Kr has been described. We hypothesized that the heterogeneity of native I(Kr can be reproduced by differential expression of ERG1a and ERG1b isoforms. Furthermore, the functional consequences of differential expression of ERG1 isoforms were explored as a potential mechanism underlying native heterogeneity of action potential duration (APD and restitution. METHODOLOGY/PRINCIPAL FINDINGS: The results show that the heterogeneity of native I(Kr can be reproduced in heterologous expression systems by differential expression of ERG1a and ERG1b isoforms. Characterization of the macroscopic kinetics of ERG1 currents demonstrated that these were dependent on the relative abundance of ERG1a and ERG1b. Furthermore, we used a computational model of the ventricular cardiomyocyte to show that both APD and the slope of the restitution curve may be modulated by varying the relative abundance of ERG1a and ERG1b. As the relative abundance of ERG1b was increased, APD was gradually shortened and the slope of the restitution curve was decreased. CONCLUSIONS/SIGNIFICANCE: Our results show that differential expression of ERG1 isoforms may explain regional heterogeneity of I(Kr kinetics. The data demonstrate that subunit dependent changes in channel kinetics are important for the functional properties of ERG1 currents and hence I(Kr. Importantly, our results suggest that regional differences in the relative abundance of ERG1 isoforms may represent a potential mechanism underlying the heterogeneity of both APD and APD restitution observed in mammalian hearts.

  20. Role of the pH in state-dependent blockade of hERG currents

    Science.gov (United States)

    Wang, Yibo; Guo, Jiqing; Perissinotti, Laura L.; Lees-Miller, James; Teng, Guoqi; Durdagi, Serdar; Duff, Henry J.; Noskov, Sergei Yu.

    2016-10-01

    Mutations that reduce inactivation of the voltage-gated Kv11.1 potassium channel (hERG) reduce binding for a number of blockers. State specific block of the inactivated state of hERG block may increase risks of drug-induced Torsade de pointes. In this study, molecular simulations of dofetilide binding to the previously developed and experimentally validated models of the hERG channel in open and open-inactivated states were combined with voltage-clamp experiments to unravel the mechanism(s) of state-dependent blockade. The computations of the free energy profiles associated with the drug block to its binding pocket in the intra-cavitary site display startling differences in the open and open-inactivated states of the channel. It was also found that drug ionization may play a crucial role in preferential targeting to the open-inactivated state of the pore domain. pH-dependent hERG blockade by dofetilie was studied with patch-clamp recordings. The results show that low pH increases the extent and speed of drug-induced block. Both experimental and computational findings indicate that binding to the open-inactivated state is of key importance to our understanding of the dofetilide’s mode of action.

  1. Plant ion channels: gene families, physiology, and functional genomics analyses.

    Science.gov (United States)

    Ward, John M; Mäser, Pascal; Schroeder, Julian I

    2009-01-01

    Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarization- and depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide-gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport.

  2. Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke.

    Science.gov (United States)

    Seki, Maki; Tsuruta, Osamu; Tatsumi, Ryo; Soejima, Aki

    2013-07-15

    A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Functional characterization of a novel hERG variant in a family with recurrent sudden infant death syndrome: Retracting a genetic diagnosis.

    Science.gov (United States)

    Sergeev, Valentine; Perry, Frances; Roston, Thomas M; Sanatani, Shubhayan; Tibbits, Glen F; Claydon, Thomas W

    2018-03-01

    Long QT syndrome (LQTS) is the most common cardiac ion channelopathy and has been found to be responsible for approximately 10% of sudden infant death syndrome (SIDS) cases. Despite increasing use of broad panels and now whole exome sequencing (WES) in the investigation of SIDS, the probability of identifying a pathogenic mutation in a SIDS victim is low. We report a family-based study who are afflicted by recurrent SIDS in which several members harbor a variant, p.Pro963Thr, in the C-terminal region of the human-ether-a-go-go (hERG) gene, published to be responsible for cases of LQTS type 2. Functional characterization was undertaken due to the variable phenotype in carriers, the discrepancy with published cases, and the importance of identifying a cause for recurrent deaths in a single family. Studies of the mutated ion channel in in vitro heterologous expression systems revealed that the mutation has no detectable impact on membrane surface expression, biophysical gating properties such as activation, deactivation and inactivation, or the amplitude of the protective current conducted by hERG channels during early repolarization. These observations suggest that the p.Pro963Thr mutation is not a monogenic disease-causing LQTS mutation despite evidence of co-segregation in two siblings affected by SIDS. Our findings demonstrate some of the potential pitfalls in post-mortem molecular testing and the importance of functional testing of gene variants in determining disease-causation, especially where the impacts of cascade screening can affect multiple generations. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Oxycodone is associated with dose-dependent QTc prolongation in patients and low-affinity inhibiting of hERG activity in vitro

    DEFF Research Database (Denmark)

    Fanoe, Søren; Jensen, Gorm Boje; Sjøgren, Per

    2008-01-01

    with the use of these drugs. WHAT THIS PAPER ADDS: This study is the first to show that oxycodone dose is associated with QT prolongation and in vitro blockade of hERG channels expressed in HEK293. Neither morphine nor tramadol doses are associated with the QT interval length. AIMS: During recent years some...... and TdP could be a more general problem associated with the use of these drugs. The aims of this study were to evaluate the association between different opioids and the QTc among patients and measure hERG activity under influence by opioids in vitro. METHODS: One hundred chronic nonmalignant pain...... patients treated with methadone, oxycodone, morphine or tramadol were recruited in a cross-sectional study. The QTc was estimated from a 12-lead ECG. To examine hERG activity in the presence of oxycodone, electrophysiological testing was conducted using Xenopus laevis oocytes and HEK293 cells expressing h...

  5. Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.

    Science.gov (United States)

    Smith, Jennifer L; Reloj, Allison R; Nataraj, Parvathi S; Bartos, Daniel C; Schroder, Elizabeth A; Moss, Arthur J; Ohno, Seiko; Horie, Minoru; Anderson, Corey L; January, Craig T; Delisle, Brian P

    2013-11-01

    KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.

  6. Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology.

    Science.gov (United States)

    Wu, Wei; Sanguinetti, Michael C

    2016-06-01

    Human cardiomyocytes express 3 distinct types of delayed rectifier potassium channels. Human ether-a-go-go-related gene (hERG) channels conduct the rapidly activating current IKr; KCNQ1/KCNE1 channels conduct the slowly activating current IKs; and Kv1.5 channels conduct an ultrarapid activating current IKur. Here the authors provide a general overview of the mechanistic and structural basis of ion selectivity, gating, and pharmacology of the 3 types of cardiac delayed rectifier potassium ion channels. Most blockers bind to S6 residues that line the central cavity of the channel, whereas activators interact with the channel at 4 symmetric binding sites outside the cavity. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

    Science.gov (United States)

    Lehmann, David F; Eggleston, William D; Wang, Dongliang

    2018-03-01

    Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (C max ) is used during drug development to screen out chemical entities likely to cause TdP. To validate the use of the hERG IC50:C max ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. Medline (between 1966 and March 2017) was accessed for hERG IC50 and C max values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. Negligible risk drugs were defined by an hERG IC50:C max ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). The hERG IC50:C max ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, pratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. The hERG IC50:C max ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:C max ratio for clinical decision making in instances of drug selection where TdP risk is a concern. © 2018

  8. Support for calcium channel gene defects in autism spectrum disorders

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    Lu Ake Tzu-Hui

    2012-12-01

    Full Text Available Abstract Background Alternation of synaptic homeostasis is a biological process whose disruption might predispose children to autism spectrum disorders (ASD. Calcium channel genes (CCG contribute to modulating neuronal function and evidence implicating CCG in ASD has been accumulating. We conducted a targeted association analysis of CCG using existing genome-wide association study (GWAS data and imputation methods in a combined sample of parent/affected child trios from two ASD family collections to explore this hypothesis. Methods A total of 2,176 single-nucleotide polymorphisms (SNP (703 genotyped and 1,473 imputed covering the genes that encode the α1 subunit proteins of 10 calcium channels were tested for association with ASD in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP. SNP imputation using IMPUTE2 and a combined reference panel from the HapMap3 and the 1,000 Genomes Project increased coverage density of the CCG. Family-based association was tested using the FBAT software which controls for population stratification and accounts for the non-independence of siblings within multiplex families. The level of significance for association was set at 2.3E-05, providing a Bonferroni correction for this targeted 10-gene panel. Results Four SNPs in three CCGs were associated with ASD. One, rs10848653, is located in CACNA1C, a gene in which rare de novo mutations are responsible for Timothy syndrome, a Mendelian disorder that features ASD. Two others, rs198538 and rs198545, located in CACN1G, and a fourth, rs5750860, located in CACNA1I, are in CCGs that encode T-type calcium channels, genes with previous ASD associations. Conclusions These associations support a role for common CCG SNPs in ASD.

  9. Topology of transmembrane channel-like gene 1 protein.

    Science.gov (United States)

    Labay, Valentina; Weichert, Rachel M; Makishima, Tomoko; Griffith, Andrew J

    2010-10-05

    Mutations of transmembrane channel-like gene 1 (TMC1) cause hearing loss in humans and mice. TMC1 is the founding member of a family of genes encoding proteins of unknown function that are predicted to contain multiple transmembrane domains. The goal of our study was to define the topology of mouse TMC1 expressed heterologously in tissue culture cells. TMC1 was retained in the endoplasmic reticulum (ER) membrane of five tissue culture cell lines that we tested. We used anti-TMC1 and anti-HA antibodies to probe the topologic orientation of three native epitopes and seven HA epitope tags along full-length TMC1 after selective or complete permeabilization of transfected cells with digitonin or Triton X-100, respectively. TMC1 was present within the ER as an integral membrane protein containing six transmembrane domains and cytosolic N- and C-termini. There is a large cytoplasmic loop, between the fourth and fifth transmembrane domains, with two highly conserved hydrophobic regions that might associate with or penetrate, but do not span, the plasma membrane. Our study is the first to demonstrate that TMC1 is a transmembrane protein. The topologic organization revealed by this study shares some features with that of the shaker-TRP superfamily of ion channels.

  10. Activation of human ether-a-go-go-related gene potassium channels by the diphenylurea 1,3-bis-(2-hydroxy-5-trifluoromethyl-phenyl)-urea (NS1643)

    DEFF Research Database (Denmark)

    Hansen, Rie Schultz; Diness, Thomas Goldin; Christ, Torsten

    2005-01-01

    The cardiac action potential is generated by a concerted action of different ion channels and transporters. Dysfunction of any of these membrane proteins can give rise to cardiac arrhythmias, which is particularly true for the repolarizing potassium channels. We suggest that an increased repolari......The cardiac action potential is generated by a concerted action of different ion channels and transporters. Dysfunction of any of these membrane proteins can give rise to cardiac arrhythmias, which is particularly true for the repolarizing potassium channels. We suggest that an increased......M. Application of NS1643 also resulted in a prolonged postrepolarization refractory time. Finally, cardiomyocytes exposed to NS1643 resisted reactivation by small depolarizing currents mimicking early afterdepolarizations. In conclusion, HERG channel activation by small molecules such as NS1643 increases...

  11. Molecular Cloning and Sequencing of Hemoglobin-Beta Gene of Channel Catfish, Ictalurus Punctatus Rafinesque

    Science.gov (United States)

    : Hemoglobin-y gene of channel catfish , lctalurus punctatus, was cloned and sequenced . Total RNA from head kidneys was isolated, reverse transcribed and amplified . The sequence of the channel catfish hemoglobin-y gene consists of 600 nucleotides . Analysis of the nucleotide sequence reveals one o...

  12. Mechanism of action of a novel human ether-a-go-go-related gene channel activator

    DEFF Research Database (Denmark)

    Casis, Oscar; Olesen, Søren-Peter; Sanguinetti, Michael C

    2005-01-01

    depolarizations, NS1643 enhanced the magnitude of wild-type hERG current in a concentration- and voltage-dependent manner with an EC(50) of 10.4 microM at -10 mV. The fully activated current-voltage relationship revealed that the drug increased outward but not inward currents, consistent with altered inactivation...

  13. A remarkably stable TipE gene cluster: evolution of insect Para sodium channel auxiliary subunits

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    Li Jia

    2011-11-01

    Full Text Available Abstract Background First identified in fruit flies with temperature-sensitive paralysis phenotypes, the Drosophila melanogaster TipE locus encodes four voltage-gated sodium (NaV channel auxiliary subunits. This cluster of TipE-like genes on chromosome 3L, and a fifth family member on chromosome 3R, are important for the optional expression and functionality of the Para NaV channel but appear quite distinct from auxiliary subunits in vertebrates. Here, we exploited available arthropod genomic resources to trace the origin of TipE-like genes by mapping their evolutionary histories and examining their genomic architectures. Results We identified a remarkably conserved synteny block of TipE-like orthologues with well-maintained local gene arrangements from 21 insect species. Homologues in the water flea, Daphnia pulex, suggest an ancestral pancrustacean repertoire of four TipE-like genes; a subsequent gene duplication may have generated functional redundancy allowing gene losses in the silk moth and mosquitoes. Intronic nesting of the insect TipE gene cluster probably occurred following the divergence from crustaceans, but in the flour beetle and silk moth genomes the clusters apparently escaped from nesting. Across Pancrustacea, TipE gene family members have experienced intronic nesting, escape from nesting, retrotransposition, translocation, and gene loss events while generally maintaining their local gene neighbourhoods. D. melanogaster TipE-like genes exhibit coordinated spatial and temporal regulation of expression distinct from their host gene but well-correlated with their regulatory target, the Para NaV channel, suggesting that functional constraints may preserve the TipE gene cluster. We identified homology between TipE-like NaV channel regulators and vertebrate Slo-beta auxiliary subunits of big-conductance calcium-activated potassium (BKCa channels, which suggests that ion channel regulatory partners have evolved distinct lineage

  14. Expanded functional diversity of shaker K(+ channels in cnidarians is driven by gene expansion.

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    Timothy Jegla

    Full Text Available The genome of the cnidarian Nematostella vectensis (starlet sea anemone provides a molecular genetic view into the first nervous systems, which appeared in a late common ancestor of cnidarians and bilaterians. Nematostella has a surprisingly large and diverse set of neuronal signaling genes including paralogs of most neuronal signaling molecules found in higher metazoans. Several ion channel gene families are highly expanded in the sea anemone, including three subfamilies of the Shaker K(+ channel gene family: Shaker (Kv1, Shaw (Kv3 and Shal (Kv4. In order to better understand the physiological significance of these voltage-gated K(+ channel expansions, we analyzed the function of 18 members of the 20 gene Shaker subfamily in Nematostella. Six of the Nematostella Shaker genes express functional homotetrameric K(+ channels in vitro. These include functional orthologs of bilaterian Shakers and channels with an unusually high threshold for voltage activation. We identified 11 Nematostella Shaker genes with a distinct "silent" or "regulatory" phenotype; these encode subunits that function only in heteromeric channels and serve to further diversify Nematostella Shaker channel gating properties. Subunits with the regulatory phenotype have not previously been found in the Shaker subfamily, but have evolved independently in the Shab (Kv2 family in vertebrates and the Shal family in a cnidarian. Phylogenetic analysis indicates that regulatory subunits were present in ancestral cnidarians, but have continued to diversity at a high rate after the split between anthozoans and hydrozoans. Comparison of Shaker family gene complements from diverse metazoan species reveals frequent, large scale duplication has produced highly unique sets of Shaker channels in the major metazoan lineages.

  15. Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.

    Science.gov (United States)

    DeMarco, Kevin R; Bekker, Slava; Clancy, Colleen E; Noskov, Sergei Y; Vorobyov, Igor

    2018-01-01

    Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel K v 11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology

  16. Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

    Directory of Open Access Journals (Sweden)

    Kevin R. DeMarco

    2018-02-01

    Full Text Available Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety

  17. Paramecium BBS genes are key to presence of channels in Cilia

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    Valentine Megan

    2012-09-01

    Full Text Available Abstract Background Changes in genes coding for ciliary proteins contribute to complex human syndromes called ciliopathies, such as Bardet-Biedl Syndrome (BBS. We used the model organism Paramecium to focus on ciliary ion channels that affect the beat form and sensory function of motile cilia and evaluate the effects of perturbing BBS proteins on these channels. Methods We used immunoprecipitations and mass spectrometry to explore whether Paramecium proteins interact as in mammalian cells. We used RNA interference (RNAi and swimming behavior assays to examine the effects of BBS depletion on ciliary ion channels that control ciliary beating. Combining RNA interference and epitope tagging, we examined the effects of BBS depletion of BBS 7, 8 and 9 on the location of three channels and a chemoreceptor in cilia. Results We found 10 orthologs of 8 BBS genes in P. tetraurelia. BBS1, 2, 4, 5, 7, 8 and 9 co-immunoprecipitate. While RNAi reduction of BBS 7 and 9 gene products caused loss and shortening of cilia, RNAi for all BBS genes except BBS2 affected patterns of ciliary motility that are governed by ciliary ion channels. Swimming behavior assays pointed to loss of ciliary K+ channel function. Combining RNAi and epitope tagged ciliary proteins we demonstrated that a calcium activated K+ channel was no longer located in the cilia upon depletion of BBS 7, 8 or 9, consistent with the cells’ swimming behavior. The TRPP channel PKD2 was also lost from the cilia. In contrast, the ciliary voltage gated calcium channel was unaffected by BBS depletion, consistent with behavioral assays. The ciliary location of a chemoreceptor for folate was similarly unperturbed by the depletion of BBS 7, 8 or 9. Conclusions The co-immunoprecipitation of BBS 1,2,4,5,7,8, and 9 suggests a complex of BBS proteins. RNAi for BBS 7, 8 or 9 gene products causes the selective loss of K+ and PKD2 channels from the cilia while the critical voltage gated calcium channel and a

  18. Micro- and nanofabrication methods for ion channel reconstitution in bilayer lipid membranes

    Science.gov (United States)

    Tadaki, Daisuke; Yamaura, Daichi; Arata, Kohei; Ohori, Takeshi; Ma, Teng; Yamamoto, Hideaki; Niwano, Michio; Hirano-Iwata, Ayumi

    2018-03-01

    The self-assembled bilayer lipid membrane (BLM) forms the basic structure of the cell membrane and serves as a major barrier against ion movement. Ion channel proteins function as gated pores that permit ion permeation across the BLM. The reconstitution of ion channel proteins in artificially formed BLMs represents a well-defined system for investigating channel functions and screening drug effects on ion channels. In this review, we will discuss our recent microfabrication approaches to the formation of stable BLMs containing ion channel proteins as a potential platform for next-generation drug screening systems. BLMs formed in a microaperture having a tapered edge exhibited highly stable properties, such as a lifetime of ∼65 h and tolerance to solution changes even after the incorporation of the human ether-a-go-go-related gene (hERG) channel. We also explore a new method of efficiently incorporating human ion channels into BLMs by centrifugation. Our approaches to the formation of stable BLMs and efficient channel incorporation markedly improve the experimental efficiency of BLM reconstitution systems, leading to the realization of a BLM-based high-throughput platform for functional assays of various ion channels.

  19. Differential gene expression of cardiac ion channels in human dilated cardiomyopathy.

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    Maria Micaela Molina-Navarro

    Full Text Available BACKGROUND: Dilated cardiomyopathy (DCM is characterized by idiopathic dilation and systolic contractile dysfunction of the cardiac chambers. The present work aimed to study the alterations in gene expression of ion channels involved in cardiomyocyte function. METHODS AND RESULTS: Microarray profiling using the Affymetrix Human Gene® 1.0 ST array was performed using 17 RNA samples, 12 from DCM patients undergoing cardiac transplantation and 5 control donors (CNT. The analysis focused on 7 cardiac ion channel genes, since this category has not been previously studied in human DCM. SCN2B was upregulated, while KCNJ5, KCNJ8, CLIC2, CLCN3, CACNB2, and CACNA1C were downregulated. The RT-qPCR (21 DCM and 8 CNT samples validated the gene expression of SCN2B (p < 0.0001, KCNJ5 (p < 0.05, KCNJ8 (p < 0.05, CLIC2 (p < 0.05, and CACNB2 (p < 0.05. Furthermore, we performed an IPA analysis and we found a functional relationship between the different ion channels studied in this work. CONCLUSION: This study shows a differential expression of ion channel genes involved in cardiac contraction in DCM that might partly underlie the changes in left ventricular function observed in these patients. These results could be the basis for new genetic therapeutic approaches.

  20. Ion channel gene expressions in infertile men: A case-control study

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    Serkan Carkci

    2017-12-01

    Full Text Available Background: Infertility is described as not receiving pregnancy despite unprotected and regular sexual intercourse in a 1 yr period. It is detected by 15% of the couples. Male and female factor in the etiology may be detected in similar rates. Objective: The present study aims to investigate ion channel gene expression in semen samples of infertile male compared with fertile men. Materials and Methods: A total of 150 men who applied to the urology clinic due to infertility were divided into five equal groups: asthenozoospermia, oligozoospermia, oligoasthenoteratozoospermia, teratozoospermia, and normozoospermia (control. All paticipants were evaluated with Cation Channel Spermia (CatSper 1, 2, 3, 4, Proton Voltage Gated Ion Channel1 (Hv1, Potassium Channel Subfamily U1 (KCNU1, and transmembrane protein (TMEM16A gene expression in semen samples. Results: “CatSper1, 4, HV1, KCNU1, and TMEM16A gene expression were detected higher in the oligozoospermia group compared to the controls. CatSper1, 2, 3, 4, KCNU1, and TMEM16A gene expression in the asthenozoospermia group and CatSper1, 2, 3, 4, KCNU1, and TMEM16A gene expression in the teratozoospermia group were detected lower compared to the controls. CatSper1, 4, HV1, and TMEM16A gen expression were higher in the oligoasthenoteratozoospermia men than the controls while CatSper3 gen expression was detected as lower.” Conclusion: It was detected that these ion channels have an effect on sperm progressive motility and morphology. It may be considered that mutations in these ion channels may result in infertility

  1. Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy.

    Science.gov (United States)

    Wei, Feng; Yan, Li-Min; Su, Tao; He, Na; Lin, Zhi-Jian; Wang, Jie; Shi, Yi-Wu; Yi, Yong-Hong; Liao, Wei-Ping

    2017-08-01

    Ion channels are crucial in the generation and modulation of excitability in the nervous system and have been implicated in human epilepsy. Forty-one epilepsy-associated ion channel genes and their mutations are systematically reviewed. In this paper, we analyzed the genotypes, functional alterations (funotypes), and phenotypes of these mutations. Eleven genes featured loss-of-function mutations and six had gain-of-function mutations. Nine genes displayed diversified funotypes, among which a distinct funotype-phenotype correlation was found in SCN1A. These data suggest that the funotype is an essential consideration in evaluating the pathogenicity of mutations and a distinct funotype or funotype-phenotype correlation helps to define the pathogenic potential of a gene.

  2. An evolutionarily conserved gene family encodes proton-selective ion channels.

    Science.gov (United States)

    Tu, Yu-Hsiang; Cooper, Alexander J; Teng, Bochuan; Chang, Rui B; Artiga, Daniel J; Turner, Heather N; Mulhall, Eric M; Ye, Wenlei; Smith, Andrew D; Liman, Emily R

    2018-03-02

    Ion channels form the basis for cellular electrical signaling. Despite the scores of genetically identified ion channels selective for other monatomic ions, only one type of proton-selective ion channel has been found in eukaryotic cells. By comparative transcriptome analysis of mouse taste receptor cells, we identified Otopetrin1 (OTOP1), a protein required for development of gravity-sensing otoconia in the vestibular system, as forming a proton-selective ion channel. We found that murine OTOP1 is enriched in acid-detecting taste receptor cells and is required for their zinc-sensitive proton conductance. Two related murine genes, Otop2 and Otop3 , and a Drosophila ortholog also encode proton channels. Evolutionary conservation of the gene family and its widespread tissue distribution suggest a broad role for proton channels in physiology and pathophysiology. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  3. APETx4, a Novel Sea Anemone Toxin and a Modulator of the Cancer-Relevant Potassium Channel KV10.1

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    Lien Moreels

    2017-09-01

    Full Text Available The human ether-à-go-go channel (hEag1 or KV10.1 is a cancer-relevant voltage-gated potassium channel that is overexpressed in a majority of human tumors. Peptides that are able to selectively inhibit this channel can be lead compounds in the search for new anticancer drugs. Here, we report the activity-guided purification and electrophysiological characterization of a novel KV10.1 inhibitor from the sea anemone Anthopleura elegantissima. Purified sea anemone fractions were screened for inhibitory activity on KV10.1 by measuring whole-cell currents as expressed in Xenopus laevis oocytes using the two-microelectrode voltage clamp technique. Fractions that showed activity on Kv10.1 were further purified by RP-HPLC. The amino acid sequence of the peptide was determined by a combination of MALDI- LIFT-TOF/TOF MS/MS and CID-ESI-FT-ICR MS/MS and showed a high similarity with APETx1 and APETx3 and was therefore named APETx4. Subsequently, the peptide was electrophysiologically characterized on KV10.1. The selectivity of the toxin was investigated on an array of voltage-gated ion channels, including the cardiac human ether-à-go-go-related gene potassium channel (hERG or Kv11.1. The toxin inhibits KV10.1 with an IC50 value of 1.1 μM. In the presence of a similar toxin concentration, a shift of the activation curve towards more positive potentials was observed. Similar to the effect of the gating modifier toxin APETx1 on hERG, the inhibition of Kv10.1 by the isolated toxin is reduced at more positive voltages and the peptide seems to keep the channel in a closed state. Although the peptide also induces inhibitory effects on other KV and NaV channels, it exhibits no significant effect on hERG. Moreover, APETx4 induces a concentration-dependent cytotoxic and proapoptotic effect in various cancerous and noncancerous cell lines. This newly identified KV10.1 inhibitor can be used as a tool to further characterize the oncogenic channel KV10.1 or as a

  4. Ca2+ Channel Re-localization to Plasma-Membrane Microdomains Strengthens Activation of Ca2+-Dependent Nuclear Gene Expression

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    Krishna Samanta

    2015-07-01

    Full Text Available In polarized cells or cells with complex geometry, clustering of plasma-membrane (PM ion channels is an effective mechanism for eliciting spatially restricted signals. However, channel clustering is also seen in cells with relatively simple topology, suggesting it fulfills a more fundamental role in cell biology than simply orchestrating compartmentalized responses. Here, we have compared the ability of store-operated Ca2+ release-activated Ca2+ (CRAC channels confined to PM microdomains with a similar number of dispersed CRAC channels to activate transcription factors, which subsequently increase nuclear gene expression. For similar levels of channel activity, we find that channel confinement is considerably more effective in stimulating gene expression. Our results identify a long-range signaling advantage to the tight evolutionary conservation of channel clustering and reveal that CRAC channel aggregation increases the strength, fidelity, and reliability of the general process of excitation-transcription coupling.

  5. An ERG channel inhibitor from the scorpion Buthus eupeus

    DEFF Research Database (Denmark)

    Korolkova, Y.V.; Kozlov, S.A.; Lipkin, A.V.

    2001-01-01

    and the three mutants partly inhibited the native M-like current in NG108-15 at 100 nm. The effect of the recombinant BeKm-1 on different K(+) channels was also studied. BeKm-1 inhibited hERG1 channels with an IC(50) of 3.3 nm, but had no effect at 100 nm on hEAG, hSK1, rSK2, hIK, hBK, KCNQ1/KCNE1, KCNQ2/KCNQ3......, KCNQ4 channels, and minimal effect on rELK1. Thus, BeKm-1 was shown to be a novel specific blocker of hERG1 potassium channels....

  6. Kuifjes katholieke jeugd. De katholieke achtergrond van Hergé. Deel 1 van 2

    NARCIS (Netherlands)

    de Groot, C.N.

    2013-01-01

    Following the launch of Steven Spielberg’s ‘Tintin and the Secret of the Unicorn’, l’Osservore Romano hailed Tintin as a ‘catholic hero’. This article demonstrates that the comic originates, more specifically, in conservative and reactionary milieus in Belgian Catholicism. Hergé (ps. for Georges

  7. Characterization of the chicken inward rectifier K+ channel IRK1/Kir2.1 gene

    Directory of Open Access Journals (Sweden)

    Locke Emily

    2004-11-01

    Full Text Available Abstract Background Inward rectifier potassium channels (IRK contribute to the normal function of skeletal and cardiac muscle cells. The chick inward rectifier K+ channel cIRK1/Kir2.1 is expressed in skeletal muscle, heart, brain, but not in liver; a distribution similar but not identical to that of mouse Kir2.1. We set out to explore regulatory domains of the cIRK1 promoter that enhance or inhibit expression of the gene in different cell types. Results We cloned and characterized the 5'-flanking region of cIRK1. cIRK1 contains two exons with splice sites in the 5'-untranslated region, a structure similar to mouse and human orthologs. cIRK1 has multiple transcription initiation sites, a feature also seen in mouse. However, while the chicken and mouse promoter regions share many regulatory motifs, cIRK1 possesses a GC-richer promoter and a putative TATA box, which appears to positively regulate gene expression. We report here the identification of several candidate cell/tissue specific cIRK1 regulatory domains by comparing promoter activities in expressing (Qm7 and non-expressing (DF1 cells using in vitro transcription assays. Conclusion While multiple transcription initiation sites and the combinatorial function of several domains in activating cIRK1 expression are similar to those seen in mKir2.1, the cIRK1 promoter differs by the presence of a putative TATA box. In addition, several domains that regulate the gene's expression differentially in muscle (Qm7 and fibroblast cells (DF1 were identified. These results provide fundamental data to analyze cIRK1 transcriptional mechanisms. The control elements identified here may provide clues to the tissue-specific expression of this K+ channel.

  8. Sequence Alterations of I(Ks Potassium Channel Genes in Kazakhstani Patients with Atrial Fibrillation

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    Ainur Akilzhanova

    2014-12-01

    Full Text Available Introduction. Atrial fibrillation (AF is the most common sustained arrhythmia, and it results in significant morbidity and mortality. However, the pathogenesis of AF remains unclear to date. Recently, more pieces of evidence indicated that AF is a multifactorial disease resulting from the interaction between environmental factors and genetics. Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks may underlie AF.Objective. To investigate sequence alterations of I(Ks potassium channel genes KCNQ1, KCNE1 and KCNE2 in Kazakhstani patients with atrial fibrillation.Methods. Genomic DNA of 69 cases with atrial fibrillation and 27 relatives were analyzed for mutations in all protein-coding exons and their flanking splice site regions of the genes KCNQ1 (NM_000218.2 and NM_181798.1, KCNE1 (NM_000219.2, and KCNE2 (NM_172201.1 using bidirectional sequencing on the ABI 3730xL DNA Analyzer (Applied Biosystems, Foster City, CA, USA.Results. In total, a disease-causing mutation was identified in 39 of the 69 (56.5% index cases. Of these, altered sequence variants in the KCNQ1 gene accounted for 14.5% of the mutations, whereas a KCNE1 mutation accounted for 43.5% of the mutations and KCNE2 mutation accounted for 1.4% of the mutations. The majority of the distinct mutations were found in a single case (80%, whereas 20% of the mutations were observed more than once. We found two sequence variants in KCNQ1 exon 13 (S546S G1638A and exon 16 (Y662Y, C1986T in ten patients (14.5%. In KCNE1 gene in exon 3 mutation, S59G A280G was observed in 30 of 69 patients (43.5% and KCNE2 exon 2 T10K C29A in 1 patient (1.4%. Genetic cascade screening of 27 relatives to the 69 index cases with an identified mutation revealed 26.9% mutation carriers  who were at risk of cardiac events such as syncope or sudden unexpected death.Conclusion. In this cohort of Kazakhstani index cases with AF, a disease-causing mutation was identified in

  9. dyschronic, a Drosophila homolog of a deaf-blindness gene, regulates circadian output and Slowpoke channels.

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    James E C Jepson

    Full Text Available Many aspects of behavior and physiology are under circadian control. In Drosophila, the molecular clock that regulates rhythmic patterns of behavior has been extensively characterized. In contrast, genetic loci involved in linking the clock to alterations in motor activity have remained elusive. In a forward-genetic screen, we uncovered a new component of the circadian output pathway, which we have termed dyschronic (dysc. dysc mutants exhibit arrhythmic locomotor behavior, yet their eclosion rhythms are normal and clock protein cycling remains intact. Intriguingly, dysc is the closest Drosophila homolog of whirlin, a gene linked to type II Usher syndrome, the leading cause of deaf-blindness in humans. Whirlin and other Usher proteins are expressed in the mammalian central nervous system, yet their function in the CNS has not been investigated. We show that DYSC is expressed in major neuronal tracts and regulates expression of the calcium-activated potassium channel SLOWPOKE (SLO, an ion channel also required in the circadian output pathway. SLO and DYSC are co-localized in the brain and control each other's expression post-transcriptionally. Co-immunoprecipitation experiments demonstrate they form a complex, suggesting they regulate each other through protein-protein interaction. Furthermore, electrophysiological recordings of neurons in the adult brain show that SLO-dependent currents are greatly reduced in dysc mutants. Our work identifies a Drosophila homolog of a deaf-blindness gene as a new component of the circadian output pathway and an important regulator of ion channel expression, and suggests novel roles for Usher proteins in the mammalian nervous system.

  10. Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression

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    Mats Wiedemann

    2015-10-01

    Full Text Available The glucose-lowering effects of lupin seeds involve the combined action of several components. The present study investigates the influence of one of the main quinolizidine alkaloids, lupanine, on pancreatic beta cells and in an animal model of type-2 diabetes mellitus. In vitro studies were performed with insulin-secreting INS-1E cells or islets of C57BL/6 mice. In the in vivo experiments, hyperglycemia was induced in rats by injecting streptozotocin (65 mg/kg body weight. In the presence of 15 mmol/L glucose, insulin secretion was significantly elevated by 0.5 mmol/L lupanine, whereas the alkaloid did not stimulate insulin release with lower glucose concentrations. In islets treated with l-arginine, the potentiating effect of lupanine already occurred at 8 mmol/L glucose. Lupanine increased the expression of the Ins-1 gene. The potentiating effect on secretion was correlated to membrane depolarization and an increase in the frequency of Ca2+ action potentials. Determination of the current through ATP-dependent K+ channels (KATP channels revealed that lupanine directly inhibited the channel. The effect was dose-dependent but, even with a high lupanine concentration of 1 mmol/L or after a prolonged exposure time (12 h, the KATP channel block was incomplete. Oral administration of lupanine did not induce hypoglycemia. By contrast, lupanine improved glycemic control in response to an oral glucose tolerance test in streptozotocin-diabetic rats. In summary, lupanine acts as a positive modulator of insulin release obviously without a risk for hypoglycemic episodes.

  11. Molecular Characterization of LRB7 Gene and a Water Channel Protein TIP2 in Chorispora bungeana

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    Ming Li

    2016-01-01

    Full Text Available Background. Water channel proteins, also called aquaporins, are integral membrane proteins from major intrinsic protein (MIP family and involved in several pathways including not only water transport but also cell signaling, reproduction, and photosynthesis. The full cDNA and protein sequences of aquaporin in Chorispora bungeana Fisch. & C.A. Mey (C. bungeana are still unknown. Results. In this study, PCR and rapid amplification of cDNA ends approaches were used to clone the full cDNA of LRB7 (GenBank accession number: EU636988 of C. bungeana. Sequence analysis indicated that it was 1235 bp, which had two introns and encoded a protein of 250 amino acids. Structure analysis revealed that the protein had two conserved NPA motifs, one of which is MIP signature sequence (SGxHxNPAVT, six membrane helix regions, and additional membrane-embedded domains. Phylogenetic analysis suggested that the protein was from TIP2 subgroup. Surprisingly, semiquantitative RT-PCR experiment and western blot analysis showed that LRB7 and TIP2 were only detectable in roots, unlike Arabidopsis and Raphanus. Connecting with our previous studies, LRB7 was supported to associate with chilling-tolerance in C. bungeana. Conclusion. This is the first time to characterize the full sequences of LRB7 gene and water channel protein in C. bungeana. Our findings contribute to understanding the water transports in plants under low temperatures.

  12. New Trends in Cancer Therapy: Targeting Ion Channels and Transporters

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    Annarosa Arcangeli

    2010-04-01

    Full Text Available The expression and activity of different channel types mark and regulate specific stages of cancer establishment and progression. Blocking channel activity impairs the growth of some tumors, both in vitro and in vivo, which opens a new field for pharmaceutical research. However, ion channel blockers may produce serious side effects, such as cardiac arrhythmias. For instance, Kv11.1 (hERG1 channels are aberrantly expressed in several human cancers, in which they control different aspects of the neoplastic cell behaviour. hERG1 blockers tend to inhibit cancer growth. However they also retard the cardiac repolarization, thus lengthening the electrocardiographic QT interval, which can lead to life-threatening ventricular arrhythmias. Several possibilities exist to produce less harmful compounds, such as developing specific drugs that bind hERG1 channels in the open state or disassemble the ion channel/integrin complex which appears to be crucial in certain stages of neoplastic progression. The potential approaches to improve the efficacy and safety of ion channel targeting in oncology include: (1 targeting specific conformational channel states; (2 finding ever more specific inhibitors, including peptide toxins, for channel subtypes mainly expressed in well-identified tumors; (3 using specific ligands to convey traceable or cytotoxic compounds; (4 developing channel blocking antibodies; (5 designing new molecular tools to decrease channel expression in selected cancer types. Similar concepts apply to ion transporters such as the Na+/K+ pump and the Na+/H+ exchanger. Pharmacological targeting of these transporters is also currently being considered in anti-neoplastic therapy.

  13. KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction.

    Science.gov (United States)

    Padula, Audrey E; Griffin, William C; Lopez, Marcelo F; Nimitvilai, Sudarat; Cannady, Reginald; McGuier, Natalie S; Chesler, Elissa J; Miles, Michael F; Williams, Robert W; Randall, Patrick K; Woodward, John J; Becker, Howard C; Mulholland, Patrick J

    2015-07-01

    Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

  14. The Drosophila gene CheB42a is a novel modifier of Deg/ENaC channel function.

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    Yehuda Ben-Shahar

    2010-02-01

    Full Text Available Degenerin/epithelial Na(+ channels (DEG/ENaC represent a diverse family of voltage-insensitive cation channels whose functions include Na(+ transport across epithelia, mechanosensation, nociception, salt sensing, modification of neurotransmission, and detecting the neurotransmitter FMRFamide. We previously showed that the Drosophila melanogaster Deg/ENaC gene lounge lizard (llz is co-transcribed in an operon-like locus with another gene of unknown function, CheB42a. Because operons often encode proteins in the same biochemical or physiological pathway, we hypothesized that CHEB42A and LLZ might function together. Consistent with this hypothesis, we found both genes expressed in cells previously implicated in sensory functions during male courtship. Furthermore, when coexpressed, LLZ coprecipitated with CHEB42A, suggesting that the two proteins form a complex. Although LLZ expressed either alone or with CHEB42A did not generate ion channel currents, CHEB42A increased current amplitude of another DEG/ENaC protein whose ligand (protons is known, acid-sensing ion channel 1a (ASIC1a. We also found that CHEB42A was cleaved to generate a secreted protein, suggesting that CHEB42A may play an important role in the extracellular space. These data suggest that CHEB42A is a modulatory subunit for sensory-related Deg/ENaC signaling. These results are consistent with operon-like transcription of CheB42a and llz and explain the similar contributions of these genes to courtship behavior.

  15. Calcium Channel Genes Associated with Bipolar Disorder Modulate Lithium's Amplification of Circadian Rhythms

    Science.gov (United States)

    McCarthy, Michael J.; LeRoux, Melissa; Wei, Heather; Beesley, Stephen; Kelsoe, John R.; Welsh, David K.

    2015-01-01

    Bipolar disorder (BD) is associated with mood episodes and low amplitude circadian rhythms. Previously, we demonstrated that fibroblasts grown from BD patients show weaker amplification of circadian rhythms by lithium compared to control cells. Since calcium signals impact upon the circadian clock, and L-type calcium channels (LTCC) have emerged as genetic risk factors for BD, we examined whether loss of function in LTCCs accounts for the attenuated response to lithium in BD cells. We used fluorescent dyes to measure Ca2+ changes in BD and control fibroblasts after lithium treatment, and bioluminescent reporters to measure Per2∷luc rhythms in fibroblasts from BD patients, human controls, and mice while pharmacologically or genetically manipulating calcium channels. Longitudinal expression of LTCC genes (CACNA1C, CACNA1D and CACNB3) was then measured over 12-24 hr in BD and control cells. Our results indicate that independently of LTCCs, lithium stimulated intracellular Ca2+ less effectively in BD vs. control fibroblasts. In longitudinal studies, pharmacological inhibition of LTCCs or knockdown of CACNA1A, CACNA1C, CACNA1D and CACNB3 altered circadian rhythm amplitude. Diltiazem and knockdown of CACNA1C or CACNA1D eliminated lithium's ability to amplify rhythms. Knockdown of CACNA1A or CACNB3 altered baseline rhythms, but did not affect rhythm amplification by lithium. In human fibroblasts, CACNA1C genotype predicted the amplitude response to lithium, and the expression profiles of CACNA1C, CACNA1D and CACNB3 were altered in BD vs. controls. We conclude that in cells from BD patients, calcium signaling is abnormal, and that LTCCs underlie the failure of lithium to amplify circadian rhythms. PMID:26476274

  16. Novel transcripts of the estrogen receptor α gene in channel catfish

    Science.gov (United States)

    Patino, Reynaldo; Xia, Zhenfang; Gale, William L.; Wu, Chunfa; Maule, Alec G.; Chang, Xiaotian

    2000-01-01

    Complementary DNA libraries from liver and ovary of an immature female channel catfish were screened with a homologous ERα cDNA probe. The hepatic library yielded two new channel catfish ER cDNAs that encode N-terminal ERα variants of different sizes. Relative to the catfish ERα (medium size; 581 residues) previously reported, these new cDNAs encode Long-ERα (36 residues longer) and Short-ERα (389 residues shorter). The 5′-end of Long-ERα cDNA is identical to that of Medium-ERα but has an additional 503-bp segment with an upstream, in-frame translation-start codon. Recombinant Long-ERα binds estrogen with high affinity (Kd = 3.4 nM), similar to that previously reported for Medium-ERα but lower than reported for catfish ERβ. Short-ERα cDNA encodes a protein that lacks most of the receptor protein and does not bind estrogen. Northern hybridization confirmed the existence of multiple hepatic ERα RNAs that include the size range of the ERα cDNAs obtained from the libraries as well as additional sizes. Using primers for RT-PCR that target locations internal to the protein-coding sequence, we also established the presence of several ERα cDNA variants with in-frame insertions in the ligand-binding and DNA-binding domains and in-frame or out-of-frame deletions in the ligand-binding domain. These internal variants showed patterns of expression that differed between the ovary and liver. Further, the ovarian library yielded a full-length, ERα antisense cDNA containing a poly(A) signal and tail. A limited survey of histological preparations from juvenile catfish by in situ hybridization using directionally synthesized cRNA probes also suggested the expression of ERα antisense RNA in a tissue-specific manner. In conclusion, channel catfish seemingly have three broad classes of ERα mRNA variants: those encoding N-terminal truncated variants, those encoding internal variants (including C-terminal truncated variants), and antisense mRNA. The sense variants may

  17. Pharmacokinetic–pharmacodynamic modelling of drug‐induced QTc interval prolongation in man: prediction from in vitro human ether‐à‐go‐go‐related gene binding and functional inhibition assays and conscious dog studies

    Science.gov (United States)

    Dubois, V F S; Casarotto, E; Danhof, M

    2016-01-01

    Background and Purpose Functional measures of human ether‐à‐go‐go‐related gene (hERG; Kv11.1) channel inhibition have been prioritized as an in vitro screening tool for candidate molecules. However, it is unclear how these results can be translated to humans. Here, we explore how data on drug binding and functional inhibition in vitro relate to QT prolongation in vivo. Using cisapride, sotalol and moxifloxacin as paradigm compounds, we assessed the relationship between drug concentrations, binding, functional measures and in vivo effects in preclinical species and humans. Experimental Approach Pharmacokinetic–pharmacodynamic modelling was used to characterize the drug effects in hERG functional patch clamp, hERG radio‐labelled dofetilide displacement experiments and QT interval in conscious dogs. Data were analysed in parallel to identify potential correlations between pharmacological activity in vitro and in vivo. Key Results An Emax model could not be used due to large variability in the functional patch clamp assay. Dofetilide displacement revealed that binding curves are unrelated to the in vivo potency estimates for QTc prolongation in dogs and humans. Mean in vitro potency estimates ranged from 99.9 nM for cisapride to 1030 μM for moxifloxacin. Conclusions and Implications The lack of standardized protocols for in vitro assays leads to significant differences in experimental conditions, making the assessment of in vitro–in vivo correlations unreliable. Identification of an accurate safety window during the screening of candidate molecules requires a quantitative framework that disentangles system‐ from drug‐specific properties under physiological conditions, enabling translation of the results to humans. Similar considerations will be relevant for the comprehensive in vitro pro‐arrhythmia assay initiative. PMID:27427789

  18. Association analysis of a highly polymorphic CAG Repeat in the human potassium channel gene KCNN3 and migraine susceptibility

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    Ovcaric Mick

    2005-09-01

    Full Text Available Abstract Background Migraine is a polygenic multifactorial disease, possessing environmental and genetic causative factors with multiple involved genes. Mutations in various ion channel genes are responsible for a number of neurological disorders. KCNN3 is a neuronal small conductance calcium-activated potassium channel gene that contains two polyglutamine tracts, encoded by polymorphic CAG repeats in the gene. This gene plays a critical role in determining the firing pattern of neurons and acts to regulate intracellular calcium channels. Methods The present association study tested whether length variations in the second (more 3' polymorphic CAG repeat in exon 1 of the KCNN3 gene, are involved in susceptibility to migraine with and without aura (MA and MO. In total 423 DNA samples from unrelated individuals, of which 202 consisted of migraine patients and 221 non-migraine controls, were genotyped and analysed using a fluorescence labelled primer set on an ABI310 Genetic Analyzer. Allele frequencies were calculated from observed genotype counts for the KCNN3 polymorphism. Analysis was performed using standard contingency table analysis, incorporating the chi-squared test of independence and CLUMP analysis. Results Overall, there was no convincing evidence that KCNN3 CAG lengths differ between Caucasian migraineurs and controls, with no significant difference in the allelic length distribution of CAG repeats between the population groups (P = 0.090. Also the MA and MO subtypes did not differ significantly between control allelic distributions (P > 0.05. The prevalence of the long CAG repeat (>19 repeats did not reach statistical significance in migraineurs (P = 0.15, nor was there a significant difference between the MA and MO subgroups observed compared to controls (P = 0.46 and P = 0.09, respectively, or between MA vs MO (P = 0.40. Conclusion This association study provides no evidence that length variations of the second polyglutamine array in

  19. The transient outward current in mice lacking the potassium channel gene Kv1.4

    Science.gov (United States)

    London, Barry; Wang, Dao W; Hill, Joseph A; Bennett, Paul B

    1998-01-01

    The transient outward current (Ito) plays a prominent role in the repolarization phase of the cardiac action potential. Several K+ channel genes, including Kv1.4, are expressed in the heart, produce rapidly inactivating currents when heterologously expressed, and may be the molecular basis of Ito.We engineered mice homozygous for a targeted disruption of the K+ channel gene Kv1.4 and compared Ito in wild-type (Kv1.4+/+), heterozygous (Kv1.4+/-) and homozygous ‘knockout’ (Kv1.4−/−) mice. Kv1.4 RNA was truncated in Kv1.4−/− mice and protein expression was absent.Adult myocytes isolated from Kv1.4+/+, Kv1.4+/− and Kv1.4−/− mice had large rapidly inactivating outward currents. The peak current densities at 60 mV (normalized by cellular capacitance, in pA pF−1; means ± s.e.m.) were 53.8 ± 5.3, 45.3 ± 2.2 and 44.4 ± 2.8 in cells from Kv1.4+/+, Kv1.4+/− and Kv1.4−/− mice, respectively (P mice.The voltage dependence and time course of inactivation were not changed by targeted disruption of Kv1.4. The mean best-fitting V½ (membrane potential at 50 % inactivation) values for myocytes from Kv1.4 +/+, Kv1.4+/− and Kv1.4−/− mice were -53.5 ± 3.7, -51.1 ± 2.6 and -54.2 ± 2.4 mV, respectively. The slope factors (k) were -10.1 ± 1.4, -8.8 ± 1.4 and -9.5 ± 1.2 mV, respectively. The fast time constants for development of inactivation at -30 mV were 27.8 ± 2.2, 26.2 ± 5.1 and 19.6 ± 2.1 ms in Kv1.4+/+, Kv1.4+/− and Kv1.4−/− myocytes, respectively. At +30 mV, they were 35.5 ± 2.6, 30.0 ± 2.1 and 28.7 ± 1.6 ms, respectively. The time constants for the rapid phase of recovery from inactivation at -80 mV were 32.5 ± 8.2, 23.3 ± 1.8 and 39.0 ± 3.7 ms, respectively.Nearly the entire inactivating component as well as more than 60 % of the steady-state outward current was eliminated by 1 mm 4-aminopyridine in Kv1.4+/+, Kv1.4+/− and Kv1.4−/− myocytes.Western blot analysis of heart membrane extracts showed no significant

  20. Kuifjes katholieke jeugd. De katholieke achtergrond van Hergé. Deel 1 van 2

    OpenAIRE

    de Groot, C.N.

    2013-01-01

    Following the launch of Steven Spielberg’s ‘Tintin and the Secret of the Unicorn’, l’Osservore Romano hailed Tintin as a ‘catholic hero’. This article demonstrates that the comic originates, more specifically, in conservative and reactionary milieus in Belgian Catholicism. Hergé (ps. for Georges Rémi) designed Tintin for the children’s weekly of a newspaper that, in this period, shared its main themes with the Catholic fascist movement Rex: anti-communism, anti-capitalism, anti-semitism and t...

  1. Automated Electrophysiology Makes the Pace for Cardiac Ion Channel Safety Screening

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    Clemens eMoeller

    2011-11-01

    Full Text Available The field of automated patch-clamp electrophysiology has emerged from the tension between the pharmaceutical industry’s need for high-throughput compound screening versus its need to be conservative due to regulatory requirements. On the one hand, hERG channel screening was increasingly requested for new chemical entities, as the correlation between blockade of the ion channel coded by hERG and Torsades de Pointes cardiac arrhythmia gained increasing attention. On the other hand, manual patch-clamping, typically quoted as the gold-standard for understanding ion channel function and modulation, was far too slow (and, consequently, too expensive for keeping pace with the numbers of compounds submitted for hERG channel investigations from pharmaceutical R&D departments. In consequence it became more common for some pharmaceutical companies to outsource safety pharmacological investigations, with a focus on hERG channel interactions. This outsourcing has allowed those pharmaceutical companies to build up operational flexibility and greater independence from internal resources, and allowed them to obtain access to the latest technological developments that emerged in automated patch-clamp electrophysiology – much of which arose in specialized biotech companies. Assays for nearly all major cardiac ion channels are now available by automated patch-clamping using heterologous expression systems, and recently, automated action potential recordings from stem-cell derived cardiomyocytes have been demonstrated. Today, most of the large pharmaceutical companies have acquired automated electrophysiology robots and have established various automated cardiac ion channel safety screening assays on these, in addition to outsourcing parts of their needs for safety screening.

  2. hERG classification model based on a combination of support vector machine method and GRIND descriptors

    DEFF Research Database (Denmark)

    Li, Qiyuan; Jorgensen, Flemming Steen; Oprea, Tudor

    2008-01-01

    and diverse library of 495 compounds. The models combine pharmacophore-based GRIND descriptors with a support vector machine (SVM) classifier in order to discriminate between hERG blockers and nonblockers. Our models were applied at different thresholds from 1 to 40 mu m and achieved an overall accuracy up...

  3. Hergé, Tintín y la medicina

    OpenAIRE

    Álvarez Calatayud, Guillermo

    2015-01-01

    Se ha demostrado la validez de la historieta como fuente histórica a la hora de rescatar imágenes, saberes, valores y actitudes frente a la Medicina. El estudio de este medio de comunicación de masas puede proporcionar al historiador una visión privilegiada que ahonde en el conocimiento desde el punto de vista popular del mundo de la Medicina y sus profesionales en una época determinada a través de la creación de los historietistas y la respuesta de sus lectores. La historieta más famosa e in...

  4. Localization of large conductance calcium-activated potassium channels and their effect on calcitonin gene-related peptide release in the rat trigemino-neuronal pathway

    DEFF Research Database (Denmark)

    Wulf-Johansson, H.; Amrutkar, D.V.; Hay-Schmidt, Anders

    2010-01-01

    Large conductance calcium-activated potassium (BK(Ca)) channels are membrane proteins contributing to electrical propagation through neurons. Calcitonin gene-related peptide (CGRP) is a neuropeptide found in the trigeminovascular system (TGVS). Both BK(Ca) channels and CGRP are involved in migrai...

  5. Molecular cloning and analysis of zebrafish voltage-gated sodium channel beta subunit genes: implications for the evolution of electrical signaling in vertebrates

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    Zhong Tao P

    2007-07-01

    Full Text Available Abstract Background Action potential generation in excitable cells such as myocytes and neurons critically depends on voltage-gated sodium channels. In mammals, sodium channels exist as macromolecular complexes that include a pore-forming alpha subunit and 1 or more modulatory beta subunits. Although alpha subunit genes have been cloned from diverse metazoans including flies, jellyfish, and humans, beta subunits have not previously been identified in any non-mammalian species. To gain further insight into the evolution of electrical signaling in vertebrates, we investigated beta subunit genes in the teleost Danio rerio (zebrafish. Results We identified and cloned single zebrafish gene homologs for beta1-beta3 (zbeta1-zbeta3 and duplicate genes for beta4 (zbeta4.1, zbeta4.2. Sodium channel beta subunit loci are similarly organized in fish and mammalian genomes. Unlike their mammalian counterparts, zbeta1 and zbeta2 subunit genes display extensive alternative splicing. Zebrafish beta subunit genes and their splice variants are differentially-expressed in excitable tissues, indicating tissue-specific regulation of zbeta1-4 expression and splicing. Co-expression of the genes encoding zbeta1 and the zebrafish sodium channel alpha subunit Nav1.5 in Chinese Hamster Ovary cells increased sodium current and altered channel gating, demonstrating functional interactions between zebrafish alpha and beta subunits. Analysis of the synteny and phylogeny of mammalian, teleost, amphibian, and avian beta subunit and related genes indicated that all extant vertebrate beta subunits are orthologous, that beta2/beta4 and beta1/beta3 share common ancestry, and that beta subunits are closely related to other proteins sharing the V-type immunoglobulin domain structure. Vertebrate sodium channel beta subunit genes were not identified in the genomes of invertebrate chordates and are unrelated to known subunits of the para sodium channel in Drosophila. Conclusion The

  6. The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels.

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    Ting-Feng Lin

    Full Text Available Eag (Kv10 and Erg (Kv11 belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH. While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1 and human Erg (hERG1 channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4-S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels.

  7. Patients with Long QT Syndrome Due to Impaired hERG-encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated with Reactive Hypoglycemia

    DEFF Research Database (Denmark)

    Hyltén-Cavallius, Louise; Iepsen, Eva W; Wewer Albrechtsen, Nicolai J

    2017-01-01

    Background -Loss-of-function mutations in hERG (encoding the Kv11.1 voltage-gated potassium channel) cause long QT syndrome (LQT2) due to prolonged cardiac repolarization. However, Kv11.1 is also present in pancreatic α and β cells and intestinal L and K cells, secreting glucagon, insulin, and th...

  8. Characterization of potassium channel modulators with QPatch automated patch-clamp technology: system characteristics and performance

    DEFF Research Database (Denmark)

    Kutchinsky, Jonatan; Friis, Søren; Asmild, Margit

    2003-01-01

    Planar silicon chips with 1-2-microm etched holes (average resistance: 2.04 +/- 0.02 MOmega in physiological buffer, n = 274) have been developed for patch-clamp recordings of whole-cell currents from cells in suspension. An automated 16-channel parallel screening system, QPatch 16, has been deve......-response relationship characterizations of verapamil and rBeKm-1 blockage of hERG currents provided IC(50) values similar to values reported in the literature....

  9. Parallel evolution of tetrodotoxin resistance in three voltage-gated sodium channel genes in the garter snake Thamnophis sirtalis.

    Science.gov (United States)

    McGlothlin, Joel W; Chuckalovcak, John P; Janes, Daniel E; Edwards, Scott V; Feldman, Chris R; Brodie, Edmund D; Pfrender, Michael E; Brodie, Edmund D

    2014-11-01

    Members of a gene family expressed in a single species often experience common selection pressures. Consequently, the molecular basis of complex adaptations may be expected to involve parallel evolutionary changes in multiple paralogs. Here, we use bacterial artificial chromosome library scans to investigate the evolution of the voltage-gated sodium channel (Nav) family in the garter snake Thamnophis sirtalis, a predator of highly toxic Taricha newts. Newts possess tetrodotoxin (TTX), which blocks Nav's, arresting action potentials in nerves and muscle. Some Thamnophis populations have evolved resistance to extremely high levels of TTX. Previous work has identified amino acid sites in the skeletal muscle sodium channel Nav1.4 that confer resistance to TTX and vary across populations. We identify parallel evolution of TTX resistance in two additional Nav paralogs, Nav1.6 and 1.7, which are known to be expressed in the peripheral nervous system and should thus be exposed to ingested TTX. Each paralog contains at least one TTX-resistant substitution identical to a substitution previously identified in Nav1.4. These sites are fixed across populations, suggesting that the resistant peripheral nerves antedate resistant muscle. In contrast, three sodium channels expressed solely in the central nervous system (Nav1.1-1.3) showed no evidence of TTX resistance, consistent with protection from toxins by the blood-brain barrier. We also report the exon-intron structure of six Nav paralogs, the first such analysis for snake genes. Our results demonstrate that the molecular basis of adaptation may be both repeatable across members of a gene family and predictable based on functional considerations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  10. Effect of nutrient restriction and re-feeding on calpain family genes in skeletal muscle of channel catfish (Ictalurus punctatus.

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    Elena Preziosa

    Full Text Available BACKGROUND: Calpains, a superfamily of intracellular calcium-dependent cysteine proteases, are involved in the cytoskeletal remodeling and wasting of skeletal muscle. Calpains are generated as inactive proenzymes which are activated by N-terminal autolysis induced by calcium-ions. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we characterized the full-length cDNA sequences of three calpain genes, clpn1, clpn2, and clpn3 in channel catfish, and assessed the effect of nutrient restriction and subsequent re-feeding on the expression of these genes in skeletal muscle. The clpn1 cDNA sequence encodes a protein of 704 amino acids, Clpn2 of 696 amino acids, and Clpn3 of 741 amino acids. Phylogenetic analysis of deduced amino acid sequences indicate that catfish Clpn1 and Clpn2 share a sequence similarity of 61%; catfish Clpn1 and Clpn3 of 48%, and Clpn2 and Clpn3 of only 45%. The domain structure architectures of all three calpain genes in channel catfish are similar to those of other vertebrates, further supported by strong bootstrap values during phylogenetic analyses. Starvation of channel catfish (average weight, 15-20 g for 35 days influenced the expression of clpn1 (2.3-fold decrease, P<0.05, clpn2 (1.3-fold increase, P<0.05, and clpn3 (13.0-fold decrease, P<0.05, whereas the subsequent refeeding did not change the expression of these genes as measured by quantitative real-time PCR analysis. Calpain catalytic activity in channel catfish skeletal muscle showed significant differences only during the starvation period, with a 1.2- and 1.4- fold increase (P<0.01 after 17 and 35 days of starvation, respectively. CONCLUSION/SIGNIFICANCE: We have assessed that fasting and refeeding may provide a suitable experimental model to provide us insight into the role of calpains during fish muscle atrophy and how they respond to changes in nutrient supply.

  11. Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia.

    Science.gov (United States)

    Kane, Garvan C; Lam, Chen-Fuh; O'Cochlain, Fearghas; Hodgson, Denice M; Reyes, Santiago; Liu, Xiao-Ke; Miki, Takashi; Seino, Susumu; Katusic, Zvonimir S; Terzic, Andre

    2006-11-01

    Sepsis, the systemic inflammatory response to infection, imposes a high demand for bodily adaptation, with the cardiovascular response a key determinant of outcome. The homeostatic elements that secure cardiac tolerance in the setting of the sepsis syndrome are poorly understood. Here, in a model of acute septic shock induced by endotoxin challenge with Escherichia coli lipopolysaccharide (LPS), knockout of the KCNJ8 gene encoding the vascular Kir6.1 K(ATP) channel pore predisposed to an early and profound survival disadvantage. The exaggerated susceptibility provoked by disruption of this stress-responsive sensor of cellular metabolism was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction. Deletion of KCNJ8 blunted the responsiveness of coronary vessels to cytokine- or metabolic-mediated vasodilation necessary to support myocardial perfusion in the wild-type (WT), creating a deficit in adaptive response in the Kir6.1 knockout. Application of a K(ATP) channel opener drug improved survival in the endotoxic WT but had no effect in the Kir6.1 knockout. Restoration of the dilatory capacity of coronary vessels was required to rescue the Kir6.1 knockout phenotype and reverse survival disadvantage in lethal endotoxemia. Thus, the Kir6.1-containing K(ATP) channel, by coupling vasoreactivity with metabolic demand, provides a vital feedback element for cardiovascular tolerance in endotoxic shock.

  12. Systematic and quantitative mRNA expression analysis of TRP channel genes at the single trigeminal and dorsal root ganglion level in mouse

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    Vandewauw Ine

    2013-02-01

    Full Text Available Abstract Background Somatosensory nerve fibres arising from cell bodies within the trigeminal ganglia (TG in the head and from a string of dorsal root ganglia (DRG located lateral to the spinal cord convey endogenous and environmental stimuli to the central nervous system. Although several members of the transient receptor potential (TRP superfamily of cation channels have been implicated in somatosensation, the expression levels of TRP channel genes in the individual sensory ganglia have never been systematically studied. Results Here, we used quantitative real-time PCR to analyse and compare mRNA expression of all TRP channels in TG and individual DRGs from 27 anatomically defined segments of the spinal cord of the mouse. At the mRNA level, 17 of the 28 TRP channel genes, TRPA1, TRPC1, TRPC3, TRPC4, TRPC5, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV4, TRPML1 and TRPP2, were detectable in every tested ganglion. Notably, four TRP channels, TRPC4, TRPM4, TRPM8 and TRPV1, showed statistically significant variation in mRNA levels between DRGs from different segments, suggesting ganglion-specific regulation of TRP channel gene expression. These ganglion-to-ganglion differences in TRP channel transcript levels may contribute to the variability in sensory responses in functional studies. Conclusions We developed, compared and refined techniques to quantitatively analyse the relative mRNA expression of all TRP channel genes at the single ganglion level. This study also provides for the first time a comparative mRNA distribution profile in TG and DRG along the entire vertebral column for the mammalian TRP channel family.

  13. Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat.

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    Schuhmacher, Laura-Nadine; Smith, Ewan St John

    2016-12-13

    Acid-sensing ion channels (ASICs) are a family of ion channels comprised of six subunits encoded by four genes and they are expressed throughout the peripheral and central nervous systems. ASICs have been implicated in a wide range of physiological and pathophysiological processes: pain, breathing, synaptic plasticity and excitotoxicity. Unlike mice and humans, naked mole-rats do not perceive acid as a noxious stimulus, even though their sensory neurons express functional ASICs, likely an adaptation to living in a hypercapnic subterranean environment. Previous studies of ASIC expression in the mammalian nervous system have often not examined all subunits, or have failed to adequately quantify expression between tissues; to date there has been no attempt to determine ASIC expression in the central nervous system of the naked mole-rat. Here we perform a geNorm study to identify reliable housekeeping genes in both mouse and naked mole-rat and then use quantitative real-time PCR to estimate the relative amounts of ASIC transcripts in different tissues of both species. We identify RPL13A (ribosomal protein L13A) and CANX (calnexin), and β-ACTIN and EIF4A (eukaryotic initiation factor 4a) as being the most stably expressed housekeeping genes in mouse and naked mole-rat, respectively. In both species, ASIC3 was most highly expressed in dorsal root ganglia (DRG), and ASIC1a, ASIC2b and ASIC3 were more highly expressed across all brain regions compared to the other subunits. We also show that ASIC4, a proton-insensitive subunit of relatively unknown function, was highly expressed in all mouse tissues apart from DRG and hippocampus, but was by contrast the lowliest expressed ASIC in all naked mole-rat tissues.

  14. A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia

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    Vargas-Alarcon Gilberto

    2012-02-01

    Full Text Available Abstract Background A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM; and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7 act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms. Methods We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ. Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637. Results The frequency of the rs6754031 polymorphism was significantly different in both groups (P = 0.036 mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88 than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; P = 0.002 and the TT genotype (median = 71; percentile 25/75 = 64/77; P = 0.001. Conclusion In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that

  15. A deleterious gene-by-environment interaction imposed by calcium channel blockers in Marfan syndrome.

    Science.gov (United States)

    Doyle, Jefferson J; Doyle, Alexander J; Wilson, Nicole K; Habashi, Jennifer P; Bedja, Djahida; Whitworth, Ryan E; Lindsay, Mark E; Schoenhoff, Florian; Myers, Loretha; Huso, Nick; Bachir, Suha; Squires, Oliver; Rusholme, Benjamin; Ehsan, Hamid; Huso, David; Thomas, Craig J; Caulfield, Mark J; Van Eyk, Jennifer E; Judge, Daniel P; Dietz, Harry C

    2015-10-27

    Calcium channel blockers (CCBs) are prescribed to patients with Marfan syndrome for prophylaxis against aortic aneurysm progression, despite limited evidence for their efficacy and safety in the disorder. Unexpectedly, Marfan mice treated with CCBs show accelerated aneurysm expansion, rupture, and premature lethality. This effect is both extracellular signal-regulated kinase (ERK1/2) dependent and angiotensin-II type 1 receptor (AT1R) dependent. We have identified protein kinase C beta (PKCβ) as a critical mediator of this pathway and demonstrate that the PKCβ inhibitor enzastaurin, and the clinically available anti-hypertensive agent hydralazine, both normalize aortic growth in Marfan mice, in association with reduced PKCβ and ERK1/2 activation. Furthermore, patients with Marfan syndrome and other forms of inherited thoracic aortic aneurysm taking CCBs display increased risk of aortic dissection and need for aortic surgery, compared to patients on other antihypertensive agents.

  16. BDNF gene delivery within and beyond templated agarose multi-channel guidance scaffolds enhances peripheral nerve regeneration

    Science.gov (United States)

    Gao, Mingyong; Lu, Paul; Lynam, Dan; Bednark, Bridget; Campana, W. Marie; Sakamoto, Jeff; Tuszynski, Mark

    2016-12-01

    Objective. We combined implantation of multi-channel templated agarose scaffolds with growth factor gene delivery to examine whether this combinatorial treatment can enhance peripheral axonal regeneration through long sciatic nerve gaps. Approach. 15 mm long scaffolds were templated into highly organized, strictly linear channels, mimicking the linear organization of natural nerves into fascicles of related function. Scaffolds were filled with syngeneic bone marrow stromal cells (MSCs) secreting the growth factor brain derived neurotrophic factor (BDNF), and lentiviral vectors expressing BDNF were injected into the sciatic nerve segment distal to the scaffold implantation site. Main results. Twelve weeks after injury, scaffolds supported highly linear regeneration of host axons across the 15 mm lesion gap. The incorporation of BDNF-secreting cells into scaffolds significantly increased axonal regeneration, and additional injection of viral vectors expressing BDNF into the distal segment of the transected nerve significantly enhanced axonal regeneration beyond the lesion. Significance. Combinatorial treatment with multichannel bioengineered scaffolds and distal growth factor delivery significantly improves peripheral nerve repair, rivaling the gold standard of autografts.

  17. The role of the potassium channel gene KCNK2 in major depressive disorder.

    Science.gov (United States)

    Congiu, Chiara; Minelli, Alessandra; Bonvicini, Cristian; Bortolomasi, Marco; Sartori, Riccardo; Maj, Carlo; Scassellati, Catia; Maina, Giuseppe; Trabucchi, Luigi; Segala, Matilde; Gennarelli, Massimo

    2015-02-28

    Six single nucleotide polymorphisms (SNPs) of the KCNK2 gene were investigated for their association with major depressive disorder (MDD) and treatment efficacy in 590 MDD patients and 441 controls. The A homozygotes of rs10779646 were significantly more frequent in patients than controls whereas G allele of rs7549184 was associated with the presence of psychotic symptoms and the severity of disease. Evaluating the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) dataset, we confirmed our findings. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Identification of Chloride Intracellular Channel Protein 3 as a Novel Gene Affecting Human Bone Formation

    DEFF Research Database (Denmark)

    Brum, A M; Leije, M; J, Schreuders-Koedam

    2017-01-01

    is diminished and more adipocytes are seen in the bone marrow, suggesting a shift in MSC lineage commitment. Identification of specific factors that stimulate osteoblast differentiation from human MSCs may deliver therapeutic targets to treat osteoporosis. The aim of this study was to identify novel genes...... an in vivo human bone formation model in which hMSCs lentivirally transduced with the CLIC3 overexpression construct were loaded onto a scaffold (hydroxyapatite-tricalcium-phosphate), implanted under the skin of NOD-SCID mice, and analyzed for bone formation 8 weeks later. CLIC3 overexpression led to a 15...

  19. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    International Nuclear Information System (INIS)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

    2013-01-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

  20. Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

    Energy Technology Data Exchange (ETDEWEB)

    Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

    2013-12-01

    The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na{sub v}1.5 sodium and Ca{sub v}1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on

  1. Thyrotoxic periodic paralysis associated with a mutation in the sodium channel gene SCN4A.

    Science.gov (United States)

    Lane, Andrew H; Markarian, Katherine; Braziunene, Ieva

    2004-12-01

    Thyrotoxic hypokalemic periodic paralysis (THypoKPP) is an uncommon disorder with an unknown etiology. We describe a family in which the proband presented with paralysis and thyrotoxicosis. Because of similarities between familial hypokalemic periodic paralysis (FHypoKPP) and THypoKPP, we sequenced exon 12 of the SCN4A gene, which is known to be mutated in FHypoKPP. We identified an Arg672Ser mutation in the proband and his affected father, as well as the proband's brother. As the brother has paralysis without thyrotoxicosis, our finding suggests that the genetic spectrum of FHypoKPP and THypoKPP overlap. We speculate that thyroid hormone may exert a threshold or permissive effect in hypokalemic periodic paralysis. Non-thyrotoxic family members of individuals with THypoKPP may have an unrecognized risk for paralysis.

  2. Electric organ discharge diversification in mormyrid weakly electric fish is associated with differential expression of voltage-gated ion channel genes.

    Science.gov (United States)

    Nagel, Rebecca; Kirschbaum, Frank; Tiedemann, Ralph

    2017-03-01

    In mormyrid weakly electric fish, the electric organ discharge (EOD) is used for species recognition, orientation and prey localization. Produced in the muscle-derived adult electric organ, the EOD exhibits a wide diversity across species in both waveform and duration. While certain defining EOD characteristics can be linked to anatomical features of the electric organ, many factors underlying EOD differentiation are yet unknown. Here, we report the differential expression of 13 Kv1 voltage-gated potassium channel genes, two inwardly rectifying potassium channel genes, two previously studied sodium channel genes and an ATPase pump in two sympatric species of the genus Campylomormyrus in both the adult electric organ and skeletal muscle. Campylomormyrus compressirostris displays a basal EOD, largely unchanged during development, while C. tshokwe has an elongated, putatively derived discharge. We report an upregulation in all Kv1 genes in the electric organ of Campylomormyrus tshokwe when compared to both skeletal muscle and C. compressirostris electric organ. This pattern of upregulation in a species with a derived EOD form suggests that voltage-gated potassium channels are potentially involved in the diversification of the EOD signal among mormyrid weakly electric fish.

  3. Salt Sensitive Tet-Off-Like Systems to Knockdown Primordial Germ Cell Genes for Repressible Transgenic Sterilization in Channel Catfish, Ictalurus punctatus.

    Science.gov (United States)

    Li, Hanbo; Su, Baofeng; Qin, Guyu; Ye, Zhi; Alsaqufi, Ahmed; Perera, Dayan A; Shang, Mei; Odin, Ramjie; Vo, Khoi; Drescher, David; Robinson, Dalton; Zhang, Dan; Abass, Nermeen; Dunham, Rex A

    2017-05-31

    Repressible knockdown approaches were investigated for transgenic sterilization in channel catfish, Ictalurus punctatus . Two primordial germ cell (PGC) marker genes, nanos and dead end , were targeted for knockdown, and an off-target gene, vasa , was monitored. Two potentially salt sensitive repressible promoters, zebrafish adenylosuccinate synthase 2 (ADSS) and zebrafish racemase (Rm), were each coupled with four knockdown strategies: ds-sh RNA targeting the 5' end (N1) or 3' end (N2) of channel catfish nanos , full-length cDNA sequence of channel catfish nanos for overexpression (cDNA) and ds-sh RNA targeting channel catfish dead end (DND). Each construct had an untreated group and treated group with sodium chloride as the repressor compound. Spawning rates of full-sibling P₁ fish exposed or not exposed to the constructs as treated and untreated embryos were 93% and 59%, respectively, indicating potential sterilization of fish and repression of the constructs. Although the mRNA expression data of PGC marker genes were inconsistent in P₁ fish, most F₁ individuals were able to downregulate the target genes in untreated groups and repress the knockdown process in treated groups. The results indicate that repressible transgenic sterilization is feasible for reproductive control of fish, but more data from F₂ or F₃ are needed for evaluation.

  4. Salt Sensitive Tet-Off-Like Systems to Knockdown Primordial Germ Cell Genes for Repressible Transgenic Sterilization in Channel Catfish, Ictalurus punctatus

    Directory of Open Access Journals (Sweden)

    Hanbo Li

    2017-05-01

    Full Text Available Repressible knockdown approaches were investigated for transgenic sterilization in channel catfish, Ictalurus punctatus. Two primordial germ cell (PGC marker genes, nanos and dead end, were targeted for knockdown, and an off-target gene, vasa, was monitored. Two potentially salt sensitive repressible promoters, zebrafish adenylosuccinate synthase 2 (ADSS and zebrafish racemase (Rm, were each coupled with four knockdown strategies: ds-sh RNA targeting the 5′ end (N1 or 3′ end (N2 of channel catfish nanos, full-length cDNA sequence of channel catfish nanos for overexpression (cDNA and ds-sh RNA targeting channel catfish dead end (DND. Each construct had an untreated group and treated group with sodium chloride as the repressor compound. Spawning rates of full-sibling P1 fish exposed or not exposed to the constructs as treated and untreated embryos were 93% and 59%, respectively, indicating potential sterilization of fish and repression of the constructs. Although the mRNA expression data of PGC marker genes were inconsistent in P1 fish, most F1 individuals were able to downregulate the target genes in untreated groups and repress the knockdown process in treated groups. The results indicate that repressible transgenic sterilization is feasible for reproductive control of fish, but more data from F2 or F3 are needed for evaluation.

  5. hERG blocking potential of acids and zwitterions characterized by three thresholds for acidity, size and reactivity

    DEFF Research Database (Denmark)

    Nikolov, Nikolai Georgiev; Dybdahl, Marianne; Jonsdottir, Svava Osk

    2014-01-01

    with a concordance of 91% by a decision tree based on the rule. Two external validations were performed with sets of 35 and 48 observations, respectively, both showing concordances of 91%. In addition, a global QSAR model of hERG blocking was constructed based on a large diverse training set of 1374 chemicals...... covering all ionization classes, externally validated showing high predictivity and compared to the decision tree. The decision tree was found to be superior for the acids and zwitterionic ampholytes classes....

  6. ATP sensitive potassium channels in the skeletal muscle functions : involvement of the KCNJ11(Kir6.2 gene in the determination of Warner Bratzer shear force

    Directory of Open Access Journals (Sweden)

    Domenico eTricarico

    2016-05-01

    Full Text Available The ATP-sensitive K+-channels (KATP are distributed in the tissues coupling metabolism with K+ ions efflux. KATP subunits are encoded by KCNJ8 (Kir6.1, KCNJ11 (Kir6.2, ABCC8 (SUR1 and ABCC9 (SUR2 genes, alternative RNA splicing give rise to SUR variants that confer distinct physiological properties on the channel. An high expression/activity of the sarco-KATP channel is observed in various rat fast-twitch muscles, characterized by elevated muscle strength, while a low expression/activity is observed in the slow-twitch muscles characterized by reduced strength and frailty. Down-regulation of the KATP subunits of fast-twitch fibres is found in conditions characterized by weakness and frailty. KCNJ11 gene knockout mice have reduced glycogen, lean phenotype, lower body fat, and weakness. KATP channel is also a sensor of muscle atrophy. The KCNJ11 gene is located on BTA15, close to a QTL for meat tenderness, it has also a role in glycogen storage, a key mechanism of the postmortem transformation of muscle into meat. The role of KCNJ11 gene in muscle function may underlie an effect of KCNJ11 genotypes on meat tenderness, as recently reported. The fiber phenotype and genotype are important in livestock production science. Quantitative traits including meat production and quality are influenced both by environment and genes. Molecular markers can play an important role in the genetic improvement of animals through breeding strategies. Many factors influence the muscle Warner-Bratzler shear force including breed, age, feeding, the biochemical and functional parameters. The role of KCNJ11gene and related genes on muscle tenderness will be discussed in the present review.

  7. Knockdown resistance (kdr) of the voltage-gated sodium channel gene of Aedes aegypti population in Denpasar, Bali, Indonesia.

    Science.gov (United States)

    Hamid, Penny Humaidah; Prastowo, Joko; Widyasari, Anis; Taubert, Anja; Hermosilla, Carlos

    2017-06-05

    Aedes aegypti is the main vector of several arthropod-borne viral infections in the tropics profoundly affecting humans, such as dengue fever (DF), West Nile (WN), chikungunya and more recently Zika. Eradication of Aedes still largely depends on insecticides, which is the most cost-effective strategy, and often inefficient due to resistance development in exposed Aedes populations. We here conducted a study of Ae. aegypti resistance towards several insecticides regularly used in the city of Denpasar, Bali, Indonesia. Aedes aegypti egg samples were collected with ovitraps and thereafter hatched in the insectary of the Gadjah Mada University. The F0 generation was used for all bioassay-related experiments and knockdown resistance (kdr) assays. Results clearly showed resistance development of Ae. aegypti against tested insecticides. Mortalities of Ae. aegypti were less than 90% with highest resistance observed against 0.75% permethrin. Mosquitoes from the southern parts of Denpasar presented high level of resistance pattern in comparison to those from the western and northern parts of Denpasar. Kdr analysis of voltage-gated sodium channel (Vgsc) gene showed significant association to S989P and V1016G mutations linked to resistance phenotypes against 0.75% permethrin. Conversely, Ae. aegypti F1534C gene mutation did not result in any significant correlation to resistance development. Periodically surveillance of insecticide resistances in Ae. aegypti mosquitoes will help local public health authorities to set better goals and allow proper evaluation of on-going mosquito control strategies. Initial detection of insecticide resistance will contribute to conduct proper actions in delaying mosquito resistance development such as insecticide rotation or combination of compounds in order to prolong chemical efficacy in combating Ae. aegypti vectors in Indonesia.

  8. HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner.

    Science.gov (United States)

    Pai, Vaibhav P; Willocq, Valerie; Pitcairn, Emily J; Lemire, Joan M; Paré, Jean-François; Shi, Nian-Qing; McLaughlin, Kelly A; Levin, Michael

    2017-10-15

    Laterality is a basic characteristic of all life forms, from single cell organisms to complex plants and animals. For many metazoans, consistent left-right asymmetric patterning is essential for the correct anatomy of internal organs, such as the heart, gut, and brain; disruption of left-right asymmetry patterning leads to an important class of birth defects in human patients. Laterality functions across multiple scales, where early embryonic, subcellular and chiral cytoskeletal events are coupled with asymmetric amplification mechanisms and gene regulatory networks leading to asymmetric physical forces that ultimately result in distinct left and right anatomical organ patterning. Recent studies have suggested the existence of multiple parallel pathways regulating organ asymmetry. Here, we show that an isoform of the hyperpolarization-activated cyclic nucleotide-gated (HCN) family of ion channels (hyperpolarization-activated cyclic nucleotide-gated channel 4, HCN4) is important for correct left-right patterning. HCN4 channels are present very early in Xenopus embryos. Blocking HCN channels ( I h currents) with pharmacological inhibitors leads to errors in organ situs. This effect is only seen when HCN4 channels are blocked early (pre-stage 10) and not by a later block (post-stage 10). Injections of HCN4-DN (dominant-negative) mRNA induce left-right defects only when injected in both blastomeres no later than the 2-cell stage. Analysis of key asymmetric genes' expression showed that the sidedness of Nodal , Lefty , and Pitx2 expression is largely unchanged by HCN4 blockade, despite the randomization of subsequent organ situs, although the area of Pitx2 expression was significantly reduced. Together these data identify a novel, developmental role for HCN4 channels and reveal a new Nodal-Lefty-Pitx2 asymmetric gene expression-independent mechanism upstream of organ positioning during embryonic left-right patterning. © 2017. Published by The Company of Biologists Ltd.

  9. "A Nightmare Land, a Place of Death": An Exploration of the Moon as a Motif in Herge's "Destination Moon" (1953) and "Explorers on the Moon" (1954)

    Science.gov (United States)

    Beauvais, Clementine

    2010-01-01

    This article analyses the symbolic meaning of the Moon in two "bande dessinee" books from the Tintin series, Herge's "Destination Moon" ("Objectif Lune," 1953) and its sequel "Explorers on the Moon" ("On a Marche sur la Lune," 1954). It argues that these two volumes stand out in the series for their graphic, narrative and philosophical emphasis on…

  10. Caco-2 Permeability Studies and In Vitro hERG Liability Assessment of Tryptanthrin and Indolinone.

    Science.gov (United States)

    Jähne, Evelyn A; Eigenmann, Daniela E; Moradi-Afrapoli, Fahimeh; Verjee, Sheela; Butterweck, Veronika; Hebeisen, Simon; Hettich, Timm; Schlotterbeck, Götz; Smieško, Martin; Hamburger, Matthias; Oufir, Mouhssin

    2016-08-01

    Tryptanthrin and (E,Z)-3-(4-hydroxy-3,5-dimethoxybenzylidene)indolinone (indolinone) were recently isolated from Isatis tinctoria as potent anti-inflammatory and antiallergic alkaloids, and shown to inhibit COX-2, 5-LOX catalyzed leukotriene synthesis, and mast cell degranulation at low µM to nM concentrations. To assess their suitability for oral administration, we screened the compounds in an in vitro intestinal permeability assay using human colonic adenocarcinoma cells. For exact quantification of the compounds, validated UPLC-MS/MS methods were used. Tryptanthrin displayed high permeability (apparent permeability coefficient > 32.0 × 10(-6) cm/s) across the cell monolayer. The efflux ratio below 2 ( 10 µM) and indolinone (IC50 of 24.96 µM). The analysis of compounds using various in silico methods confirmed favorable pharmacokinetic properties, as well as a slight inhibition of the human ether-a-go-go-related gene potassium channel at micromolar concentrations. Georg Thieme Verlag KG Stuttgart · New York.

  11. The gene for the alpha 1 subunit of the skeletal muscle dihydropyridine-sensitive calcium channel (Cchl1a3) maps to mouse chromosome 1.

    Science.gov (United States)

    Chin, H; Krall, M; Kim, H L; Kozak, C A; Mock, B

    1992-12-01

    Cchl1a3 encodes the dihydropyridine-sensitive calcium channel alpha 1 subunit isoform predominantly expressed in skeletal muscle. mdg (muscular dysgenesis) has previously been implicated as a mutant allele of this gene. Hybridization of a rat brain cDNA probe for Cchl1a3 to Southern blots of DNAs from a panel of Chinese hamster x mouse somatic cell hybrids suggested that this gene maps to mouse Chromosome 1. Analysis of the progeny of an inbred strain cross-positioned Cchl1a3 1.3 cM proximal to the Pep-3 locus on Chr 1.

  12. Loss of functional K+ channels encoded by ether-à-go-go-related genes in mouse myometrium prior to labour onset

    Science.gov (United States)

    Greenwood, I A; Yeung, S Y; Tribe, R M; Ohya, S

    2009-01-01

    There is a growing appreciation that ion channels encoded by the ether-à-go-go-related gene family have a functional impact in smooth muscle in addition to their accepted role in cardiac myocytes and neurones. This study aimed to assess the expression of ERG1–3 (KCNH1–3) genes in the murine myometrium (smooth muscle layer of the uterus) and determine the functional impact of the ion channels encoded by these genes in pregnant and non-pregnant animals. Quantitative RT-PCR did not detect message for ERG2 and 3 in whole myometrial tissue extracts. In contrast, message for two isoforms of mERG1 were readily detected with mERG1a more abundant than mERG1b. In isometric tension studies of non-pregnant myometrium, the ERG channel blockers dofetilide (1 μm), E4031 (1 μm) and Be-KM1 (100 nm) increased spontaneous contractility and ERG activators (PD118057 and NS1643) inhibited spontaneous contractility. In contrast, neither ERG blockade nor activation had any effect on the inherent contractility in myometrium from late pregnant (19 days gestation) animals. Moreover, dofetilide-sensitive K+ currents with distinctive ‘hooked’ kinetics were considerably smaller in uterine myocytes from late pregnant compared to non-pregnant animals. Expression of mERG1 isoforms did not alter throughout gestation or upon delivery, but the expression of genes encoding auxillary subunits (KCNE) were up-regulated considerably. This study provides the first evidence for a regulation of ERG-encoded K+ channels as a precursor to late pregnancy physiological activity. PMID:19332483

  13. GAPDH-mediated posttranscriptional regulations of sodium channel Scn1a and Scn3a genes under seizure and ketogenic diet conditions.

    Science.gov (United States)

    Lin, Guo-Wang; Lu, Ping; Zeng, Tao; Tang, Hui-Ling; Chen, Yong-Hong; Liu, Shu-Jing; Gao, Mei-Mei; Zhao, Qi-Hua; Yi, Yong-Hong; Long, Yue-Sheng

    2017-02-01

    Abnormal expressions of sodium channel SCN1A and SCN3A genes alter neural excitability that are believed to contribute to the pathogenesis of epilepsy, a long-term risk of recurrent seizures. Ketogenic diet (KD), a high-fat and low-carbohydrate treatment for difficult-to-control (refractory) epilepsy in children, has been suggested to reverse gene expression patterns. Here, we reveal a novel role of GAPDH on the posttranscriptional regulation of mouse Scn1a and Scn3a expressions under seizure and KD conditions. We show that GAPDH binds to a conserved region in the 3' UTRs of human and mouse SCN1A and SCN3A genes, which decreases and increases genes' expressions by affecting mRNA stability through SCN1A 3' UTR and SCN3A 3' UTR, respectively. In seizure mice, the upregulation and phosphorylation of GAPDH enhance its binding to the 3' UTR, which lead to downregulation of Scn1a and upregulation of Scn3a. Furthermore, administration of KD generates β-hydroxybutyric acid which rescues the abnormal expressions of Scn1a and Scn3a by weakening the GAPDH's binding to the element. Taken together, these data suggest that GAPDH-mediated expression regulation of sodium channel genes may be associated with epilepsy and the anticonvulsant action of KD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Potential role of melastatin-related transient receptor potential cation channel subfamily M gene expression in the pathogenesis of urinary bladder cancer.

    Science.gov (United States)

    Ceylan, Gülay Güleç; Önalan, Ebru Etem; Kuloğlu, Tuncay; Aydoğ, Gülten; Keleş, İbrahim; Tonyali, Şenol; Ceylan, Cavit

    2016-12-01

    Urinary bladder cancer is one of the most common malignancies of the urinary tract. Ion channels and calcium homeostasis are involved in almost all basic cellular mechanisms. The transient receptor potential cation channel subfamily M (TRPM) takes its name from the melastatin protein, which is classified as potential tumor suppressor. To the best of our knowledge, there have been no previous studies in the literature investigating the role of these ion channels in bladder cancer. The present study aimed to determine whether bladder cancer is associated with mRNA expression levels of TRPM ion channel genes, and whether there is the potential to conduct further studies to establish novel treatment modalities. The present study included a total of 47 subjects, of whom 40 were bladder cancer patients and 7 were controls. Following the histopathological evaluation for bladder carcinoma, the mRNA and protein expression of TRPM were examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in tumor and normal tissues, in order to determine whether there is a difference in the expression of these channels in tumor and normal tissues. Immunoreactivity for TRPM2, TRPM4, TRPM7 and TRPM8 was observed in epithelial bladder cells in the two groups. RT-qPCR revealed a significant increase in TRPM7 expression in bladder cancer tissue compared to the controls (healthy bladder tissue), whereas no differences in TRPM2 or TRPM4 expression levels were observed. There were significant reductions in the expression levels of TRPM5 and TRPM8 in bladder cancer tissues. In the present study, the effects of TRP ion channels on the formation of bladder cancer was investigated. This study is instructive for TRPM2, TRPM4, TRPM5, TRPM7 and TRPM8 and their therapeutic role in bladder cancer. The results support the fact that these gens can be novel targets and can also be tested for during the treatment of bladder cancer.

  15. Mutations in the voltage-gated sodium channel gene of anophelines and their association with resistance to pyrethroids - a review.

    Science.gov (United States)

    Silva, Ana Paula B; Santos, Joselita Maria M; Martins, Ademir J

    2014-10-07

    Constant and extensive use of chemical insecticides has created a selection pressure and favored resistance development in many insect species worldwide. One of the most important pyrethroid resistance mechanisms is classified as target site insensitivity, due to conformational changes in the target site that impair a proper binding of the insecticide molecule. The voltage-gated sodium channel (NaV) is the target of pyrethroids and DDT insecticides, used to control insects of medical, agricultural and veterinary importance, such as anophelines. It has been reported that the presence of a few non-silent point mutations in the NaV gene are associated with pyrethroid resistance, termed as 'kdr' (knockdown resistance) for preventing the knockdown effect of these insecticides. The presence of these mutations, as well as their effects, has been thoroughly studied in Anopheles mosquitoes. So far, kdr mutations have already been detected in at least 13 species (Anopheles gambiae, Anopheles arabiensis, Anopheles sinensis, Anopheles stephensi, Anopheles subpictus, Anopheles sacharovi, Anopheles culicifacies, Anopheles sundaicus, Anopheles aconitus, Anopheles vagus, Anopheles paraliae, Anopheles peditaeniatus and Anopheles albimanus) from populations of African, Asian and, more recently, American continents. Seven mutational variants (L1014F, L1014S, L1014C, L1014W, N1013S, N1575Y and V1010L) were described, with the highest prevalence of L1014F, which occurs at the 1014 site in NaV IIS6 domain. The increase of frequency and distribution of kdr mutations clearly shows the importance of this mechanism in the process of pyrethroid resistance. In this sense, several species-specific and highly sensitive methods have been designed in order to genotype individual mosquitoes for kdr in large scale, which may serve as important tolls for monitoring the dynamics of pyrethroid resistance in natural populations. We also briefly discuss investigations concerning the course of Plasmodium

  16. G-protein inwardly rectifying potassium channel 1 (GIRK 1) gene expression correlates with tumor progression in non-small cell lung cancer

    International Nuclear Information System (INIS)

    Takanami, Iwao; Inoue, Yoshimasa; Gika, Masatoshi

    2004-01-01

    G-protein inwardly rectifying potassium channel 1 (GIRK1) is thought to play a role in cell proliferation in cancer, and GIRK1 gene expression level may define a more aggressive phenotype. We detected GIRK1 expression in tissue specimens from patients with non-small cell lung cancers (NSCLCs) and assessed their clinical characteristics. Using reverse transcription-polymerase chain reaction (RT-PCR) analyses, we quantified the expression of GIRK1 in 72 patients with NSCLCs to investigate the relationship between GIRK1 expression and clinicopathologic factors and prognosis. In 72 NSCLC patients, 50 (69%) samples were evaluated as having high GIRK1 gene expression, and 22 (31%) were evaluated as having low GIRK1 gene expression. GIRK1 gene expression was significantly associated with lymph node metastasis, stage (p = 0.0194 for lymph node metastasis; p = 0.0207 for stage). The overall and stage I survival rates for patients with high GIRK1 gene expressed tumors was significantly worse than for those individuals whose tumors had low GIRK1 expression (p = 0.0004 for the overall group; p = 0.0376 for stage I). These data indicate that GIRK1 may contribute to tumor progression and GIRK1 gene expression can serve as a useful prognostic marker in the overall and stage I NSCLCs

  17. Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion

    Science.gov (United States)

    House, Carrie D.; Vaske, Charles J.; Schwartz, Arnold M.; Obias, Vincent; Frank, Bryan; Luu, Truong; Sarvazyan, Narine; Irby, Rosalyn; Strausberg, Robert L.; Hales, Tim G.; Stuart, Joshua M.; Lee, Norman H.

    2010-01-01

    Voltage-gated Na+ channels (VGSCs) have been implicated in the metastatic potential of human breast, prostate and lung cancer cells. Specifically, the SCN5A gene encoding the VGSC isotype Nav1.5 has been defined as a key driver of human cancer cell invasion. In this study, we examined the expression and function of VGSCs in a panel of colon cancer cell lines by electrophysiological recordings. Na+ channel activity and invasive potential were inhibited pharmacologically by tetrodotoxin or genetically by siRNAs specifically targeting SCN5A. Clinical relevance was established by immunohistochemistry of patient biopsies, where there was strong Nav1.5 protein staining in colon cancer specimens but little to no staining in matched-paired normal colon tissues. We explored the mechanism of VGSC-mediated invasive potential on the basis of reported links between VGSC activity and gene expression in excitable cells. Probabilistic modeling of loss-of-function screens and microarray data established an unequivocal role of VGSC SCN5A as a high level regulator of a colon cancer invasion network, involving genes that encompass Wnt signaling, cell migration, ectoderm development, response to biotic stimulus, steroid metabolic process and cell cycle control. siRNA-mediated knockdown of predicted downstream network components caused a loss of invasive behavior, demonstrating network connectivity and its function in driving colon cancer invasion. PMID:20651255

  18. Smooth-muscle-specific gene transfer with the human maxi-k channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys.

    Science.gov (United States)

    Christ, George J; Andersson, Karl-Erik; Williams, Koudy; Zhao, Weixin; D'Agostino, Ralph; Kaplan, Jay; Aboushwareb, Tamer; Yoo, James; Calenda, Giulia; Davies, Kelvin P; Sellers, Rani S; Melman, Arnold

    2009-12-01

    Despite the advent of effective oral therapies for erectile dysfunction (ED), many patients are not successfully treated, and side effects have been documented. To further evaluate the potential utility of naked DNA-based gene transfer as an attractive treatment option for ED. The effects of gene transfer on erectile function and sexual behavior were evaluated in eight male cynomolgus monkeys with ED secondary to moderately severe, diet-induced atherosclerosis. Following establishment of baseline characteristics, animals were subjected to intracavernous injection of a smooth-muscle-specific gene transfer vector (pSMAA-hSlo) encoding the pore-forming subunit of the human large-conductance, calcium-sensitive potassium channel (Maxi-K). For the sexual behavior studies, 2 wk of baseline data were obtained, and then animals were placed in the presence of estrogen-implanted females (n=2) three times per week for 30 min, and sexual behavior was recorded. The intracavernous pressure response to papaverine injection was also monitored. Dramatic changes in erectile function and sexual behavior were observed after intracorporal gene transfer. The frequency of partial (6±2 to 10±2) and full (2±1.5 to 5±1.4) erections were significantly increased, with a parallel 2-3-fold increase in the duration of the observed erections. The frequency and latency of ejaculation were increased and decreased, respectively. Frequency and duration of grooming by the female were increased, and the latency decreased. Increased latency and decreased frequency of body contact was also observed, and this is characteristic of the typical drop in consort intimacy that occurs after mating in most macaque species. In addition, an increased responsiveness to intracavernous papaverine injection was observed. The data indicate that intracorporal Maxi-K-channel gene transfer enhances erectile capacity and sexual behavior; the data imply that increased erectile function per se may lead to increased sexual

  19. Multi-country Survey Revealed Prevalent and Novel F1534S Mutation in Voltage-Gated Sodium Channel (VGSC Gene in Aedes albopictus.

    Directory of Open Access Journals (Sweden)

    Jiabao Xu

    2016-05-01

    Full Text Available Aedes albopictus is an important dengue vector because of its aggressive biting behavior and rapid spread out of its native home range in Southeast Asia. Pyrethroids are widely used for adult mosquito control, and resistance to pyrethroids should be carefully monitored because vector control is the only effective method currently available to prevent dengue transmission. The voltage-gated sodium channel gene is the target site of pyrethroids, and mutations in this gene cause knockdown resistance (kdr. Previous studies reported various mutations in the voltage-gated sodium channel (VGSC gene, but the spatial distribution of kdr mutations in Ae. albopictus has not been systematically examined, and the association between kdr mutation and phenotypic resistance has not been established.A total of 597 Ae. albopictus individuals from 12 populations across Asia, Africa, America and Europe were examined for mutations in the voltage-gated sodium channel gene. Three domains for a total of 1,107 bp were sequenced for every individual. Two populations from southern China were examined for pyrethroid resistance using the World Health Organization standard tube bioassay, and the association between kdr mutations and phenotypic resistance was tested.A total of 29 synonymous mutations were found across domain II, III and IV of the VGSC gene. Non-synonymous mutations in two codons of the VGSC gene were detected in 5 populations from 4 countries. A novel mutation at 1532 codon (I1532T was found in Rome, Italy with a frequency of 19.7%. The second novel mutation at codon 1534 (F1534S was detected in southern China and Florida, USA with a frequency ranging from 9.5-22.6%. The WHO insecticide susceptibility bioassay found 90.1% and 96.1% mortality in the two populations from southern China, suggesting resistance and probable resistance. Positive association between kdr mutations with deltamethrin resistance was established in these two populations.Two novel kdr

  20. Multi-country Survey Revealed Prevalent and Novel F1534S Mutation in Voltage-Gated Sodium Channel (VGSC) Gene in Aedes albopictus.

    Science.gov (United States)

    Xu, Jiabao; Bonizzoni, Mariangela; Zhong, Daibin; Zhou, Guofa; Cai, Songwu; Li, Yiji; Wang, Xiaoming; Lo, Eugenia; Lee, Rebecca; Sheen, Roger; Duan, Jinhua; Yan, Guiyun; Chen, Xiao-Guang

    2016-05-01

    Aedes albopictus is an important dengue vector because of its aggressive biting behavior and rapid spread out of its native home range in Southeast Asia. Pyrethroids are widely used for adult mosquito control, and resistance to pyrethroids should be carefully monitored because vector control is the only effective method currently available to prevent dengue transmission. The voltage-gated sodium channel gene is the target site of pyrethroids, and mutations in this gene cause knockdown resistance (kdr). Previous studies reported various mutations in the voltage-gated sodium channel (VGSC) gene, but the spatial distribution of kdr mutations in Ae. albopictus has not been systematically examined, and the association between kdr mutation and phenotypic resistance has not been established. A total of 597 Ae. albopictus individuals from 12 populations across Asia, Africa, America and Europe were examined for mutations in the voltage-gated sodium channel gene. Three domains for a total of 1,107 bp were sequenced for every individual. Two populations from southern China were examined for pyrethroid resistance using the World Health Organization standard tube bioassay, and the association between kdr mutations and phenotypic resistance was tested. A total of 29 synonymous mutations were found across domain II, III and IV of the VGSC gene. Non-synonymous mutations in two codons of the VGSC gene were detected in 5 populations from 4 countries. A novel mutation at 1532 codon (I1532T) was found in Rome, Italy with a frequency of 19.7%. The second novel mutation at codon 1534 (F1534S) was detected in southern China and Florida, USA with a frequency ranging from 9.5-22.6%. The WHO insecticide susceptibility bioassay found 90.1% and 96.1% mortality in the two populations from southern China, suggesting resistance and probable resistance. Positive association between kdr mutations with deltamethrin resistance was established in these two populations. Two novel kdr mutations, I1532T

  1. Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients.

    Science.gov (United States)

    Marshall-Gradisnik, Sonya; Johnston, Samantha; Chacko, Anu; Nguyen, Thao; Smith, Peter; Staines, Donald

    2016-12-01

    Objective The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca 2+ ) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients. Methods A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software. Results Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3' untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group. Conclusion This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca 2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

  2. Critical role of a K+ channel in Plasmodium berghei transmission revealed by targeted gene disruption

    DEFF Research Database (Denmark)

    Ellekvist, Peter; Maciel, Jorge; Mlambo, Godfree

    2008-01-01

    through the mosquito vector remains unknown. We hypothesize that these two K(+) channels mediate the transport of K(+) in the parasites, and thus are important for parasite survival. To test this hypothesis, we identified the orthologue of one of the P. falciparum K(+) channels, PfKch1, in the rodent...... inhibition of the development of PbKch1-null parasites in Anopheles stephensi mosquitoes. In conclusion, these studies demonstrate that PbKch1 contributes to the transport of K(+) in P. berghei parasites and supports the growth of the parasites, in particular the development of oocysts in the mosquito midgut...

  3. Genomic characterization, phylogenetic comparison and differential expression of the cyclic nucleotide-gated channels gene family in pear (Pyrus bretchneideri Rehd.).

    Science.gov (United States)

    Chen, Jianqing; Yin, Hao; Gu, Jinping; Li, Leiting; Liu, Zhe; Jiang, Xueting; Zhou, Hongsheng; Wei, Shuwei; Zhang, Shaoling; Wu, Juyou

    2015-01-01

    The cyclic nucleotide-gated channel (CNGC) family is involved in the uptake of various cations, such as Ca(2+), to regulate plant growth and respond to biotic and abiotic stresses. However, there is far less information about this family in woody plants such as pear. Here, we provided a genome-wide identification and analysis of the CNGC gene family in pear. Phylogenetic analysis showed that the 21 pear CNGC genes could be divided into five groups (I, II, III, IVA and IVB). The majority of gene duplications in pear appeared to have been caused by segmental duplication and occurred 32.94-39.14 million years ago. Evolutionary analysis showed that positive selection had driven the evolution of pear CNGCs. Motif analyses showed that Group I CNGCs generally contained 26 motifs, which was the greatest number of motifs in all CNGC groups. Among these, eight motifs were shared by each group, suggesting that these domains play a conservative role in CNGC activity. Tissue-specific expression analysis indicated that functional diversification of the duplicated CNGC genes was a major feature of long-term evolution. Our results also suggested that the P-S6 and PBC & hinge domains had co-evolved during the evolution. These results provide valuable information to increase our understanding of the function, evolution and expression analyses of the CNGC gene family in higher plants. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Role of KATP channels in cephalic vasodilatation induced by calcitonin gene-related peptide, nitric oxide, and transcranial electrical stimulation in the rat

    DEFF Research Database (Denmark)

    Gozalov, Aydin; Jansen-Olesen, Inger; Klærke, Dan Arne

    2008-01-01

    OBJECTIVE: The objective of this study was to explore the role of K(ATP) channels in vasodilatation induced by calcitonin gene-related peptide (CGRP), nitric oxide (NO), and transcranial electrical stimulation (TES) in intracranial arteries of rat. BACKGROUND: Dilatation of cerebral and dural...... CGRP, NO, and endogenous CGRP after electrical stimulation. Also diameter changes of pial arteries, mean arterial blood pressure and local cerebral blood flow by Laser Doppler flowmetry (LCBF(Flux)) were measured. RESULTS: CGRP, NO, and TES caused dilatation of the 2 arteries in vivo and in vitro...

  5. Characterization of an Oct1 orthologue in the channel catfish, Ictalurus punctatus: A negative regulator of immunoglobulin gene transcription?

    NARCIS (Netherlands)

    Lennard, M.L.; Hikima, J.I.; Ross, D.A.; Kruiswijk, C.P.; Wilson, M.R.; Miller, N.W.; Warr, G.W.

    2007-01-01

    Background - The enhancer (E¿3') of the immunoglobulin heavy chain locus (IGH) of the channel catfish (Ictalurus punctatus) has been well characterized. The functional core region consists of two variant Oct transcription factor binding octamer motifs and one E-protein binding ¿E5 site. An

  6. Comprehensive analysis of schizophrenia-associated loci highlights ion channel pathways and biologically plausible candidate causal genes

    DEFF Research Database (Denmark)

    Pers, Tune H; Timshel, Pascal; Ripke, Stephan

    2016-01-01

    Over 100 associated genetic loci have been robustly associated with schizophrenia. Gene prioritization and pathway analysis have focused on a priori hypotheses and thus may have been unduly influenced by prior assumptions and missed important causal genes and pathways. Using a data-driven approac...

  7. Potassium and calcium channel gene expression in small arteries in porcine and rat models of diet-induced obesity (Poster)

    DEFF Research Database (Denmark)

    Jensen, Lars Jørn; Salomonsson, Max; Sørensen, Charlotte Mehlin

    2014-01-01

    Obesity is an increasing problem worldwide leading to cardiovascular morbidity. Only limited information exists on the transcriptional regulation of arterial K+ and Ca2+ channels in obesity. We quantified, by real-time PCR, mRNA expression of K+ channels and L-type Ca2+ channels (LTCC) in small...... mesenteric (MA), middle cerebral (MCA), and left coronary arteries (LCA) of lean vs. obese rats and minipigs. Male Sprague Dawley rats were fed a high-fat (FAT; N=5), high-fructose (FRUC; N=7), high-fat/high-fructose (FAT/FRUC; N=7) or standard diet (STD; N=7-11) for 28 Weeks. FAT and FAT/FRUC became obese...... increased in OB and OB+DIAB. BKca, IKca, SKca and/or LTCC mRNA was up-regulated in LCA from OB and OB+DIAB (n.s.). Expression of BKca mRNA was increased, whereas IKca mRNA decreased in MCA from OB (n.s.). SKca mRNA was decreased in MA from OB (n.s.). Diet-induced obesity in rats and minipigs lead to complex...

  8. Ménière's Disease: Molecular Analysis of Aquaporins 2, 3 and Potassium Channel KCNE1 Genes in Brazilian Patients.

    Science.gov (United States)

    Lopes, Karen de Carvalho; Sartorato, Edi Lúcia; da Silva-Costa, Sueli M; de Macedo Adamov, Nadya Soares; Ganança, Fernando Freitas

    2016-09-01

    Ménière's disease (MD) is a complex disease of unknown etiology characterized by a symptomatic tetrad of vertigo, hearing loss, tinnitus, and aural fullness. In addition to factors related to homeostasis of the inner ear, genetic factors have been implicated in its pathophysiology, including genes related to the transport of water and ionic composition maintenance of the endolymph, such as the aquaporin genes AQP2 and AQP3, and the potassium channel gene KCNE1. The aim of this study was to identify polymorphisms of these genes and determine their association with clinical characteristics of patients with MD. A case-control genetic association study was carried out, including 30 patients with definite Ménière's disease and 30 healthy controls. The coding regions of the target genes were amplified from blood samples by polymerase chain reaction (PCR), followed by direct sequencing. The associations of polymorphisms with clinical characteristics were analyzed with logistic regression. Five polymorphisms were identified: rs426496 in AQP2; rs591810 in AQP3; and rs1805127, rs1805128, and rs17173510 in KCNE1. After adjustment, rs426496 was significantly associated with tinnitus during the initial crisis and with altered electronystagmography, and rs1805127 was significantly associated with nephropathy. The genetic variant rs426496 in AQP2; rs591810 in AQP3 and rs1805127, rs1805128, and rs17173510, in KCNE1 were found in patients with Ménière's disease. The polymorphism rs426496, in AQP2, is associated with tinnitus at the onset of Ménière's disease and altered electronystagmography. In addition, rs1805127, in KCNE1, is associated with the presence of nephropathy.

  9. Gene expression profile of sodium channel subunits in the anterior cingulate cortex during experimental paclitaxel-induced neuropathic pain in mice

    Directory of Open Access Journals (Sweden)

    Willias Masocha

    2016-11-01

    Full Text Available Paclitaxel, a chemotherapeutic agent, causes neuropathic pain whose supraspinal pathophysiology is not fully understood. Dysregulation of sodium channel expression, studied mainly in the periphery and spinal cord level, contributes to the pathogenesis of neuropathic pain. We examined gene expression of sodium channel (Nav subunits by real time polymerase chain reaction (PCR in the anterior cingulate cortex (ACC at day 7 post first administration of paclitaxel, when mice had developed paclitaxel-induced thermal hyperalgesia. The ACC was chosen because increased activity in the ACC has been observed during neuropathic pain. In the ACC of vehicle-treated animals the threshold cycle (Ct values for Nav1.4, Nav1.5, Nav1.7, Nav1.8 and Nav1.9 were above 30 and/or not detectable in some samples. Thus, comparison in mRNA expression between untreated control, vehicle-treated and paclitaxel treated animals was done for Nav1.1, Nav1.2, Nav1.3, Nav1.6, Nax as well as Navβ1–Navβ4. There were no differences in the transcript levels of Nav1.1–Nav1.3, Nav1.6, Nax, Navβ1–Navβ3 between untreated and vehicle-treated mice, however, vehicle treatment increased Navβ4 expression. Paclitaxel treatment significantly increased the mRNA expression of Nav1.1, Nav1.2, Nav1.6 and Nax, but not Nav1.3, sodium channel alpha subunits compared to vehicle-treated animals. Treatment with paclitaxel significantly increased the expression of Navβ1 and Navβ3, but not Navβ2 and Navβ4, sodium channel beta subunits compared to vehicle-treated animals. These findings suggest that during paclitaxel-induced neuropathic pain (PINP there is differential upregulation of sodium channels in the ACC, which might contribute to the increased neuronal activity observed in the area during neuropathic pain.

  10. Localisation of SCN10A gene product Na(v)1.8 and novel pain-related ion channels in human heart.

    Science.gov (United States)

    Facer, Paul; Punjabi, Prakash P; Abrari, Andleeb; Kaba, Riyaz A; Severs, Nicholas J; Chambers, John; Kooner, Jaspal S; Anand, Praveen

    2011-01-01

    We have shown that the gene SCN10A encoding the sodium channel Na(v)1.8 is a susceptibility factor for heart block and serious ventricular arrhythmia. Since Na(v)1.8 is known to be present in nerve fibres that mediate pain, it may be related to both cardiac pain and dysrhythmia. The localisation of Na(v)1.8 and other key nociceptive ion channels, including Na(v)1.7, Na(v)1.9, capsaicin receptor TRPV1, and purinergic receptor P2X(3), have not been reported in human heart. The aim of this study was to determine the distribution of Na(v)1.8, related sodium and other sensory channels in human cardiac tissue, and correlate their density with sympathetic nerves, regenerating nerves (GAP-43), and vascularity. Human heart atrial appendage tissues (n = 13) were collected during surgery for valve disease. Tissues were investigated by immunohistology using specific antibodies to Na(v)1.8 and other markers. Na(v)1.8 immunoreactivity was detected in nerve fibres and fascicles in the myocardium, often closely associated with small capillaries. Na(v)1.8 nerve fibres per mm(2) correlated significantly with vascular markers. Na(v)1.8-immunoreactivity was present also in cardiomyocytes with a similar distribution pattern to that seen with connexins, the specialised gap junction proteins of myocardial intercalated discs. Na(v)1.5-immunoreactivity was detected in cardiomyocytes but not in nerve fibres. Na(v)1.7, Na(v)1.9, TRPV1, P2X(3)/P2X(2), and GAP43 positive nerve fibres were relatively sparse, whereas sympathetic innervation and connexin43 were abundant. We conclude that sodium channel Na(v)1.8 is present in sensory nerves and cardiomyocytes of human heart. Na(v)1.8 and other pain channels provide new targets for the understanding and treatment of cardiac pain and dysrhythmia.

  11. Natural attenuation in a surface water channel and a coastal aquifer by monitoring presence and removal of indicator bacteria, pathogens and antibiotic resistance gene: model development

    Science.gov (United States)

    Masciopinto, Costantino; Visino, Fabrizio; Luprano, Maria Laura; Levantesi, Caterina; Tandoi, Valter

    2015-04-01

    The spreading of microbial contamination into the environment, represents a very relevant problem, which leads to an increasing health concern. For this reason, it is important to identify and characterize the extent of natural depuration in water environmental particularly for reducing the presence of faecal contamination indicator bacteria, pathogens and antibiotic resistance genes (ARG). In this study, the presence of the above reported microbial parameters was analyzed in a surface water channel and in a coastal aquifer in southern Italy (Ostuni) southern Italy, both affected by Ostuni municipal treatment plant effluents and by local run-off. Several samples were collected from surface water, flowing in channels, and from wells in our study area. In particular, the water samples were analyzed to detect 7 fecal contamination indicators (E. coli, total coliforms, Clostridium p. spores, somatic coliphages, Enterococci and heterotrophic bacteria), Salmonella spp and the presence of ARGs. The water samples were also tested for chemical constituents. Finally a mathematical model has been developed in order to simulate pathogen migration pathways in the fractured groundwater and corresponding possible mitigation of pathogens in pumping wells.

  12. Estudio electrofisiológico de canales Herg en células de cáncer de colón

    OpenAIRE

    Granja del Río, Alejandra

    2013-01-01

    En el presente estudio, mostramos que en las células de colon normales (NCM460) y en las tumorales (HT29) las principales corrientes activadas por voltaje son corrientes de K+. Sin embargo, el hallazgo más interesante fue mostrar que, en contraste con las células normales de colon, las células tumorales, al parecer, expresan corrientes de K+ activadas por voltaje que podrían ser mediadas por canales herg. Departamento de Bioquímica y Biología Molecular y Fisiología Máster en Investigaci...

  13. Ion channels in plants.

    Science.gov (United States)

    Hedrich, Rainer

    2012-10-01

    Since the first recordings of single potassium channel activities in the plasma membrane of guard cells more than 25 years ago, patch-clamp studies discovered a variety of ion channels in all cell types and plant species under inspection. Their properties differed in a cell type- and cell membrane-dependent manner. Guard cells, for which the existence of plant potassium channels was initially documented, advanced to a versatile model system for studying plant ion channel structure, function, and physiology. Interestingly, one of the first identified potassium-channel genes encoding the Shaker-type channel KAT1 was shown to be highly expressed in guard cells. KAT1-type channels from Arabidopsis thaliana and its homologs from other species were found to encode the K(+)-selective inward rectifiers that had already been recorded in early patch-clamp studies with guard cells. Within the genome era, additional Arabidopsis Shaker-type channels appeared. All nine members of the Arabidopsis Shaker family are localized at the plasma membrane, where they either operate as inward rectifiers, outward rectifiers, weak voltage-dependent channels, or electrically silent, but modulatory subunits. The vacuole membrane, in contrast, harbors a set of two-pore K(+) channels. Just very recently, two plant anion channel families of the SLAC/SLAH and ALMT/QUAC type were identified. SLAC1/SLAH3 and QUAC1 are expressed in guard cells and mediate Slow- and Rapid-type anion currents, respectively, that are involved in volume and turgor regulation. Anion channels in guard cells and other plant cells are key targets within often complex signaling networks. Here, the present knowledge is reviewed for the plant ion channel biology. Special emphasis is drawn to the molecular mechanisms of channel regulation, in the context of model systems and in the light of evolution.

  14. Linking stomatal traits and expression of slow anion channel genes HvSLAH1 2 HvSLAC1 with grain yield for increasing salinity tolerance in barley

    Directory of Open Access Journals (Sweden)

    Xiaohui eLiu

    2014-11-01

    Full Text Available Soil salinity is an environmental and agricultural problem in many parts of the world. One of the keys to breeding barley for adaptation to salinity lies in a better understanding of the genetic control of stomatal regulation. We have employed a range of physiological and molecular techniques (stomata assay, gas exchange, phylogenetic analysis, QTL analysis, and gene expression to investigate stomatal behaviour and genotypic variation in barley cultivars and a genetic population in four experimental trials. A set of relatively efficient and reliable methods were developed for the characterisation of stomatal behaviour of large numbers of varieties and genetic lines. Furthermore, we have found a large genetic variation of gas exchange and stomatal traits in barley in response to salinity stress. Salt-tolerant CM72 showed significantly larger stomatal aperture in 200 mM NaCl treatment than that of salt-sensitive Gairdner. Stomatal traits such as aperture width/length were found to significantly correlate with grain yield in salt treatment. Phenotypic characterisation and QTL analysis of a segregating double haploid population of the CM72/Gairdner resulted in the identification of significant stomatal traits-related QTLs for salt tolerance. Moreover, expression analysis of the slow anion channel genes HvSLAH1 and HvSLAC1 demonstrated that their up-regulation is linked to high barley grain yield in the field.

  15. Over-Expression of Dopamine D2 Receptor and Inwardly Rectifying Potassium Channel Genes in Drug-Naive Schizophrenic Peripheral Blood Lymphocytes as Potential Diagnostic Markers

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    Ágnes Zvara

    2005-01-01

    Full Text Available Schizophrenia is one of the most common neuropsychiatric disorders affecting nearly 1% of the human population. Current diagnosis of schizophrenia is based on complex clinical symptoms. The use of easily detectable peripheral molecular markers could substantially help the diagnosis of psychiatric disorders. Recent studies showed that peripheral blood lymphocytes (PBL express subtypes of D1 and D2 subclasses of dopamine receptors. Recently, dopamine receptor D3 (DRD3 was found to be over-expressed in schizophrenic PBL and proposed to be a diagnostic and follow-up marker for schizophrenia. In this study we screened PBL of 13 drug-naive/drug-free schizophrenic patients to identify additional markers of schizophrenia. One of the benefits of our study is the use of blood samples of non-medicated, drug-naive patients. This excludes the possibility that changes detected in gene expression levels might be attributed to the medication rather than to the disorder itself. Among others, genes for dopamine receptor D2 (DRD2 and the inwardly rectifying potassium channel (Kir2.3 were found to be over-expressed in microarray analysis. Increased mRNA levels were confirmed by quantitative real-time PCR (QRT-PCR using the SybrGreen method and dual labeled TaqMan probes. The use of both molecular markers allows a more rapid and precise prediction of schizophrenia and might help find the optimal medication for schizophrenic patients.

  16. Mutation in the Sodium Channel Gene Corresponds With Phenotypic Resistance of Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) to Pyrethroids.

    Science.gov (United States)

    Klafke, G M; Miller, R J; Tidwell, J; Barreto, R; Guerrero, F D; Kaufman, P E; Pérez de León, A A

    2017-11-07

    The brown dog tick, Rhipicephalus sanguineus sensu lato (Latreille), is a cosmopolitan ectoparasite and vector of pathogens that kill humans and animals. Pyrethroids represent a class of synthetic acaricides that have been used intensely to try to control the brown dog tick and mitigate the risk of tick-borne disease transmission. However, acaricide resistance is an emerging problem in the management of the brown dog tick. Understanding the mechanism of resistance to acaricides, including pyrethroids, is important to adapt brown dog tick control strategies. The main objective of this study was to determine if target-site mutations associated with pyrethroid resistance in other pests could be associated with phenotypic resistance detected in a brown dog tick population from Florida. We amplified segment 6 of the domain III of the voltage-sensitive sodium channel protein, using cDNAs synthesized from pyrethroid-susceptible and pyrethroid-resistant tick strains. A single nucleotide point mutation (SNP) identified in a highly conserved region of domain III S6 in the resistant ticks resulted in an amino acid change from phenylalanine to leucine. This mutation is characteristic of resistance phenotypes in other tick species, and is the first report of this mutation in R. sanguineus. Molecular assays based on this knowledge could be developed to diagnose the risk for pyrethroid resistance, and to inform decisions on integrated brown dog tick management practices. © The Authors 2017. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Genome-Wide Identification of Cyclic Nucleotide-Gated Ion Channel Gene Family in Wheat and Functional Analyses of TaCNGC14 and TaCNGC16

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    Jia Guo

    2018-01-01

    Full Text Available Cyclic nucleotide gated channels (CNGCs play multifaceted roles in plants, particularly with respect to signaling processes associated with abiotic stress signaling and during host-pathogen interactions. Despite key roles during plant survival and response to environment, little is known about the activity and function of CNGC family in common wheat (Triticum aestivum L., a key stable food around the globe. In this study, we performed a genome-wide identification of CNGC family in wheat and identified a total 47 TaCNGCs in wheat, classifying these genes into four major groups (I–IV with two sub-groups (IVa and IVb. Sequence analysis revealed the presence of several conserved motifs, including a phosphate binding cassette (PBC and a “hinge” region, both of which have been hypothesized to be critical for the function of wheat CNGCs. During wheat infection with Pst, the transcript levels of TaCNGC14 and TaCNGC16, both members of group IVb, showed significant induction during a compatible interaction, while a reduction in gene expression was observed in incompatible interactions. In addition, TaCNGC14 and TaCNGC16 mRNA accumulation was significantly influenced by exogenously applied hormones, including abscisic acid (ABA, methyl jasmonate (MeJA, and salicylic acid (SA, suggesting a role in hormone signaling and/or perception. Silencing of TaCNGC14 and TaCNGC16 limited Pst growth and increased wheat resistance against Pst. The results presented herein contribute to our understanding of the wheat CNGC gene family and the mechanism of TaCNGCs signaling during wheat-Pst interaction.

  18. Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics.

    Science.gov (United States)

    Beattie, Kylie A; Hill, Adam P; Bardenet, Rémi; Cui, Yi; Vandenberg, Jamie I; Gavaghan, David J; de Boer, Teun P; Mirams, Gary R

    2018-03-24

    Ion current kinetics are commonly represented by current-voltage relationships, time constant-voltage relationships and subsequently mathematical models fitted to these. These experiments take substantial time, which means they are rarely performed in the same cell. Rather than traditional square-wave voltage clamps, we fitted a model to the current evoked by a novel sum-of-sinusoids voltage clamp that was only 8 s long. Short protocols that can be performed multiple times within a single cell will offer many new opportunities to measure how ion current kinetics are affected by changing conditions. The new model predicts the current under traditional square-wave protocols well, with better predictions of underlying currents than literature models. The current under a novel physiologically relevant series of action potential clamps is predicted extremely well. The short sinusoidal protocols allow a model to be fully fitted to individual cells, allowing us to examine cell-cell variability in current kinetics for the first time. Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fitted a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells overexpressing hERG1a. The model was then used to predict over 5 minutes of recordings in the same cell in response to

  19. A mutation in the gene encoding mitochondrial Mg²+ channel MRS2 results in demyelination in the rat.

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    Takashi Kuramoto

    2011-01-01

    Full Text Available The rat demyelination (dmy mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg²+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg²+ homeostasis in CNS mitochondria is essential for the maintenance of myelin.

  20. Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

    Science.gov (United States)

    Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

    2014-01-01

    Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety

  1. A new sodium channel {alpha}-subunit gene (Scn9a) from Schwann cells maps to the Scn1a, Scn2a, Scn3a cluster of mouse chromosome 2

    Energy Technology Data Exchange (ETDEWEB)

    Beckers, M.C.; Ernst, E.; Gros, P. [McGill Univ., Montreal (Canada)

    1996-08-15

    We have used a total of 27 AXB/BXA recombinant inbred mouse strains to determine the chromosomal location of a newly identified gene encoding an {alpha}-subunit isoform of the sodium channel from Schwann cells, Scn9a. Linkage analysis established that Scn9a mapped to the proximal segment of mouse chromosome 2. The segregation of restriction fragment length polymorphisms in 145 progeny from a Mus spretus x C57BL/6J backcross indicates that Scn9a is very tightly linked to Scn1a (gene encoding the type I sodium channel {alpha}-subunit of the brain) and forms part of a cluster of four Scna genes located on mouse chromosome 2. 17 refs., 1 fig., 3 tabs.

  2. Soluble adenylyl cyclase in vascular endothelium: gene expression control of epithelial sodium channel-α, Na+/K+-ATPase-α/β, and mineralocorticoid receptor.

    Science.gov (United States)

    Schmitz, Boris; Nedele, Johanna; Guske, Katrin; Maase, Martina; Lenders, Malte; Schelleckes, Michael; Kusche-Vihrog, Kristina; Brand, Stefan-Martin; Brand, Eva

    2014-04-01

    The Ca(2+)- and bicarbonate-activated soluble adenylyl cyclase (sAC) has been identified recently as an important mediator of aldosterone signaling in the kidney. Nuclear sAC has been reported to stimulate cAMP response element-binding protein 1 phosphorylation via protein kinase A, suggesting an alternative cAMP pathway in the nucleus. In this study, we analyzed the sAC as a potential modulator of endothelial stiffness in the vascular endothelium. We determined the contribution of sAC to cAMP response element-mediated transcriptional activation in vascular endothelial cells and kidney collecting duct cells. Inhibition of sAC by the specific inhibitor KH7 significantly reduced cAMP response element-mediated promoter activity and affected cAMP response element-binding protein 1 phosphorylation. Furthermore, KH7 and anti-sAC small interfering RNA significantly decreased mRNA and protein levels of epithelial sodium channel-α and Na(+)/K(+)-ATPase-α. Using atomic force microscopy, a nano-technique that measures stiffness and deformability of living cells, we detected significant endothelial cell softening after sAC inhibition. Our results suggest that the sAC is a regulator of gene expression involved in aldosterone signaling and an important regulator of endothelial stiffness. Additional studies are warranted to investigate the protective action of sAC inhibitors in humans for potential clinical use.

  3. Frequency of V1016I and F1534C mutations in the voltage-gated sodium channel gene in Aedes aegypti in Venezuela.

    Science.gov (United States)

    Alvarez, Leslie C; Ponce, Gustavo; Saavedra-Rodriguez, Karla; Lopez, Beatriz; Flores, Adriana E

    2015-06-01

    The V1016I and F1534C mutations in the voltage-gated sodium channel gene have been associated with resistance to pyrethroids and DDT in Aedes aegypti mosquitoes. A study was carried out to determine the frequency of I1016 and C1534 by real-time PCR in five natural populations of Ae. aegypti in Venezuela during 2008, 2010 and 2012, as well as in a strain selected with 0.14 µg of deltamethrin for 15 generations. In natural populations, frequencies of I1016 varied between 0.01 and 0.37, and frequencies of C1534 between 0.35 and 1.0. In the Pampanito strain, the frequency of I1016 increased from 0.02 in F1 up to 0.5 in F15 and from 0.35 up to fixation for C1534 after selection with deltamethrin. The results showed that C1534 frequencies are higher than I1016 frequencies in natural populations of Ae. aegypti in Venezuela, and that deltamethrin selected the C1534 more rapidly than I1016. © 2014 Society of Chemical Industry.

  4. Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia.

    Science.gov (United States)

    Saito, Kosuke; Moore, Rick; Negishi, Masahiko

    2013-03-01

    KCNK1, a member of the family of two-pore K(+) ion channels, is specifically induced in the livers of male mice after phenobarbital treatment. Here, we have determined the molecular mechanism of this male-specific activation of the Kcnk1 gene and characterized KCNK1 as a phenobarbital-inducible antihyperplasia factor. Upon activation by phenobarbital, nuclear receptor CAR binds the 97-bp response element (-2441/-2345) within the Kcnk1 promoter. This binding is observed in the livers of male mice, but not in the livers of female mice and requires the pituitary gland, because hypophysectomy abrogates it. Hyperplasia further progressed in the livers of Kcnk1 ( -/- ) male mice compared with those of Kcnk1 ( +/+ ) males after phenobarbital treatment. Thus, KCNK1 suppresses phenobarbital-induced hyperplasia. These results indicate that phenobarbital treatment induces KCNK1 to elicit a male-specific and growth-suppressing signal. Thus, KCNK1 and Kcnk1 ( -/- ) mice provide an experimental tool for further investigation into the molecular mechanism of CAR-mediated promotion of the development of hepatocellular carcinoma in mice.

  5. Fluorescence-tracking of activation gating in human ERG channels reveals rapid S4 movement and slow pore opening.

    Directory of Open Access Journals (Sweden)

    Zeineb Es-Salah-Lamoureux

    2010-05-01

    Full Text Available hERG channels are physiologically important ion channels which mediate cardiac repolarization as a result of their unusual gating properties. These are very slow activation compared with other mammalian voltage-gated potassium channels, and extremely rapid inactivation. The mechanism of slow activation is not well understood and is investigated here using fluorescence as a direct measure of S4 movement and pore opening.Tetramethylrhodamine-5-maleimide (TMRM fluorescence at E519 has been used to track S4 voltage sensor movement, and channel opening and closing in hERG channels. Endogenous cysteines (C445 and C449 in the S1-S2 linker bound TMRM, which caused a 10 mV hyperpolarization of the V((1/2 of activation to -27.5+/-2.0 mV, and showed voltage-dependent fluorescence signals. Substitution of S1-S2 linker cysteines with valines allowed unobstructed recording of S3-S4 linker E519C and L520C emission signals. Depolarization of E519C channels caused rapid initial fluorescence quenching, fit with a double Boltzmann relationship, F-V(ON, with V((1/2 (,1 = -37.8+/-1.7 mV, and V((1/2 (,2 = 43.5+/-7.9 mV. The first phase, V((1/2 (,1, was approximately 20 mV negative to the conductance-voltage relationship measured from ionic tail currents (G-V((1/2 = -18.3+/-1.2 mV, and relatively unchanged in a non-inactivating E519C:S620T mutant (V((1/2 = -34.4+/-1.5 mV, suggesting the fast initial fluorescence quenching tracked S4 voltage sensor movement. The second phase of rapid quenching was absent in the S620T mutant. The E519C fluorescence upon repolarization (V((1/2 = -20.6+/-1.2, k = 11.4 mV and L520C quenching during depolarization (V((1/2 = -26.8+/-1.0, k = 13.3 mV matched the respective voltage dependencies of hERG ionic tails, and deactivation time constants from -40 to -110 mV, suggesting they detected pore-S4 rearrangements related to ionic current flow during pore opening and closing.THE DATA INDICATE: 1 that rapid environmental changes occur at the

  6. Identification of an alternative knockdown resistance (kdr)-like mutation, M918L, and a novel mutation, V1010A, in the Thrips tabaci voltage-gated sodium channel gene.

    Science.gov (United States)

    Wu, Meixiang; Gotoh, Hiroki; Waters, Timothy; Walsh, Douglas B; Lavine, Laura Corley

    2014-06-01

    Knockdown resistance (kdr) has been identified as a main mechanism against pyrethroid insecticides in many arthropod pests including in the onion thrips, Thrips tabaci. To characterize and identify pyrethroid-resistance in onion thrips in Washington state, we conducted insecticide bioassays and sequenced a region of the voltage gated sodium channel gene from several different T. tabaci populations. Field collected Thrips tabaci were found to have large variations in resistance to the pyrethroid insecticide lambda-cyhalothrin. We identified two single nucleotide substitutions in our analysis of a partial sequence of the T. tabaci voltage-gated sodium channel gene. One mutation resulted in the non-synonymous substitution of methionine with leucine (M918L), which is well known to be responsible for super knockdown resistance in some pest species. Another non-synonymous substitution, a valine (GTT) to alanine (GCT) replacement at amino acid 1010 (V1010A) was identified in our study and was associated with lambda-cyhalothrin resistance. We have characterized a known kdr mutation and identified a novel mutation in the voltage-gated sodium channel gene of Thrips tabaci associated with resistance to lambda-cyhalothrin. This gene region and these mutations are expected to be useful in the development of a diagnostic test to detect kdr resistance in many onion thrips populations. © 2013 Society of Chemical Industry.

  7. Gene

    Data.gov (United States)

    U.S. Department of Health & Human Services — Gene integrates information from a wide range of species. A record may include nomenclature, Reference Sequences (RefSeqs), maps, pathways, variations, phenotypes,...

  8. Polymorphism of intron-1 in the voltage-gated sodium channel gene of Anopheles gambiae s.s. populations from Cameroon with emphasis on insecticide knockdown resistance mutations.

    Science.gov (United States)

    Etang, Josiane; Vicente, Jose L; Nwane, Philippe; Chouaibou, Mouhamadou; Morlais, Isabelle; Do Rosario, Virgilio E; Simard, Frederic; Awono-Ambene, Parfait; Toto, Jean Claude; Pinto, Joao

    2009-07-01

    Sequence variation at the intron-1 of the voltage-gated sodium channel gene in Anopheles gambiae M- and S-forms from Cameroon was assessed to explore the number of mutational events originating knockdown resistance (kdr) alleles. Mosquitoes were sampled between December 2005 and June 2006 from three geographical areas: (i) Magba in the western region; (ii) Loum, Tiko, Douala, Kribi, and Campo along the Atlantic coast; and (iii) Bertoua, in the eastern continental plateau. Both 1014S and 1014F kdr alleles were found in the S-form with overall frequencies of 14% and 42% respectively. Only the 1014F allele was found in the M-form at lower frequency (11%). Analysis of a 455 bp region of intron-1 upstream the kdr locus revealed four independent mutation events originating kdr alleles, here named MS1 -1014F, S1-1014S and S2-1014S kdr-intron-1 haplotypes in S-form and MS3-1014F kdr-intron-1 haplotype in the M-form. Furthermore, there was evidence for mutual introgression of kdr 1014F allele between the two molecular forms, MS1 and MS3 being widely shared by them. Although no M/S hybrid was observed in analysed samples, this wide distribution of haplotypes MS1 and MS3 suggests inter-form hybridizing at significant level and emphasizes the rapid diffusion of the kdr alleles in Africa. The mosaic of genetic events found in Cameroon is representative of the situation in the West-Central African region and highlights the importance of evaluating the spatial and temporal evolution of kdr alleles for a better management of insecticide resistance.

  9. Discovery of Point Mutations in the Voltage-Gated Sodium Channel from African Aedes aegypti Populations: Potential Phylogenetic Reasons for Gene Introgression

    Science.gov (United States)

    Muranami, Yuto; Kawashima, Emiko; Osei, Joseph H. N.; Sakyi, Kojo Yirenkyi; Dadzie, Samuel; de Souza, Dziedzom K.; Appawu, Maxwell; Ohta, Nobuo; Minakawa, Noboru

    2016-01-01

    Background Yellow fever is endemic in some countries in Africa, and Aedes aegpyti is one of the most important vectors implicated in the outbreak. The mapping of the nation-wide distribution and the detection of insecticide resistance of vector mosquitoes will provide the beneficial information for forecasting of dengue and yellow fever outbreaks and effective control measures. Methodology/Principal Findings High resistance to DDT was observed in all mosquito colonies collected in Ghana. The resistance and the possible existence of resistance or tolerance to permethrin were suspected in some colonies. High frequencies of point mutations at the voltage-gated sodium channel (F1534C) and one heterozygote of the other mutation (V1016I) were detected, and this is the first detection on the African continent. The frequency of F1534C allele and the ratio of F1534C homozygotes in Ae. aegypti aegypti (Aaa) were significantly higher than those in Ae. aegypti formosus (Aaf). We could detect the two types of introns between exon 20 and 21, and the F1534C mutations were strongly linked with one type of intron, which was commonly found in South East Asian and South and Central American countries, suggesting the possibility that this mutation was introduced from other continents or convergently selected after the introgression of Aaa genes from the above area. Conclusions/Significance The worldwide eradication programs in 1940s and 1950s might have caused high selection pressure on the mosquito populations and expanded the distribution of insecticide-resistant Ae. aegypti populations. Selection of the F1534C point mutation could be hypothesized to have taken place during this period. The selection of the resistant population of Ae. aegypti with the point mutation of F1534C, and the worldwide transportation of vector mosquitoes in accordance with human activity such as trading of used tires, might result in the widespread distribution of F1534C point mutation in tropical countries

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Ion channeling

    International Nuclear Information System (INIS)

    Erramli, H.; Blondiaux, G.

    1994-01-01

    Channeling phenomenon was predicted, many years ago, by stark. The first channeling experiments were performed in 1963 by Davies and his coworkers. Parallely Robinson and Oen have investigated this process by simulating trajectories of ions in monocrystals. This technique has been combined with many methods like Rutherford Backscattering Spectrometry (R.B.S.), Particles Induced X-rays Emission (P.I.X.E) and online Nuclear Reaction (N.R.A.) to localize trace elements in the crystal or to determine crystalline quality. To use channeling for material characterization we need data about the stopping power of the incident particle in the channeled direction. The ratios of channeled to random stopping powers of silicon for irradiation in the direction have been investigated and compared to the available theoretical results. We describe few applications of ion channeling in the field of materials characterization. Special attention is given to ion channeling combined with Charged Particle Activation Analysis (C.P.A.A.) for studying the behaviour of oxygen atoms in Czochralski silicon lattices under the influence of internal gettering and in different gaseous atmospheres. Association between ion channeling and C.P.A.A was also utilised for studying the influence of the growing conditions on concentration and position of carbon atoms at trace levels in the MOVPE Ga sub (1-x) Al sub x lattice. 6 figs., 1 tab., 32 refs. (author)

  12. Genotypic to expression profiling of bovine calcium channel, voltage-dependent, alpha-2/delta subunit 1 gene, and their association with bovine mastitis among Frieswal (HFX Sahiwal) crossbred cattle of Indian origin.

    Science.gov (United States)

    Deb, Rajib; Singh, Umesh; Kumar, Sushil; Kumar, Arun; Singh, Rani; Sengar, Gyanendra; Mann, Sandeep; Sharma, Arjava

    2014-04-03

    Calcium channel, voltage-dependent, alpha-2/delta subunit 1 (CACNA2D1) gene is considered to be an important noncytokine candidate gene influencing mastitis. Scanty of reports are available until today regarding the role play of CACNA2D1 gene on the susceptibility of bovine mastitis. We interrogated the CACNA2D1 G519663A [A>G] SNP by PCR-RFLP among two hundreds Frieswal (HF X Sahiwal) crossbred cattle of Indian origin. Genotypic frequency of AA (51.5, n=101) was comparatively higher than AG (35, n=70) and GG (14.5, n=29). Association of Somatic cell score (SCS) with genotypes revealed that, GG genotypes showing lesser count (less susceptible to mastitis) compare to AA and AG. Relative expression of CACNA2D1 transcript (in milk samples) was significantly higher among GG than AG and AA. Further we have also isolated blood sample from the all groups and PBMCs were cultured from each blood sample as per the standard protocol. They were treated with Calcium channel blocker and the expression level of the CACNA2D1 gene was evaluated by Real Time PCR. Results show that expression level decline in each genotypic group after treatment and expression level of GG are again significantly higher than AA and AG. Thus, it may be concluded that GG genotypic animals are favorable for selecting disease resistant breeds.

  13. Channel box

    International Nuclear Information System (INIS)

    Tanabe, Akira.

    1993-01-01

    In a channel box of a BWR type reactor, protruding pads are disposed in axial position on the lateral side of a channel box opposing to a control rod and facing the outer side portion of the control rod in a reactor core loaded state. In the initial loading stage of fuel assemblies, channel fasteners and spacer pads are abutted against each other in the upper portion between the channel boxes sandwiching the control rod therebetween. Further, in the lower portion, a gap as a channel for the movement of the control rod is ensured by the support of fuel support metals. If the channel box is bent toward the control rod along with reactor operation, the pads are abutted against each other to always ensure the gap through which the control rod can move easily. Further, when the pads are brought into contact with each other, the bending deformation of the channel box is corrected by urging to each other. Thus, the control rod can always be moved smoothly to attain reactor safety operation. (N.H.)

  14. Ginseng gintonin activates the human cardiac delayed rectifier K+ channel: involvement of Ca2+/calmodulin binding sites.

    Science.gov (United States)

    Choi, Sun-Hye; Lee, Byung-Hwan; Kim, Hyeon-Joong; Jung, Seok-Won; Kim, Hyun-Sook; Shin, Ho-Chul; Lee, Jun-Hee; Kim, Hyoung-Chun; Rhim, Hyewhon; Hwang, Sung-Hee; Ha, Tal Soo; Kim, Hyun-Ji; Cho, Hana; Nah, Seung-Yeol

    2014-09-01

    Gintonin, a novel, ginseng-derived G protein-coupled lysophosphatidic acid (LPA) receptor ligand, elicits [Ca(2+)]i transients in neuronal and non-neuronal cells via pertussis toxin-sensitive and pertussis toxin-insensitive G proteins. The slowly activating delayed rectifier K(+) (I(Ks)) channel is a cardiac K(+) channel composed of KCNQ1 and KCNE1 subunits. The C terminus of the KCNQ1 channel protein has two calmodulin-binding sites that are involved in regulating I(Ks) channels. In this study, we investigated the molecular mechanisms of gintonin-mediated activation of human I(Ks) channel activity by expressing human I(Ks) channels in Xenopus oocytes. We found that gintonin enhances IKs channel currents in concentration- and voltage-dependent manners. The EC50 for the I(Ks) channel was 0.05 ± 0.01 μg/ml. Gintonin-mediated activation of the I(Ks) channels was blocked by an LPA1/3 receptor antagonist, an active phospholipase C inhibitor, an IP3 receptor antagonist, and the calcium chelator BAPTA. Gintonin-mediated activation of both the I(Ks) channel was also blocked by the calmodulin (CaM) blocker calmidazolium. Mutations in the KCNQ1 [Ca(2+)]i/CaM-binding IQ motif sites (S373P, W392R, or R539W)blocked the action of gintonin on I(Ks) channel. However, gintonin had no effect on hERG K(+) channel activity. These results show that gintonin-mediated enhancement of I(Ks) channel currents is achieved through binding of the [Ca(2+)]i/CaM complex to the C terminus of KCNQ1 subunit.

  15. Surface channeling

    International Nuclear Information System (INIS)

    Sizmann, R.; Varelas, C.

    1976-01-01

    There is experimental evidence that swift light ions incident at small angles towards single crystalline surfaces can lose an appreciable fraction of their kinetic energy during reflection. It is shown that these projectiles penetrate into the bulk surface region of the crystal. They can travel as channeled particles along long paths through the solid (surface channeling). The angular distribution and the depth history of the re-emerged projectiles are investigated by computer simulations. A considerable fraction of the penetrating projectiles re-emerges from the crystal with constant transverse energy if the angle of incidence is smaller than the critical angle for axial channeling. Analytical formulae are derived based on a diffusion model for surface channeling. A comparison with experimental data exhibits the relevance of the analytical solutions. (Auth.)

  16. Spark Channels

    Energy Technology Data Exchange (ETDEWEB)

    Haydon, S. C. [Department of Physics, University of New England, Armidale, NSW (Australia)

    1968-04-15

    A brief summary is given of the principal methods used for initiating spark channels and the various highly time-resolved techniques developed recently for studies with nanosecond resolution. The importance of the percentage overvoltage in determining the early history and subsequent development of the various phases of the growth of the spark channel is discussed. An account is then given of the recent photographic, oscillographic and spectroscopic investigations of spark channels initiated by co-axial cable discharges of spark gaps at low [{approx} 1%] overvoltages. The phenomena observed in the development of the immediate post-breakdown phase, the diffuse glow structure, the growth of the luminous filament and the final formation of the spark channel in hydrogen are described. A brief account is also given of the salient features emerging from corresponding studies of highly overvolted spark gaps in which the spark channel develops from single avalanche conditions. The essential differences between the two types of channel formation are summarized and possible explanations of the general features are indicated. (author)

  17. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    International Nuclear Information System (INIS)

    Nilsson, Mats F; Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma; Cebers, Gvido; Hellmold, Heike; Gustafson, Anne-Lee; Webster, William S

    2013-01-01

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development

  18. Comparative effects of sodium channel blockers in short term rat whole embryo culture

    Energy Technology Data Exchange (ETDEWEB)

    Nilsson, Mats F, E-mail: Mats.Nilsson@farmbio.uu.se [Department of Pharmaceutical Biosciences, Uppsala University (Sweden); Sköld, Anna-Carin; Ericson, Ann-Christin; Annas, Anita; Villar, Rodrigo Palma [AstraZeneca R and D Södertälje (Sweden); Cebers, Gvido [AstraZeneca R and D, iMed, 141 Portland Street, Cambridge, MA 02139 (United States); Hellmold, Heike; Gustafson, Anne-Lee [AstraZeneca R and D Södertälje (Sweden); Webster, William S [Department of Anatomy and Histology, University of Sydney (Australia)

    2013-10-15

    This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the L-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the L-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3 h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB > bupivacaine > AZA > lidocaine > nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart. - Highlights: • Study of the effect of sodium channel blocking drugs on embryonic heart function • We used a modified method rat whole embryo culture with image analysis. • The drugs tested caused a concentration dependent bradycardia and heart block. • The effect of drugs acting on multiple ion channels is difficult to predict. • This method may be used to detect cardiotoxicity in prenatal development.

  19. Molecular mechanisms underlying the pilsicainide-induced stabilization of hERG proteins in transfected mammalian cells

    Directory of Open Access Journals (Sweden)

    Takeshi Onohara, MD

    2017-06-01

    Conclusions: Pilsicainide penetrates the plasma membrane, stabilizes WT-hERG proteins by acting as a chemical chaperone, and enhances WT-hERG channel currents. This mechanism could also be applicable to modulations of certain mutant-hERG proteins.

  20. Molecular Cloning and Functional Expression of the Equine K+ Channel KV11.1 (Ether à Go-Go-Related/KCNH2 Gene and the Regulatory Subunit KCNE2 from Equine Myocardium.

    Directory of Open Access Journals (Sweden)

    Philip Juul Pedersen

    Full Text Available The KCNH2 and KCNE2 genes encode the cardiac voltage-gated K+ channel KV11.1 and its auxiliary β subunit KCNE2. KV11.1 is critical for repolarization of the cardiac action potential. In humans, mutations or drug therapy affecting the KV11.1 channel are associated with prolongation of the QT intervals on the ECG and increased risk of ventricular tachyarrhythmia and sudden cardiac death--conditions known as congenital or acquired Long QT syndrome (LQTS, respectively. In horses, sudden, unexplained deaths are a well-known problem. We sequenced the cDNA of the KCNH2 and KCNE2 genes using RACE and conventional PCR on mRNA purified from equine myocardial tissue. Equine KV11.1 and KCNE2 cDNA had a high homology to human genes (93 and 88%, respectively. Equine and human KV11.1 and KV11.1/KCNE2 were expressed in Xenopus laevis oocytes and investigated by two-electrode voltage-clamp. Equine KV11.1 currents were larger compared to human KV11.1, and the voltage dependence of activation was shifted to more negative values with V1/2 = -14.2±1.1 mV and -17.3±0.7, respectively. The onset of inactivation was slower for equine KV11.1 compared to the human homolog. These differences in kinetics may account for the larger amplitude of the equine current. Furthermore, the equine KV11.1 channel was susceptible to pharmacological block with terfenadine. The physiological importance of KV11.1 was investigated in equine right ventricular wedge preparations. Terfenadine prolonged action potential duration and the effect was most pronounced at slow pacing. In conclusion, these findings indicate that horses could be disposed to both congenital and acquired LQTS.

  1. Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico.

    Directory of Open Access Journals (Sweden)

    Farah Z Vera-Maloof

    2015-12-01

    Full Text Available Worldwide the mosquito Aedes aegypti (L. is the principal urban vector of dengue viruses. Currently 2.5 billion people are at risk for infection and reduction of Ae. aegypti populations is the most effective means to reduce the risk of transmission. Pyrethroids are used extensively for adult mosquito control, especially during dengue outbreaks. Pyrethroids promote activation and prolong the activation of the voltage gated sodium channel protein (VGSC by interacting with two distinct pyrethroid receptor sites [1], formed by the interfaces of the transmembrane helix subunit 6 (S6 of domains II and III. Mutations of S6 in domains II and III synergize so that double mutants have higher pyrethroid resistance than mutants in either domain alone. Computer models predict an allosteric interaction between mutations in the two domains. In Ae. aegypti, a Ile1,016 mutation in the S6 of domain II was discovered in 2006 and found to be associated with pyrethroid resistance in field populations in Mexico. In 2010 a second mutation, Cys1,534 in the S6 of domain III was discovered and also found to be associated with pyrethroid resistance and correlated with the frequency of Ile1,016.A linkage disequilibrium analysis was performed on Ile1,016 and Cys1,534 in Ae. aegypti collected in Mexico from 2000-2012 to test for statistical associations between S6 in domains II and III in natural populations. We estimated the frequency of the four dilocus haplotypes in 1,016 and 1,534: Val1,016/Phe1,534 (susceptible, Val1,016/Cys1,534, Ile1,016/Phe1,534, and Ile1,016/Cys1,534 (resistant. The susceptible Val1,016/Phe1,534 haplotype went from near fixation to extinction and the resistant Ile1,016/Cys1,534 haplotype increased in all collections from a frequency close to zero to frequencies ranging from 0.5-0.9. The Val1,016/Cys1,534 haplotype increased in all collections until 2008 after which it began to decline as Ile1,016/Cys1,534 increased. However, the Ile1,016/Phe1

  2. A calcium-accumulating region, CAR, in the channel Orai1 enhances Ca2+ permeation and SOCE-induced gene transcription

    Czech Academy of Sciences Publication Activity Database

    Frischauf, I.; Zayats, Vasilina; Deix, M.; Hochreiter, A.; Jardin, I.; Muik, M.; Lackner, B.; Svobodová, B.; Pammer, T.; Litviňuková, M.; Sridhar, A.A.; Derler, I.; Bogeski, I.; Romanin, Ch.; Ettrich, Rüdiger; Schindel, R.

    2015-01-01

    Roč. 8, č. 408 (2015), ra131 ISSN 1945-0877 R&D Projects: GA ČR GA13-21053S Institutional support: RVO:61388971 Keywords : MOLECULAR-DYNAMICS SIMULATIONS * CRAC CHANNEL * PORE ARCHITECTURE Subject RIV: EE - Microbiology, Virology Impact factor: 7.359, year: 2015

  3. MARKETING CHANNELS

    Directory of Open Access Journals (Sweden)

    Ljiljana Stošić Mihajlović

    2014-07-01

    Full Text Available Marketing channel is a set of entities and institutions, completion of distribution and marketing activities, attend the efficient and effective networking of producers and consumers. Marketing channels include the total flows of goods, money and information taking place between the institutions in the system of marketing, establishing a connection between them. The functions of the exchange, the physical supply and service activities, inherent in the system of marketing and trade. They represent paths which products and services are moving after the production, which will ultimately end up buying and eating by the user.

  4. Development of multitissue microfluidic dynamic array for assessing changes in gene expression associated with channel catfish appetite, growth, metabolism, and intestinal health

    Science.gov (United States)

    Large-scale, gene expression methods allow for high throughput analysis of physiological pathways at a fraction of the cost of individual gene expression analysis. Systems, such as the Fluidigm quantitative PCR array described here, can provide powerful assessments of the effects of diet, environme...

  5. Targeted gene panels and microbiota analysis provide insight into the effects of effects of alternative production diet formulations on channel catfish nutritional physiology

    Science.gov (United States)

    The present research evaluated targeted gene panels and microbiota analysis to provide greater insight into the effects of alternatively-sourced dietary ingredients on production indices, gut health, changes in the gut microbiota and genes involved in the regulation of appetite, growth, metabolism, ...

  6. Anion channels: master switches of stress responses.

    Science.gov (United States)

    Roelfsema, M Rob G; Hedrich, Rainer; Geiger, Dietmar

    2012-04-01

    During stress, plant cells activate anion channels and trigger the release of anions across the plasma membrane. Recently, two new gene families have been identified that encode major groups of anion channels. The SLAC/SLAH channels are characterized by slow voltage-dependent activation (S-type), whereas ALMT genes encode rapid-activating channels (R-type). Both S- and R-type channels are stimulated in guard cells by the stress hormone ABA, which leads to stomatal closure. Besides their role in ABA-dependent stomatal movement, anion channels are also activated by biotic stress factors such as microbe-associated molecular patterns (MAMPs). Given that anion channels occur throughout the plant kingdom, they are likely to serve a general function as master switches of stress responses. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Skeletal Muscle Na+ Channel Disorders

    Directory of Open Access Journals (Sweden)

    Dina eSimkin

    2011-10-01

    Full Text Available Five inherited human disorders affecting skeletal muscle contraction have been traced to mutations in the gene encoding the voltage-gated sodium channel Nav1.4. The main symptoms of these disorders are myotonia or periodic paralysis caused by changes in skeletal muscle fiber excitability. Symptoms of these disorders vary from mild or latent disease to incapacitating or even death in severe cases. As new human sodium channel mutations corresponding to disease states become discovered, the importance of understanding the role of the sodium channel in skeletal muscle function and disease state grows.

  8. MITOCHONDRIAL BKCa CHANNEL

    Directory of Open Access Journals (Sweden)

    Enrique eBalderas

    2015-03-01

    Full Text Available Since its discovery in a glioma cell line 15 years ago, mitochondrial BKCa channel (mitoBKCa has been studied in brain cells and cardiomyocytes sharing general biophysical properties such as high K+ conductance (~300 pS, voltage-dependency and Ca2+-sensitivity. Main advances in deciphering the molecular composition of mitoBKCa have included establishing that it is encoded by the Kcnma1 gene, that a C-terminal splice insert confers mitoBKCa ability to be targeted to cardiac mitochondria, and evidence for its potential coassembly with β subunits. Notoriously, β1 subunit directly interacts with cytochrome c oxidase and mitoBKCa can be modulated by substrates of the respiratory chain. mitoBKCa channel has a central role in protecting the heart from ischemia, where pharmacological activation of the channel impacts the generation of reactive oxygen species and mitochondrial Ca2+ preventing cell death likely by impeding uncontrolled opening of the mitochondrial transition pore. Supporting this view, inhibition of mitoBKCa with Iberiotoxin, enhances cytochrome c release from glioma mitochondria. Many tantalizing questions remain. Some of them are: how is mitoBKCa coupled to the respiratory chain? Does mitoBKCa play non-conduction roles in mitochondria physiology? Which are the functional partners of mitoBKCa? What are the roles of mitoBKCa in other cell types? Answers to these questions are essential to define the impact of mitoBKCa channel in mitochondria biology and disease.

  9. Channel Power in Multi-Channel Environments

    NARCIS (Netherlands)

    M.G. Dekimpe (Marnik); B. Skiera (Bernd)

    2004-01-01

    textabstractIn the literature, little attention has been paid to instances where companies add an Internet channel to their direct channel portfolio. However, actively managing multiple sales channels requires knowing the customers’ channel preferences and the resulting channel power. Two key

  10. On the Capacity of the Dirty Paper Channel with Fast Fading and Discrete Channel States

    OpenAIRE

    Rini, Stefano; Shitz, Shlomo Shamai

    2016-01-01

    The "writing dirty paper" capacity result crucially dependents on the perfect channel knowledge at the transmitter as the presence of even a small uncertainty in the channel realization gravely hampers the ability of the transmitter to pre-code its transmission against the channel state. This is particularly disappointing as it implies that interference pre-coding in practical systems is effective only when the channel estimates at the users have very high precision, a condition which is gene...

  11. Detection of Extended Spectrum Beta-Lactamases Resistance Genes among Bacteria Isolated from Selected Drinking Water Distribution Channels in Southwestern Nigeria.

    Science.gov (United States)

    Adesoji, Ayodele T; Ogunjobi, Adeniyi A

    2016-01-01

    Extended Spectrum Beta-Lactamases (ESBL) provide high level resistance to beta-lactam antibiotics among bacteria. In this study, previously described multidrug resistant bacteria from raw, treated, and municipal taps of DWDS from selected dams in southwestern Nigeria were assessed for the presence of ESBL resistance genes which include bla TEM, bla SHV, and bla CTX by PCR amplification. A total of 164 bacteria spread across treated (33), raw (66), and municipal taps (68), belonging to α-Proteobacteria, β-Proteobacteria, γ-Proteobacteria, Flavobacteriia, Bacilli, and Actinobacteria group, were selected for this study. Among these bacteria, the most commonly observed resistance was for ampicillin and amoxicillin/clavulanic acid (61 isolates). Sixty-one isolates carried at least one of the targeted ESBL genes with bla TEM being the most abundant (50/61) and bla CTX being detected least (3/61). Klebsiella was the most frequently identified genus (18.03%) to harbour ESBL gene followed by Proteus (14.75%). Moreover, combinations of two ESBL genes, bla SHV + bla TEM or bla CTX + bla TEM, were observed in 11 and 1 isolate, respectively. In conclusion, classic bla TEM ESBL gene was present in multiple bacterial strains that were isolated from DWDS sources in Nigeria. These environments may serve as foci exchange of genetic traits in a diversity of Gram-negative bacteria.

  12. A deletion in the Hermansky-Pudlak syndrome 4 (Hps4) gene appears to be responsible for albinism in channel catfish.

    Science.gov (United States)

    Li, Yueru; Geng, Xin; Bao, Lisui; Elaswad, Ahmed; Huggins, Kevin W; Dunham, Rex; Liu, Zhanjiang

    2017-06-01

    Albinism is caused by a series of genetic abnormalities leading to reduction of melanin production. Albinism is quite frequent in catfish, but the causative gene and the molecular basis were unknown. In this study, we conducted a genome-wide association study (GWAS) using the 250 K SNP array. The GWAS analysis allowed mapping of the albino phenotype in the Hermansky-Pudlak syndrome 4 (Hps4) gene, which is known to be involved in melanosome biosynthesis. Sequencing analysis revealed that a 99-bp deletion was present in all analyzed albino catfish at the intron 2 and exon 3 junction. This deletion led to the skipping of the entire exon 3 which was confirmed by RT-PCR. Therefore, Hps4 was determined to be the candidate gene of the catfish albinism.

  13. TRPV6 channels.

    Science.gov (United States)

    Fecher-Trost, Claudia; Weissgerber, Petra; Wissenbach, Ulrich

    2014-01-01

    TRPV6 (former synonyms ECAC2, CaT1, CaT-like) displays several specific features which makes it unique among the members of the mammalian Trp gene family (1) TRPV6 (and its closest relative, TRPV5) are the only highly Ca(2+)-selective channels of the entire TRP superfamily (Peng et al. 1999; Wissenbach et al. 2001; Voets et al. 2004). (2) Translation of Trpv6 initiates at a non-AUG codon, at ACG, located upstream of the annotated AUG, which is not used for initiation (Fecher-Trost et al. 2013). The ACG codon is nevertheless decoded by methionine. Not only a very rare event in eukaryotic biology, the full-length TRPV6 protein existing in vivo comprises an amino terminus extended by 40 amino acid residues compared to the annotated truncated TRPV6 protein which has been used in most studies on TRPV6 channel activity so far. (In the following numbering occurs according to this full-length protein, with the numbers of the so far annotated truncated protein in brackets). (3) Only in humans a coupled polymorphism of Trpv6 exists causing three amino acid exchanges and resulting in an ancestral Trpv6 haplotype and a so-called derived Trpv6 haplotype (Wissenbach et al. 2001). The ancestral allele encodes the amino acid residues C197(157), M418(378) and M721(681) and the derived alleles R197(157), V418(378) and T721(681). The ancestral haplotype is found in all species, the derived Trpv6 haplotype has only been identified in humans, and its frequency increases with the distance to the African continent. Apparently the Trpv6 gene has been a strong target for selection in humans, and its derived variant is one of the few examples showing consistently differences to the orthologues genes of other primates (Akey et al. 2004, 2006; Stajich and Hahn 2005; Hughes et al. 2008). (4) The Trpv6 gene expression is significantly upregulated in several human malignancies including the most common cancers, prostate and breast cancer (Wissenbach et al. 2001; Zhuang et al. 2002; Fixemer et al

  14. Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression.

    Science.gov (United States)

    Kwan, Patrick; Poon, Wai Sang; Ng, Ho-Keung; Kang, David E; Wong, Virginia; Ng, Ping Wing; Lui, Colin H T; Sin, Ngai Chuen; Wong, Ka S; Baum, Larry

    2008-11-01

    Many antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels. However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes. We investigated the association of AED responsiveness with genetic polymorphisms and correlated any association with mRNA expression of the neuronal sodium channels. We performed genotyping of tagging and candidate single nucleotide polymorphisms (SNPs) of SCN1A, 2A, and 3A in 471 Chinese epilepsy patients (272 drug responsive and 199 drug resistant). A total of 27 SNPs were selected based on the HapMap database. Genotype distributions in drug-responsive and drug-resistant patients were compared. SCN2A mRNA was quantified by real-time PCR in 24 brain and 57 blood samples. Its level was compared between patients with different genotypes of an SCN2A SNP found to be associated with drug responsiveness. SCN2A IVS7-32A>G (rs2304016) A alleles were associated with drug resistance (odds ratio = 2.1, 95% confidence interval: 1.2-3.7, P=0.007). Haplotypes containing the IVS7-32A>G allele A were also associated with drug resistance. IVS7-32A>G is located within the putative splicing branch site for splicing exons 7 and 9. PCR of reverse-transcribed RNA from blood or brain of patients with different IVS7-32A>G genotypes using primers in exons 7 and 9 showed no skipping of exon 8, and real-time PCR showed no difference in SCN2A mRNA levels among genotypes. Results of this study suggest an association between SCN2A IVS7-32A>G and AED responsiveness, without evidence of an effect on splicing or mRNA expression.

  15. CO-independent modification of K+ channels by tricarbonyldichlororuthenium(II) dimer (CORM-2).

    Science.gov (United States)

    Gessner, Guido; Sahoo, Nirakar; Swain, Sandip M; Hirth, Gianna; Schönherr, Roland; Mede, Ralf; Westerhausen, Matthias; Brewitz, Hans Henning; Heimer, Pascal; Imhof, Diana; Hoshi, Toshinori; Heinemann, Stefan H

    2017-11-15

    Although toxic when inhaled in high concentrations, the gas carbon monoxide (CO) is endogenously produced in mammals, and various beneficial effects are reported. For potential medicinal applications and studying the molecular processes underlying the pharmacological action of CO, so-called CO-releasing molecules (CORMs), such as tricabonyldichlororuthenium(II) dimer (CORM-2), have been developed and widely used. Yet, it is not readily discriminated whether an observed effect of a CORM is caused by the released CO gas, the CORM itself, or any of its intermediate or final breakdown products. Focusing on Ca 2+ - and voltage-dependent K + channels (K Ca 1.1) and voltage-gated K + channels (Kv1.5, Kv11.1) relevant for cardiac safety pharmacology, we demonstrate that, in most cases, the functional impacts of CORM-2 on these channels are not mediated by CO. Instead, when dissolved in aqueous solutions, CORM-2 has the propensity of forming Ru(CO) 2 adducts, preferentially to histidine residues, as demonstrated with synthetic peptides using mass-spectrometry analysis. For K Ca 1.1 channels we show that H365 and H394 in the cytosolic gating ring structure are affected by CORM-2. For Kv11.1 channels (hERG1) the extracellularly accessible histidines H578 and H587 are CORM-2 targets. The strong CO-independent action of CORM-2 on Kv11.1 and Kv1.5 channels can be completely abolished when CORM-2 is applied in the presence of an excess of free histidine or human serum albumin; cysteine and methionine are further potential targets. Off-site effects similar to those reported here for CORM-2 are found for CORM-3, another ruthenium-based CORM, but are diminished when using iron-based CORM-S1 and absent for manganese-based CORM-EDE1. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Effect of heat stress on the gene expression of ion transporters/channels in the uterus of laying hens during eggshell formation.

    Science.gov (United States)

    Bahadoran, Shahab; Dehghani Samani, Amir; Hassanpour, Hossein

    2018-01-01

    Heat stress is a problem in laying hens as it decreases egg quality by decreasing eggshell mineralization. Heat stress alters gene expression, hence our aim was to investigate effects of heat stress on gene expression of ion transport elements involving in uterine mineralization (TRPV6, CALB1, ITPR3, SCNN1G, SLC4A4, KCNJ15, SLC4A9, and CLCN2) by real time quantitative PCR. Forty 23-week-old White Leghorn laying hens were housed in two rooms. The control group (n = 20) was maintained at 21-23 °C, and the heat stress group (n = 20) was exposed to 36-38 °C for 8 weeks. All parameters of egg quality including egg weight, surface area, volume, and eggshell weight, thickness, ash weight, and calcium content were decreased in the heat stress group compared to the control group (by 26.9%, 32.7%, 44.1%, 38.4%, 31.7%, 39.4%, and 11.1%, respectively). Total plasma calcium was decreased by 13.4%. Levels of ITPR3, SLC4A4, and SLC4A9 transcripts in the uterine lining were decreased in the heat stress group compared to the control group (by 61.4%, 66.1%, and 66.1%, respectively). CALB1 transcript level was increased (by 34.2 fold) in the heat stress group of hens compared to controls. TRPV6, SCNN1G, KCNJ15, and CLCN2 transcript levels did not significantly differ between control and heat stress groups of laying hens. It is concluded that the down-expression of ITPR3, SLC4A4, and SLC4A9 genes may impair transportation of Cl - , HCO 3 - , and Na + in eggshell mineralization during heat stress. Increased CALB1 gene expression may increase resistance of uterine cells to detrimental effects of heat stress.

  17. Channelling and electromagnetic radiation of channelling particles

    International Nuclear Information System (INIS)

    Kalashnikov, N.

    1983-01-01

    A brief description is presented of the channelling of charged particles between atoms in the crystal lattice. The specificities are discussed of the transverse motion of channelling particles as are the origin and properties of quasi-characteristic radiation of channelling particles which accompany transfers from one band of permissible energies of the transverse motion of channelling particles to the other. (B.S.)

  18. Ca2+-dependent K+ Channels in Exocrine Salivary Glands

    Science.gov (United States)

    Catalán, Marcelo A.; Peña-Munzenmayer, Gaspar; Melvin, James E.

    2014-01-01

    In the last 15 years, remarkable progress has been realized in identifying the genes that encode the ion-transporting proteins involved in exocrine gland function, including salivary glands. Among these proteins, Ca2+-dependent K+ channels take part in key functions including membrane potential regulation, fluid movement and K+ secretion in exocrine glands. Two K+ channels have been identified in exocrine salivary glands: 1) a Ca2+-activated K+ channel of intermediate single channel conductance encoded by the KCNN4 gene; and, 2) a voltage- and Ca2+-dependent K+ channel of large single channel conductance encoded by the KCNMA1 gene. This review focuses on the physiological roles of Ca2+-dependent K+ channels in exocrine salivary glands. We also discuss interesting recent findings on the regulation of Ca2+-dependent K+ channels by protein-protein interactions that may significantly impact exocrine gland physiology. PMID:24559652

  19. Channel Modeling

    Science.gov (United States)

    Schmitz, Arne; Schinnenburg, Marc; Gross, James; Aguiar, Ana

    For any communication system the Signal-to-Interference-plus-Noise-Ratio of the link is a fundamental metric. Recall (cf. Chapter 9) that the SINR is defined as the ratio between the received power of the signal of interest and the sum of all "disturbing" power sources (i.e. interference and noise). From information theory it is known that a higher SINR increases the maximum possible error-free transmission rate (referred to as Shannon capacity [417] of any communication system and vice versa). Conversely, the higher the SINR, the lower will be the bit error rate in practical systems. While one aspect of the SINR is the sum of all distracting power sources, another issue is the received power. This depends on the transmitted power, the used antennas, possibly on signal processing techniques and ultimately on the channel gain between transmitter and receiver.

  20. Channeling experiment

    International Nuclear Information System (INIS)

    Abelin, H.; Birgersson, L.; Widen, H.; Aagren, T.; Moreno, L.; Neretnieks, I.

    1990-07-01

    Channeling of water flow and tracer transport in real fractures in a granite body at Stripa have been investigated experimentally. The experimental site was located 360 m below the ground level. Two kinds of experiments were performed. In the single hole experiments, 20 cm diameter holes were drilled about 2.5 m into the rock in the plane of the fracture. Specially designed packers were used to inject water into the fracture in 5 cm intervals all along the fracture trace in the hole. The variation of the injection flowrates along the fracture were used to determine the transmissivity variations in the fracture plane. Detailed photographs were taken from inside the hole and the visual fracture aperture was compared with the injection flowrates in the same locations. Geostatistical methods were used to evaluate the results. Five holes were measured in great detail. In addition 7 holes were drilled and scanned by simpler packer systems. A double hole experiment was performed where two parallel holes were drilled in the same fracture plane at nearly 2 m distance. Pressure pulse tests were made between the holes in both directions. Tracers were injected in 5 locations in one hole and monitored for in many locations in the other hole. The single hole experiment and the double hole experiment show that most of the fracture planes are tight but that there are open sections which form connected channels over distances of at least 2 meters. It was also found in the double hole experiment that the investigated fracture was intersected by at least one fracture between the two holes which diverted a large amount of the injected tracers to several distant locations at the tunnel wall. (authours)

  1. Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data

    DEFF Research Database (Denmark)

    Andreasen, Charlotte Hartig; Refsgaard, Lena; Nielsen, Jonas B

    2013-01-01

    National Heart, Lung, and Blood Institute Grand Opportunity (NHLBI GO) Exome Sequencing Project (ESP) provided important knowledge on genetic variation in the background population. Our aim was to identify all variants previously associated with SIDS in ESP to improve the discrimination between plausible......Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from...

  2. 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.

  3. Variants in calcium voltage-gated channel subunit Alpha1 C-gene (CACNA1C are associated with sleep latency in infants.

    Directory of Open Access Journals (Sweden)

    Katri Kantojärvi

    Full Text Available Genetic variants in CACNA1C (calcium voltage-gated channel subunit alpha1 C are associated with bipolar disorder and schizophrenia where sleep disturbances are common. In an experimental model, Cacna1c has been found to modulate the electrophysiological architecture of sleep. There are strong genetic influences for consolidation of sleep in infancy, but only a few studies have thus far researched the genetic factors underlying the process. We hypothesized that genetic variants in CACNA1C affect the regulation of sleep in early development. Seven variants that were earlier associated (genome-wide significantly with psychiatric disorders at CACNA1C were selected for analyses. The study sample consists of 1086 infants (520 girls and 566 boys from the Finnish CHILD-SLEEP birth cohort (genotyped by Illumina Infinium PsychArray BeadChip. Sleep length, latency, and nightly awakenings were reported by the parents of the infants with a home-delivered questionnaire at 8 months of age. The genetic influence of CACNA1C variants on sleep in infants was examined by using PLINK software. Three of the examined CACNA1C variants, rs4765913, rs4765914, and rs2239063, were associated with sleep latency (permuted P<0.05. There was no significant association between studied variants and night awakenings or sleep duration. CACNA1C variants for psychiatric disorders were found to be associated with long sleep latency among 8-month-old infants. It remains to be clarified whether the findings refer to defective regulation of sleep, or to distractibility of sleep under external influences.

  4. Polymorphisms in voltage-gated sodium channel gene and susceptibility of Aedes albopictus to insecticides in three districts of northern West Bengal, India.

    Science.gov (United States)

    Chatterjee, Moytrey; Ballav, Sudeep; Maji, Ardhendu K; Basu, Nandita; Sarkar, Biplab Chandra; Saha, Pabitra

    2018-01-01

    The control and prevention of dengue largely depends on vector control measures, environmental management, and personal protection. Dengue control programmes are facing great challenges due to development of insecticide resistance among vector mosquitoes. Information on susceptibility status to different insecticides is important for national programmes to formulate vector control strategies. We have studied the larval susceptibility of Aedes albopictus to temephos and adult susceptibility to 4% DDT, 0.05% deltamethrin, and 5% malathion as per WHO protocols in the northern districts of West Bengal. Polymorphisms in the VGSC gene were studied by direct sequencing of PCR products. The Ae. albopictus larval population showed sensitive [Resistance Ratio (RR99)resistance (510) to temephos at different study sites. Adult bioassay results revealed that Ae. albopictus was highly resistant to DDT [Corrected Mortality (CM) 98%), except in Dhupguri where a low level of resistance to deltamethrin (CM = 96.25%) was recorded. None of the six important kdr mutations (S953P, I975M/V, L978, V980G, F1474C, D1703Y) were found in the VGSC of studied mosquitoes, but we identified 11 synonymous and 1 non-synonymous mutation in the VGSC gene. The higher susceptibility level to deltamethrin and malathion, along with the absence of important kdr mutations indicates that these two insecticides are still effective against Ae. albopictus in the study areas. The susceptibility status of temephos should be monitored closely as low to moderate levels of resistance were observed in few sites. A similar study is recommended for monitoring and early detection of insecticide resistance in other parts of the country.

  5. A Single Nucleotide Polymorphism (rs4236480 in TRPV5 Calcium Channel Gene Is Associated with Stone Multiplicity in Calcium Nephrolithiasis Patients

    Directory of Open Access Journals (Sweden)

    Anas Khaleel

    2015-01-01

    Full Text Available Nephrolithiasis is characterized by calcification of stones in the kidneys from an unknown cause. Animal models demonstrated the functional roles of the transient receptor potential vanilloid member 5 (TRPV5 gene in calcium renal reabsorption and hypercalciuria. Therefore, TRPV5 was suggested to be involved in calcium homeostasis. However, whether genetic polymorphisms of TRPV5 are associated with kidney stone multiplicity or recurrence is unclear. In this study, 365 Taiwanese kidney-stone patients were recruited. Both biochemical data and DNA samples were collected. Genotyping was performed by a TaqMan allelic discrimination assay. We found that a TRPV5 polymorphism (rs4236480 was observed to be associated with stone multiplicity of calcium nephrolithiasis, as the risk of stone multiplicity was higher in patients with the TT+CT genotype than in patients with the CC genotype (p=0.0271. In summary, despite the complexity of nephrolithiasis and the potential association of numerous calcium homeostatic absorption/reabsorption factors, TRPV5 plays an important role in the pathogenesis of calcium nephrolithiasis.

  6. KATP Channels in the Cardiovascular System.

    Science.gov (United States)

    Foster, Monique N; Coetzee, William A

    2016-01-01

    KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms of their biophysical properties, nucleotide sensitivities, and modification by pharmacological compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their regulation by complex biological systems, are only now emerging for many tissues. Even in tissues where their roles have been best defined, there are still many unanswered questions. This review aims to summarize the properties, molecular composition, and pharmacology of KATP channels in various cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse models and address the known roles of KATP channels in cardiovascular pathologies and how genetic variation in KATP channel genes contribute to human disease. Copyright © 2016 the American Physiological Society.

  7. Major Channels Involved In Neuropsychiatric Disorders And Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Paola eImbrici

    2013-05-01

    Full Text Available Voltage-gated ion channels are important mediators of physiological functions in the central nervous system. The cyclic activation of these channels influences neurotransmitter release, neuron excitability, gene transcription and plasticity, providing distinct brain areas with unique physiological and pharmacological response. A growing body of data has implicated ion channels in the susceptibility or pathogenesis of psychiatric diseases. Indeed, population studies support the association of polymorphisms in calcium and potassium channels with the genetic risk for bipolar disorders or schizophrenia. Moreover, point mutations in calcium, sodium and potassium channel genes have been identified in some childhood developmental disorders. Finally, antibodies against potassium channel complexes occur in a series of autoimmune psychiatric diseases. Here we report recent studies assessing the role of calcium, sodium and potassium channels in bipolar disorder, schizophrenia and autism spectrum disorders, and briefly summarize promising pharmacological strategies targeted on ion channels for the therapy of mental illness and related genetic tests.

  8. 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

  9. Long QT 1 mutation KCNQ1A344V increases local anesthetic sensitivity of the slowly activating delayed rectifier potassium current

    DEFF Research Database (Denmark)

    Siebrands, Cornelia C; Binder, Stephan; Eckhoff, Ulrike

    2006-01-01

    BACKGROUND: Anesthesia in patients with long QT syndrome (LQTS) is a matter of concern. Congenital LQTS is most frequently caused by mutations in KCNQ1 (Kv7.1), whereas drug-induced LQTS is a consequence of HERG (human ether-a-go-go-related gene) channel inhibition. The aim of this study was to i...

  10. A point mutation (L1015F) of the voltage-sensitive sodium channel gene associated with lambda-cyhalothrin resistance in Apolygus lucorum (Meyer-Dür) population from the transgenic Bt cotton field of China.

    Science.gov (United States)

    Zhen, Congai; Gao, Xiwu

    2016-02-01

    In China, the green mirid bug, Apolygus lucorum (Meyer-Dür), has caused severe economic damage to many kinds of crops, especially the cotton and jujubes. Pyrethroid insecticides have been widely used for controlling this pest in the transgenic Bt cotton field. Five populations of A. lucorum collected from cotton crops at different locations in China were evaluated for lambda-cyhalothrin resistance. The results showed that only the population collected from Shandong Province exhibited 30-fold of resistance to lambda-cyhalothrin. Neither PBO nor DEF had obvious synergism when compared the synergistic ratio between SS and RR strain which was originated from the Shandong population. Besides, there were no statistically significant differences (p>0.05) in the carboxylesterase, glutathione S-transferase, or 7-ethoxycoumarin O-deethylase activities between the Shandong population and the laboratory susceptible strain (SS). The full-length sodium channel gene named AlVSSC encoding 2028 amino acids was obtained by RT-PCR and rapid amplification of cDNA ends (RACE). One single point mutation L1015F in the AlVSSC was detected only in the Shandong population. Our results revealed that the L1015F mutation associated with pyrethroid resistance was identified in A. lucorum populations in China. These results will be useful for the rational chemical control of A. lucorum in the transgenic Bt cotton field. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Molecular cloning and functional expression of the Equine K+ channel KV11.1 (Ether à Go-Go-related/KCNH2 gene) and the regulatory subunit KCNE2 from equine myocardium

    DEFF Research Database (Denmark)

    Pedersen, Philip Juul; Thomsen, Kirsten Brolin; Olander, Emma Rie

    2015-01-01

    and conventional PCR on mRNA purified from equine myocardial tissue. Equine KV11.1 and KCNE2 cDNA had a high homology to human genes (93 and 88%, respectively). Equine and human KV11.1 and KV11.1/KCNE2 were expressed in Xenopus laevis oocytes and investigated by two-electrode voltage-clamp. Equine KV11.1 currents...... were larger compared to human KV11.1, and the voltage dependence of activation was shifted to more negative values with V1/2 = -14.2±1.1 mV and -17.3±0.7, respectively. The onset of inactivation was slower for equine KV11.1 compared to the human homolog. These differences in kinetics may account...... for the larger amplitude of the equine current. Furthermore, the equine KV11.1 channel was susceptible to pharmacological block with terfenadine. The physiological importance of KV11.1 was investigated in equine right ventricular wedge preparations. Terfenadine prolonged action potential duration and the effect...

  12. Citizens and service channels: channel choice and channel management implications

    NARCIS (Netherlands)

    Pieterson, Willem Jan

    2010-01-01

    The arrival of electronic channels in the 1990s has had a huge impact on governmental service delivery. The new channels have led to many new opportunities to improve public service delivery, not only in terms of citizen satisfaction, but also in cost reduction for governmental agencies. However,

  13. Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity.

    Science.gov (United States)

    Durdagi, Serdar; Randall, Trevor; Duff, Henry J; Chamberlin, Adam; Noskov, Sergei Y

    2014-03-08

    The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart's action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus "rehabilitation" studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market. In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the market due to its high hERG1 blocking affinity. Here we tested an a priori strategy to predict a compound's cardiotoxicity using de novo drug design with molecular docking and Molecular Dynamics (MD) simulations to generate a strategy for the rehabilitation of cisapride. We focused on two key receptors, a target interaction with the (adenosine) receptor and an off-target interaction with hERG1 channels. An analysis of the fragment interactions of cisapride at human A2A adenosine receptors and hERG1 central cavities helped us to identify the key chemical groups responsible for the drug activity and hERG1 blockade. A set of cisapride derivatives with reduced cardiotoxicity was then proposed using an in-silico two-tier approach. This set was compared against a large dataset of commercially available cisapride analogs and derivatives. An interaction decomposition of cisapride and cisapride derivatives allowed for the identification of key active scaffolds and functional groups that may be responsible for the unwanted blockade of hERG1.

  14. [Channels: a new way to revisit pathology].

    Science.gov (United States)

    Fournier, Emmanuel

    2014-02-01

    Many "essential" diseases that manifest themselves in the form of crises or fits (epilepsies, episodic ataxia, periodic paralyses, myotonia, heart rhythm disorders, etc.) are due to ionic channel dysfunction and are thus referred to as "channelopathies". Some of these disorders are congenital, due to mutations of genes encoding channel subunits, while others result from toxic, immune or hormonal disturbances affecting channelfunction. Channelopathies take on a wide variety of clinical forms, depending on the type of channel (sodium, potassium, calcium, chloride...) and the type of dysfunction (loss or gain of function). Some apparently unrelated diseases affecting distinct organs are due to a similar dysfunction of the same channel, revealing unsuspected relationships between organs and between medical specialties. In addition, a given syndrome can be caused by distinct channel dysfunctions. This provides new opportunities for diferential diagnosis and specific correction of the causal defects, although some treatments find applications across multiple medical specialties.

  15. Detection of the V1016G mutation in the voltage-gated sodium channel gene of Aedes aegypti (Diptera: Culicidae) by allele-specific PCR assay, and its distribution and effect on deltamethrin resistance in Thailand.

    Science.gov (United States)

    Stenhouse, Steven A; Plernsub, Suriya; Yanola, Jintana; Lumjuan, Nongkran; Dantrakool, Anchalee; Choochote, Wej; Somboon, Pradya

    2013-08-30

    Resistance to pyrethroid insecticides is widespread among populations of Aedes aegypti, the main vector for the dengue virus. Several different point mutations within the voltage-gated sodium channel (VGSC) gene contribute to such resistance. A mutation at position 1016 in domain II, segment 6 of the VGSC gene in Ae. aegypti leads to a valine to glycine substitution (V1016G) that confers resistance to deltamethrin. This study developed and utilized an allele-specific PCR (AS-PCR) assay that could be used to detect the V1016G mutation. The assay was validated against a number of sequenced DNA samples of known genotype and was determined to be in complete agreement. Larvae and pupae were collected from various localities throughout Thailand. Samples were reared to adulthood and their resistance status against deltamethrin was determined by standard WHO susceptibility bioassays. Deltamethrin-resistant and susceptible insects were then genotyped for the V1016G mutation. Additionally, some samples were genotyped for a second mutation at position 1534 in domain III (F1534C) which is also known to confer pyrethroid resistance. The bioassay results revealed an overall mortality of 77.6%. Homozygous 1016G individuals survived at higher rates than either heterozygous or wild-type (1016 V) mosquitoes. The 1016G mutation was significantly and positively associated with deltamethrin resistance and was widely distributed throughout Thailand. Interestingly, wild-type 1016 V mosquitoes tested were homozygous for the 1534C mutation, and all heterozygous mosquitoes were also heterozygous for 1534C. Mutant homozygous (G/G) mosquitoes expressed the wild-type (F/F) at position 1534. However, the presence of the 1534C mutation was not associated with deltamethrin resistance. Our bioassay results indicate that all populations sampled display some degree of resistance to deltamethrin. Homozygous 1016G mosquitoes were far likelier to survive such exposure. However, resistance in some

  16. Association between Three Mutations, F1565C, V1023G and S996P, in the Voltage-Sensitive Sodium Channel Gene and Knockdown Resistance in Aedes aegypti from Yogyakarta, Indonesia.

    Science.gov (United States)

    Wuliandari, Juli Rochmijati; Lee, Siu Fai; White, Vanessa Linley; Tantowijoyo, Warsito; Hoffmann, Ary Anthony; Endersby-Harshman, Nancy Margaret

    2015-07-23

    Mutations in the voltage-sensitive sodium channel gene (Vssc) have been identified in Aedes aegypti and some have been associated with pyrethroid insecticide resistance. Whether these mutations cause resistance, alone or in combination with other alleles, remains unclear, but must be understood if mutations are to become markers for resistance monitoring. We describe High Resolution Melt (HRM) genotyping assays for assessing mutations found in Ae. aegypti in Indonesia (F1565C, V1023G, S996P) and use them to test for associations with pyrethroid resistance in mosquitoes from Yogyakarta, a city where insecticide use is widespread. Such knowledge is important because Yogyakarta is a target area for releases of Wolbachia-infected mosquitoes with virus-blocking traits for dengue suppression. We identify three alleles across Yogyakarta putatively linked to resistance in previous research. By comparing resistant and susceptible mosquitoes from bioassays, we show that the 1023G allele is associated with resistance to type I and type II pyrethroids. In contrast, F1565C homozygotes were rare and there was only a weak association between individuals heterozygous for the mutation and resistance to a type I pyrethroid. As the heterozygote is expected to be incompletely recessive, it is likely that this association was due to a different resistance mechanism being present. A resistance advantage conferred to V1023G homozygotes through addition of the S996P allele in the homozygous form was suggested for the Type II pyrethroid, deltamethrin. Screening of V1023G and S996P should assist resistance monitoring in Ae. aegypti from Yogyakarta, and these mutations should be maintained in Wolbachia strains destined for release in this city to ensure that these virus-blocking strains of mosquitoes are not disadvantaged, relative to resident populations.

  17. Surfing the wave, cycle, life history, and genes/proteins expressed by testicular germ cells. Part 4: intercellular bridges, mitochondria, nuclear envelope, apoptosis, ubiquitination, membrane/voltage-gated channels, methylation/acetylation, and transcription factors.

    Science.gov (United States)

    Hermo, Louis; Pelletier, R-Marc; Cyr, Daniel G; Smith, Charles E

    2010-04-01

    As germ cells divide and differentiate from spermatogonia to spermatozoa, they share a number of structural and functional features that are common to all generations of germ cells and these features are discussed herein. Germ cells are linked to one another by large intercellular bridges which serve to move molecules and even large organelles from the cytoplasm of one cell to another. Mitochondria take on different shapes and features and topographical arrangements to accommodate their specific needs during spermatogenesis. The nuclear envelope and pore complex also undergo extensive modifications concomitant with the development of germ cell generations. Apoptosis is an event that is normally triggered by germ cells and involves many proteins. It occurs to limit the germ cell pool and acts as a quality control mechanism. The ubiquitin pathway comprises enzymes that ubiquitinate as well as deubiquitinate target proteins and this pathway is present and functional in germ cells. Germ cells express many proteins involved in water balance and pH control as well as voltage-gated ion channel movement. In the nucleus, proteins undergo epigenetic modifications which include methylation, acetylation, and phosphorylation, with each of these modifications signaling changes in chromatin structure. Germ cells contain specialized transcription complexes that coordinate the differentiation program of spermatogenesis, and there are many male germ cell-specific differences in the components of this machinery. All of the above features of germ cells will be discussed along with the specific proteins/genes and abnormalities to fertility related to each topic. Copyright 2009 Wiley-Liss, Inc.

  18. USACE Navigation Channels 2012

    Data.gov (United States)

    California Natural Resource Agency — This dataset represents both San Francisco and Los Angeles District navigation channel lines. All San Francisco District channel lines were digitized from CAD files...

  19. Calcium channel blocker overdose

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/002580.htm Calcium-channel blocker overdose To use the sharing features on this page, please enable JavaScript. Calcium-channel blockers are a type of medicine used ...

  20. Dental enamel cells express functional SOCE channels.

    Science.gov (United States)

    Nurbaeva, Meerim K; Eckstein, Miriam; Concepcion, Axel R; Smith, Charles E; Srikanth, Sonal; Paine, Michael L; Gwack, Yousang; Hubbard, Michael J; Feske, Stefan; Lacruz, Rodrigo S

    2015-10-30

    Dental enamel formation requires large quantities of Ca(2+) yet the mechanisms mediating Ca(2+) dynamics in enamel cells are unclear. Store-operated Ca(2+) entry (SOCE) channels are important Ca(2+) influx mechanisms in many cells. SOCE involves release of Ca(2+) from intracellular pools followed by Ca(2+) entry. The best-characterized SOCE channels are the Ca(2+) release-activated Ca(2+) (CRAC) channels. As patients with mutations in the CRAC channel genes STIM1 and ORAI1 show abnormal enamel mineralization, we hypothesized that CRAC channels might be an important Ca(2+) uptake mechanism in enamel cells. Investigating primary murine enamel cells, we found that key components of CRAC channels (ORAI1, ORAI2, ORAI3, STIM1, STIM2) were expressed and most abundant during the maturation stage of enamel development. Furthermore, inositol 1,4,5-trisphosphate receptor (IP3R) but not ryanodine receptor (RyR) expression was high in enamel cells suggesting that IP3Rs are the main ER Ca(2+) release mechanism. Passive depletion of ER Ca(2+) stores with thapsigargin resulted in a significant raise in [Ca(2+)]i consistent with SOCE. In cells pre-treated with the CRAC channel blocker Synta-66 Ca(2+) entry was significantly inhibited. These data demonstrate that enamel cells have SOCE mediated by CRAC channels and implicate them as a mechanism for Ca(2+) uptake in enamel formation.

  1. Quantum Channels With Memory

    International Nuclear Information System (INIS)

    Rybar, T.

    2012-01-01

    Quantum memory channels represent a very general, yet simple and comprehensible model for causal processes. As such they have attracted considerable research interest, mostly aimed on their transfer capabilities and structure properties. Most notably it was shown that memory channels can be implemented via physically naturally motivated collision models. We also define the concept of repeatable channels and show that only unital channels can be implemented repeat ably with pure memory channels. In the special case of qubit channels we also show that every unital qubit channel has a repeatable implementation. We also briefly explore the possibilities of stroboscopical simulation of channels and show that all random unitary channels can be stroboscopically simulated. Particularly in qubit case, all indivisible qubit channels are also random unitary, hence for qubit all indivisible channels can be stroboscopically simulated. Memory channels also naturally capture the framework of correlated experiments. We develop methods to gather and interpret data obtained in such setting and in detail examine the two qubit case. We also show that for control unitary interactions the measured data will never contradict a simple unitary evolution. Thus no memory effects can be spotted then. (author)

  2. Eight channel fast scalar

    Energy Technology Data Exchange (ETDEWEB)

    Waddoup, W D; Stubbs, R J [Durham Univ. (UK)

    1977-11-01

    An eight channel 64-bit scaler has been constructed with a static CMOS memory. Scaling frequencies are independently variable, at each channel, as are the number of bits/channel. The scaler, when used in conjunction with a multichannel charge to time converter results in a very flexible, gated multichannel ADC.

  3. KV7 potassium channels

    DEFF Research Database (Denmark)

    Stott, Jennifer B; Jepps, Thomas Andrew; Greenwood, Iain A

    2014-01-01

    Potassium channels are key regulators of smooth muscle tone, with increases in activity resulting in hyperpolarisation of the cell membrane, which acts to oppose vasoconstriction. Several potassium channels exist within smooth muscle, but the KV7 family of voltage-gated potassium channels have been...

  4. Fine Channel Networks

    Science.gov (United States)

    1997-01-01

    A color image of fine channel networks on Mars; north toward top. The scene shows heavily cratered highlands dissected by dendritic open channel networks that dissect steep slopes of impact crater walls. This image is a composite of Viking high-resolution images in black and white and low-resolution images in color. The image extends from latitude 9 degrees S. to 5 degrees S. and from longitude 312 degrees to 320 degrees; Mercator projection. The dendritic pattern of the fine channels and their location on steep slopes leads to the interpretation that these are runoff channels. The restriction of these types of channels to ancient highland rocks suggests that these channels are old and date from a time on Mars when conditions existed for precipitation to actively erode rocks. After the channels reach a low plain, they appear to end. Termination may have resulted from burial by younger deposits or perhaps the flows percolated into the surface materials and continued underground.

  5. Compound Wiretap Channels

    Directory of Open Access Journals (Sweden)

    Shlomo Shamai (Shitz

    2009-01-01

    Full Text Available This paper considers the compound wiretap channel, which generalizes Wyner's wiretap model to allow the channels to the (legitimate receiver and to the eavesdropper to take a number of possible states. No matter which states occur, the transmitter guarantees that the receiver decodes its message and that the eavesdropper is kept in full ignorance about the message. The compound wiretap channel can also be viewed as a multicast channel with multiple eavesdroppers, in which the transmitter sends information to all receivers and keeps the information secret from all eavesdroppers. For the discrete memoryless channel, lower and upper bounds on the secrecy capacity are derived. The secrecy capacity is established for the degraded channel and the semideterministic channel with one receiver. The parallel Gaussian channel is further studied. The secrecy capacity and the secrecy degree of freedom (s.d.o.f. are derived for the degraded case with one receiver. Schemes to achieve the s.d.o.f. for the case with two receivers and two eavesdroppers are constructed to demonstrate the necessity of a prefix channel in encoder design. Finally, the multi-antenna (i.e., MIMO compound wiretap channel is studied. The secrecy capacity is established for the degraded case and an achievable s.d.o.f. is given for the general case.

  6. Compound Wiretap Channels

    Directory of Open Access Journals (Sweden)

    Kramer Gerhard

    2009-01-01

    Full Text Available Abstract This paper considers the compound wiretap channel, which generalizes Wyner's wiretap model to allow the channels to the (legitimate receiver and to the eavesdropper to take a number of possible states. No matter which states occur, the transmitter guarantees that the receiver decodes its message and that the eavesdropper is kept in full ignorance about the message. The compound wiretap channel can also be viewed as a multicast channel with multiple eavesdroppers, in which the transmitter sends information to all receivers and keeps the information secret from all eavesdroppers. For the discrete memoryless channel, lower and upper bounds on the secrecy capacity are derived. The secrecy capacity is established for the degraded channel and the semideterministic channel with one receiver. The parallel Gaussian channel is further studied. The secrecy capacity and the secrecy degree of freedom ( are derived for the degraded case with one receiver. Schemes to achieve the for the case with two receivers and two eavesdroppers are constructed to demonstrate the necessity of a prefix channel in encoder design. Finally, the multi-antenna (i.e., MIMO compound wiretap channel is studied. The secrecy capacity is established for the degraded case and an achievable is given for the general case.

  7. ATP Release Channels

    Directory of Open Access Journals (Sweden)

    Akiyuki Taruno

    2018-03-01

    Full Text Available Adenosine triphosphate (ATP has been well established as an important extracellular ligand of autocrine signaling, intercellular communication, and neurotransmission with numerous physiological and pathophysiological roles. In addition to the classical exocytosis, non-vesicular mechanisms of cellular ATP release have been demonstrated in many cell types. Although large and negatively charged ATP molecules cannot diffuse across the lipid bilayer of the plasma membrane, conductive ATP release from the cytosol into the extracellular space is possible through ATP-permeable channels. Such channels must possess two minimum qualifications for ATP permeation: anion permeability and a large ion-conducting pore. Currently, five groups of channels are acknowledged as ATP-release channels: connexin hemichannels, pannexin 1, calcium homeostasis modulator 1 (CALHM1, volume-regulated anion channels (VRACs, also known as volume-sensitive outwardly rectifying (VSOR anion channels, and maxi-anion channels (MACs. Recently, major breakthroughs have been made in the field by molecular identification of CALHM1 as the action potential-dependent ATP-release channel in taste bud cells, LRRC8s as components of VRACs, and SLCO2A1 as a core subunit of MACs. Here, the function and physiological roles of these five groups of ATP-release channels are summarized, along with a discussion on the future implications of understanding these channels.

  8. Voltage-gated sodium channels: action players with many faces

    NARCIS (Netherlands)

    Koopmann, Tamara T.; Bezzina, Connie R.; Wilde, Arthur A. M.

    2006-01-01

    Voltage-gated sodium channels are responsible for the upstroke of the action potential and thereby play an important role in propagation of the electrical impulse in excitable tissues like muscle, nerve and the heart. Duplication of the sodium channels encoding genes during evolution generated the

  9. Volume Regulated Channels

    DEFF Research Database (Denmark)

    Klausen, Thomas Kjær

    of volume perturbations evolution have developed system of channels and transporters to tightly control volume homeostasis. In the past decades evidence has been mounting, that the importance of these volume regulated channels and transporters are not restricted to the defense of cellular volume...... but are also essential for a number of physiological processes such as proliferation, controlled cell death, migration and endocrinology. The thesis have been focusing on two Channels, namely the swelling activated Cl- channel (ICl, swell) and the transient receptor potential Vanilloid (TRPV4) channel. I: Cl......- serves a multitude of functions in the mammalian cell, regulating the membrane potential (Em), cell volume, protein activity and the driving force for facilitated transporters giving Cl- and Cl- channels a major potential of regulating cellular function. These functions include control of the cell cycle...

  10. HIPPI and Fibre Channel

    International Nuclear Information System (INIS)

    Tolmie, D.E.

    1992-01-01

    The High-Performance Parallel Interface (HIPPI) and Fibre Channel are near-gigabit per second data communications interfaces being developed in ANSI standards Task Group X3T9.3. HIPPI is the current interface of choice in the high-end and supercomputer arena, and Fibre Channel is a follow-on effort. HIPPI came from a local area network background, and Fibre Channel came from a mainframe to peripheral interface background

  11. Nuclear reactor coolant channels

    International Nuclear Information System (INIS)

    Macbeth, R.V.

    1978-01-01

    Reference is made to coolant channels for pressurised water and boiling water reactors and the arrangement described aims to improve heat transfer between the fuel rods and the coolant. Baffle means extending axially within the channel are provided and disposed relative to the fuel rods so as to restrict flow oscillations occurring within the coolant from being propagated transversely to the axis of the channel. (UK)

  12. Ca²⁺-dependent K⁺ channels in exocrine salivary glands.

    Science.gov (United States)

    Catalán, Marcelo A; Peña-Munzenmayer, Gaspar; Melvin, James E

    2014-06-01

    In the last 15 years, remarkable progress has been realized in identifying the genes that encode the ion-transporting proteins involved in exocrine gland function, including salivary glands. Among these proteins, Ca(2+)-dependent K(+) channels take part in key functions including membrane potential regulation, fluid movement and K(+) secretion in exocrine glands. Two K(+) channels have been identified in exocrine salivary glands: (1) a Ca(2+)-activated K(+) channel of intermediate single channel conductance encoded by the KCNN4 gene, and (2) a voltage- and Ca(2+)-dependent K(+) channel of large single channel conductance encoded by the KCNMA1 gene. This review focuses on the physiological roles of Ca(2+)-dependent K(+) channels in exocrine salivary glands. We also discuss interesting recent findings on the regulation of Ca(2+)-dependent K(+) channels by protein-protein interactions that may significantly impact exocrine gland physiology. Published by Elsevier Ltd.

  13. New Channels, New Possibilities

    DEFF Research Database (Denmark)

    Pieterson, Willem; Ebbers, Wolfgang; Østergaard Madsen, Christian

    2017-01-01

    In this contribution we discuss the characteristics of what we call the fourth generation of public sector service channels: social robots. Based on a review of relevant literature we discuss their characteristics and place into multi-channel models of service delivery. We argue that social robots......-channel models of service delivery. This is especially relevant given the current lack of evaluations of such models, the broad range of channels available, and their different stages of deployment at governments around the world. Nevertheless, social robots offer an potentially very relevant addition...

  14. Calcium Channel Blockers

    Science.gov (United States)

    ... Certain calcium channel blockers interact with grapefruit products. Kaplan NM, et al. Treatment of hypertension: Drug therapy. In: Kaplan's Clinical Hypertension. 11th ed. Philadelphia, Pa.: Wolters Kluwer ...

  15. A channel profile analyser

    International Nuclear Information System (INIS)

    Gobbur, S.G.

    1983-01-01

    It is well understood that due to the wide band noise present in a nuclear analog-to-digital converter, events at the boundaries of adjacent channels are shared. It is a difficult and laborious process to exactly find out the shape of the channels at the boundaries. A simple scheme has been developed for the direct display of channel shape of any type of ADC on a cathode ray oscilliscope display. This has been accomplished by sequentially incrementing the reference voltage of a precision pulse generator by a fraction of a channel and storing ADC data in alternative memory locations of a multichannel pulse height analyser. Alternative channels are needed due to the sharing at the boundaries of channels. In the flat region of the profile alternate memory locations are channels with zero counts and channels with the full scale counts. At the boundaries all memory locations will have counts. The shape of this is a direct display of the channel boundaries. (orig.)

  16. Genes and Gene Therapy

    Science.gov (United States)

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  17. Calcium homeostasis modulator (CALHM) ion channels.

    Science.gov (United States)

    Ma, Zhongming; Tanis, Jessica E; Taruno, Akiyuki; Foskett, J Kevin

    2016-03-01

    Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (∼1.5 mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of ∼14 Å. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology.

  18. A linearization of quantum channels

    Science.gov (United States)

    Crowder, Tanner

    2015-06-01

    Because the quantum channels form a compact, convex set, we can express any quantum channel as a convex combination of extremal channels. We give a Euclidean representation for the channels whose inverses are also valid channels; these are a subset of the extreme points. They form a compact, connected Lie group, and we calculate its Lie algebra. Lastly, we calculate a maximal torus for the group and provide a constructive approach to decomposing any invertible channel into a product of elementary channels.

  19. Omni channel fashion shopping

    NARCIS (Netherlands)

    Kemperman, A.D.A.M.; van Delft, L.; Borgers, A.W.J.; Pantano, E.

    2015-01-01

    This chapter gives insight into consumers' online and offline fashion shopping behavior, consumers' omni-channel usage during the shopping process, and consumer fashion shopper segments. Based on a literature review, omni-channel shopping behavior during the shopping process was operationalized.

  20. Channel electron multipliers

    International Nuclear Information System (INIS)

    Seidman, A.; Avrahami, Z.; Sheinfux, B.; Grinberg, J.

    1976-01-01

    A channel electron multiplier is described having a tubular wall coated with a secondary-electron emitting material and including an electric field for accelerating the electrons, the electric field comprising a plurality of low-resistive conductive rings each alternating with a high-resistive insulating ring. The thickness of the low-resistive rings is many times larger than that of the high-resistive rings, being in the order of tens of microns for the low-resistive rings and at least one order of magnitude lower for the high-resistive rings; and the diameter of the channel tubular walls is also many times larger than the thickness of the high-resistive rings. Both single-channel and multiple-channel electron multipliers are described. A very important advantage, particularly in making multiple-channel multipliers, is the simplicity of the procedure that may be used in constructing such multipliers. Other operational advantages are described

  1. Cardiac potassium channel subtypes

    DEFF Research Database (Denmark)

    Schmitt, Nicole; Grunnet, Morten; Olesen, Søren-Peter

    2014-01-01

    About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K(+) channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K(+) channels...... drive the late repolarization of the ventricle with some redundancy, and in atria this repolarization reserve is supplemented by the fairly atrial-specific KV1.5, Kir3, KCa, and K2P channels. The role of the latter two subtypes in atria is currently being clarified, and several findings indicate...... that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K(+) channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure...

  2. Cl- channels in apoptosis

    DEFF Research Database (Denmark)

    Wanitchakool, Podchanart; Ousingsawat, Jiraporn; Sirianant, Lalida

    2016-01-01

    A remarkable feature of apoptosis is the initial massive cell shrinkage, which requires opening of ion channels to allow release of K(+), Cl(-), and organic osmolytes to drive osmotic water movement and cell shrinkage. This article focuses on the role of the Cl(-) channels LRRC8, TMEM16/anoctamin......, and cystic fibrosis transmembrane conductance regulator (CFTR) in cellular apoptosis. LRRC8A-E has been identified as a volume-regulated anion channel expressed in many cell types. It was shown to be required for regulatory and apoptotic volume decrease (RVD, AVD) in cultured cell lines. Its presence also......(-) channels or as regulators of other apoptotic Cl(-) channels, such as LRRC8. CFTR has been known for its proapoptotic effects for some time, and this effect may be based on glutathione release from the cell and increase in cytosolic reactive oxygen species (ROS). Although we find that CFTR is activated...

  3. CHANNEL ESTIMATION TECHNIQUE

    DEFF Research Database (Denmark)

    2015-01-01

    A method includes determining a sequence of first coefficient estimates of a communication channel based on a sequence of pilots arranged according to a known pilot pattern and based on a receive signal, wherein the receive signal is based on the sequence of pilots transmitted over the communicat......A method includes determining a sequence of first coefficient estimates of a communication channel based on a sequence of pilots arranged according to a known pilot pattern and based on a receive signal, wherein the receive signal is based on the sequence of pilots transmitted over...... the communication channel. The method further includes determining a sequence of second coefficient estimates of the communication channel based on a decomposition of the first coefficient estimates in a dictionary matrix and a sparse vector of the second coefficient estimates, the dictionary matrix including...... filter characteristics of at least one known transceiver filter arranged in the communication channel....

  4. Cardiac Delayed Rectifier Potassium Channels in Health and Disease

    Science.gov (United States)

    Chen, Lei; Sampson, Kevin J.; Kass, Robert S.

    2016-01-01

    Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this chapter, we will review the molecular identities and biophysical properties of these channels. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the possibility and prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. PMID:27261823

  5. Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy

    Directory of Open Access Journals (Sweden)

    Stylianos Michalakis

    2018-03-01

    Full Text Available The first step in vision is the absorption of photons by the photopigments in cone and rod photoreceptors. After initial amplification within the phototransduction cascade the signal is translated into an electrical signal by the action of cyclic nucleotide-gated (CNG channels. CNG channels are ligand-gated ion channels that are activated by the binding of cyclic guanosine monophosphate (cGMP or cyclic adenosine monophosphate (cAMP. Retinal CNG channels transduce changes in intracellular concentrations of cGMP into changes of the membrane potential and the Ca2+ concentration. Structurally, the CNG channels belong to the superfamily of pore-loop cation channels and share a common gross structure with hyperpolarization-activated cyclic nucleotide-gated (HCN channels and voltage-gated potassium channels (KCN. In this review, we provide an overview on the molecular properties of CNG channels and describe their physiological role in the phototransduction pathways. We also discuss insights into the pathophysiological role of CNG channel proteins that have emerged from the analysis of CNG channel-deficient animal models and human CNG channelopathies. Finally, we summarize recent gene therapy activities and provide an outlook for future clinical application.

  6. Characterization of an aquaporin-2 water channel gene mutation causing partial nephrogenic diabetes insipidus in a Mexican family: evidence of increased frequency of the mutation in the town of origin.

    NARCIS (Netherlands)

    Boccalandro, C.; Mattia, F.P. de; Guo, D.C.; Xue, L.; Orlander, P.; King, T.M.; Gupta, P.; Deen, P.M.T.; Lavis, V.R.; Milewicz, D.M.

    2004-01-01

    A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the family's town of origin in Mexico. Affected individuals with profound polyuria

  7. Coherifying quantum channels

    Science.gov (United States)

    Korzekwa, Kamil; Czachórski, Stanisław; Puchała, Zbigniew; Życzkowski, Karol

    2018-04-01

    Is it always possible to explain random stochastic transitions between states of a finite-dimensional system as arising from the deterministic quantum evolution of the system? If not, then what is the minimal amount of randomness required by quantum theory to explain a given stochastic process? Here, we address this problem by studying possible coherifications of a quantum channel Φ, i.e., we look for channels {{{Φ }}}{ \\mathcal C } that induce the same classical transitions T, but are ‘more coherent’. To quantify the coherence of a channel Φ we measure the coherence of the corresponding Jamiołkowski state J Φ. We show that the classical transition matrix T can be coherified to reversible unitary dynamics if and only if T is unistochastic. Otherwise the Jamiołkowski state {J}{{Φ }}{ \\mathcal C } of the optimally coherified channel is mixed, and the dynamics must necessarily be irreversible. To assess the extent to which an optimal process {{{Φ }}}{ \\mathcal C } is indeterministic we find explicit bounds on the entropy and purity of {J}{{Φ }}{ \\mathcal C }, and relate the latter to the unitarity of {{{Φ }}}{ \\mathcal C }. We also find optimal coherifications for several classes of channels, including all one-qubit channels. Finally, we provide a non-optimal coherification procedure that works for an arbitrary channel Φ and reduces its rank (the minimal number of required Kraus operators) from {d}2 to d.

  8. CANDU channel flow verification

    International Nuclear Information System (INIS)

    Mazalu, N.; Negut, Gh.

    1997-01-01

    The purpose of this evaluation was to obtain accurate information on each channel flow that enables us to assess precisely the level of reactor thermal power and, for reasons of safety, to establish which channel is boiling. In order to assess the channel flow parameters, computer simulations were done with the NUCIRC code and the results were checked by measurements. The complete channel flow measurements were made in the zero power cold condition. In hot conditions there were made flow measurements using the Shut Down System 1 (SDS 1) flow devices from 0.1 % F.P. up to 100 % F.P. The NUCIRC prediction for CANDU channel flows and the measurements by Ultrasonic Flow Meter at zero power cold conditions and SDS 1 flow channel measurements at different reactor power levels showed an acceptable agreement. The 100 % F.P. average errors for channel flow of R, shows that suitable NUCIRC flow assessment can be made. So, it can be done a fair prediction of the reactor power distribution. NUCIRC can predict accurately the onset of boiling and helps to warn at the possible power instabilities at high powers or it can detect the flow blockages. The thermal hydraulic analyst has in NUCIRC a suitable tool to do accurate predictions for the thermal hydraulic parameters for different steady state power levels which subsequently leads to an optimal CANDU reactor operation. (authors)

  9. Reconfigurable virtual electrowetting channels.

    Science.gov (United States)

    Banerjee, Ananda; Kreit, Eric; Liu, Yuguang; Heikenfeld, Jason; Papautsky, Ian

    2012-02-21

    Lab-on-a-chip systems rely on several microfluidic paradigms. The first uses a fixed layout of continuous microfluidic channels. Such lab-on-a-chip systems are almost always application specific and far from a true "laboratory." The second involves electrowetting droplet movement (digital microfluidics), and allows two-dimensional computer control of fluidic transport and mixing. The merging of the two paradigms in the form of programmable electrowetting channels takes advantage of both the "continuous" functionality of rigid channels based on which a large number of applications have been developed to date and the "programmable" functionality of digital microfluidics that permits electrical control of on-chip functions. In this work, we demonstrate for the first time programmable formation of virtual microfluidic channels and their continuous operation with pressure driven flows using an electrowetting platform. Experimental, theoretical, and numerical analyses of virtual channel formation with biologically relevant electrolyte solutions and electrically-programmable reconfiguration are presented. We demonstrate that the "wall-less" virtual channels can be formed reliably and rapidly, with propagation rates of 3.5-3.8 mm s(-1). Pressure driven transport in these virtual channels at flow rates up to 100 μL min(-1) is achievable without distortion of the channel shape. We further demonstrate that these virtual channels can be switched on-demand between multiple inputs and outputs. Ultimately, we envision a platform that would provide rapid prototyping of microfluidic concepts and would be capable of a vast library of functions and benefitting applications from clinical diagnostics in resource-limited environments to rapid system prototyping to high throughput pharmaceutical applications.

  10. Evaluation channel performance in multichannel environments

    NARCIS (Netherlands)

    Gensler, S.; Dekimpe, M.; Skiera, B.

    2007-01-01

    Evaluating channel performance is crucial for actively managing multiple sales channels, and requires understanding the customers' channel preferences. Two key components of channel performance are (i) the existing customers' intrinsic loyalty to a particular channel and (ii) the channel's ability

  11. Channel follower leakage restrictor

    International Nuclear Information System (INIS)

    Williamson, H.E.; Smith, B.A.

    1977-01-01

    An improved means is provided to control coolant leakage between the flow channel and the lower tie plate of a nuclear fuel assembly. The means includes an opening in the lower tie plate and a movable element adjacent thereto. The coolant pressure within the tie plate biases the movable means toward the inner surface of the surrounding flow channel to compensate for any movement of the flow channel away from the lower tie plate to thereby control the leakage of coolant flow from the fuel assemblies to the spaces among the fuel assemblies of the core. 9 figures

  12. Direct channel problems and phenomena

    International Nuclear Information System (INIS)

    Cutkosky, R.E.

    1975-01-01

    Direct channel problems and phenomena are considered covering the need for precision hadron spectroscopy, the data base for precision hadron spectroscopy, some relations between direct-channel and cross-channel effects, and spin rotation phenomena

  13. Mechanisms underlying KCNQ1channel cell volume sensitivity

    DEFF Research Database (Denmark)

    Hammami, Sofia

    Cells are constantly exposed to changes in cell volume during cell metabolism, nutrient uptake, cell proliferation, cell migration and salt and water transport. In order to cope with these perturbations, potassium channels in line with chloride channels have been shown to be likely contributors...... to the process of cell volume adjustments. A great diversity of potassium channels being members of either the 6TM, 4 TM or 2 TM K+ channel gene family have been shown to be strictly regulated by small, fast changes in cell volume. However, the precise mechanism underlying the K+ channel sensitivity to cell...... volume alterations is not yet fully understood. The KCNQ1 channel belonging to the voltage gated KCNQ family is considered a precise sensor of volume changes. The goal of this thesis was to elucidate the mechanism that induces cell volume sensitivity. Until now, a number of investigators have implicitly...

  14. Many channel spectrum unfolding

    International Nuclear Information System (INIS)

    Najzer, M.; Glumac, B.; Pauko, M.

    1980-01-01

    The principle of the ITER unfolding code as used for the many channel spectrum unfolding is described. Its unfolding ability is tested on seven typical neutron spectra. The effect of the initial spectrum approximation upon the solution is discussed

  15. Channelized Streams in Iowa

    Data.gov (United States)

    Iowa State University GIS Support and Research Facility — This draft dataset consists of all ditches or channelized pieces of stream that could be identified using three input datasets; namely the1:24,000 National...

  16. Coding for optical channels

    CERN Document Server

    Djordjevic, Ivan; Vasic, Bane

    2010-01-01

    This unique book provides a coherent and comprehensive introduction to the fundamentals of optical communications, signal processing and coding for optical channels. It is the first to integrate the fundamentals of coding theory and optical communication.

  17. Sensing with Ion Channels

    CERN Document Server

    Martinac, Boris

    2008-01-01

    All living cells are able to detect and translate environmental stimuli into biologically meaningful signals. Sensations of touch, hearing, sight, taste, smell or pain are essential to the survival of all living organisms. The importance of sensory input for the existence of life thus justifies the effort made to understand its molecular origins. Sensing with Ion Channels focuses on ion channels as key molecules enabling biological systems to sense and process the physical and chemical stimuli that act upon cells in their living environment. Its aim is to serve as a reference to ion channel specialists and as a source of new information to non specialists who want to learn about the structural and functional diversity of ion channels and their role in sensory physiology.

  18. Calcium channel blocker poisoning

    Directory of Open Access Journals (Sweden)

    Miran Brvar

    2005-04-01

    Full Text Available Background: Calcium channel blockers act at L-type calcium channels in cardiac and vascular smooth muscles by preventing calcium influx into cells with resultant decrease in vascular tone and cardiac inotropy, chronotropy and dromotropy. Poisoning with calcium channel blockers results in reduced cardiac output, bradycardia, atrioventricular block, hypotension and shock. The findings of hypotension and bradycardia should suggest poisoning with calcium channel blockers.Conclusions: Treatment includes immediate gastric lavage and whole-bowel irrigation in case of ingestion of sustainedrelease products. All patients should receive an activated charcoal orally. Specific treatment includes calcium, glucagone and insulin, which proved especially useful in shocked patients. Supportive care including the use of catecholamines is not always effective. In the setting of failure of pharmacological therapy transvenous pacing, balloon pump and cardiopulmonary by-pass may be necessary.

  19. TRP channels: an overview

    DEFF Research Database (Denmark)

    Pedersen, Stine Falsig; Owsianik, Grzegorz; Nilius, Bernd

    2005-01-01

    The TRP ("transient receptor potential") family of ion channels now comprises more than 30 cation channels, most of which are permeable for Ca2+, and some also for Mg2+. On the basis of sequence homology, the TRP family can be divided in seven main subfamilies: the TRPC ('Canonical') family......, the TRPV ('Vanilloid') family, the TRPM ('Melastatin') family, the TRPP ('Polycystin') family, the TRPML ('Mucolipin') family, the TRPA ('Ankyrin') family, and the TRPN ('NOMPC') family. The cloning and characterization of members of this cation channel family has exploded during recent years, leading...... to a plethora of data on the roles of TRPs in a variety of tissues and species, including mammals, insects, and yeast. The present review summarizes the most pertinent recent evidence regarding the structural and functional properties of TRP channels, focusing on the regulation and physiology of mammalian TRPs....

  20. Authentication over Noisy Channels

    OpenAIRE

    Lai, Lifeng; Gamal, Hesham El; Poor, H. Vincent

    2008-01-01

    In this work, message authentication over noisy channels is studied. The model developed in this paper is the authentication theory counterpart of Wyner's wiretap channel model. Two types of opponent attacks, namely impersonation attacks and substitution attacks, are investigated for both single message and multiple message authentication scenarios. For each scenario, information theoretic lower and upper bounds on the opponent's success probability are derived. Remarkably, in both scenarios,...

  1. Channelling versus inversion

    DEFF Research Database (Denmark)

    Gale, A.S.; Surlyk, Finn; Anderskouv, Kresten

    2013-01-01

    Evidence from regional stratigraphical patterns in Santonian−Campanian chalk is used to infer the presence of a very broad channel system (5 km across) with a depth of at least 50 m, running NNW−SSE across the eastern Isle of Wight; only the western part of the channel wall and fill is exposed. W......−Campanian chalks in the eastern Isle of Wight, involving penecontemporaneous tectonic inversion of the underlying basement structure, are rejected....

  2. Stream Channel Stability.

    Science.gov (United States)

    1981-04-01

    Cycles of wetting and drying are also t ,v itiue swelling and shrinkage of the soil. S 11ied blocks or peds of soil fabric ,,ks. id downslope soil creep ...hydrographs of water and sediment at the point in question. By feeding the output from the hydrology-transport model into the finite element model...the banks as undercut banks fail. Channel irregularities such as seepage zones, cattle crossings, overbank drainage, buried channels, organic deposits

  3. Channeling and dynamic chaos

    Energy Technology Data Exchange (ETDEWEB)

    Bolotin, IU L; Gonchar, V IU; Truten, V I; Shulga, N F

    1986-01-01

    It is shown that axial channeling of relativistic electrons can give rise to the effect of dynamic chaos which involves essentially chaotic motion of a particle in the channel. The conditions leading to the effect of dynamic chaos and the manifestations of this effect in physical processes associated with the passage of particles through a crystal are examined using a silicon crystal as an example. 7 references.

  4. Course on Ionic Channels

    CERN Document Server

    1986-01-01

    This book is based on a series of lectures for a course on ionic channels held in Santiago, Chile, on November 17-20, 1984. It is intended as a tutorial guide on the properties, function, modulation, and reconstitution of ionic channels, and it should be accessible to graduate students taking their first steps in this field. In the presentation there has been a deliberate emphasis on the spe­ cific methodologies used toward the understanding of the workings and function of channels. Thus, in the first section, we learn to "read" single­ channel records: how to interpret them in the theoretical frame of kinetic models, which information can be extracted from gating currents in re­ lation to the closing and opening processes, and how ion transport through an open channel can be explained in terms of fluctuating energy barriers. The importance of assessing unequivocally the origin and purity of mem­ brane preparations and the use of membrane vesicles and optical tech­ niques in the stUGY of ionic channels a...

  5. Ion channelling in diamond

    International Nuclear Information System (INIS)

    Derry, T.E.

    1978-06-01

    Diamond is one of the most extreme cases from a channelling point of view, having the smallest thermal vibration amplitude and the lowest atomic number of commonly-encountered crystals. These are the two parameters most important for determining channelling behaviour. It is of consiberable interest therefore to see how well the theories explaining and predicting the channeling properties of other substance, succeed with diamond. Natural diamond, although the best available form for these experiments, is rather variable in its physical properties. Part of the project was devoted to considering and solving the problem of obtaining reproducible results representative of the ideal crystal. Channelling studies were performed on several good crystals, using the Rutherford backscattering method. Critical angles for proton channelling were measured for incident energies from 0.6 to 4.5 MeV, in the three most open axes and three most open planes of the diamond structure, and for α-particle channelling at 0.7 and 1.0 MeV (He + ) in the same axes and planes. For 1.0 MeV protons, the crystal temperature was varied from 20 degrees Celsius to 700 degrees Celsius. The results are presented as curves of backscattered yield versus angle in the region of each axis or plane, and summarised in the form of tables and graphs. Generally the critical angles, axial minimum yields, and temperature dependence are well predicted by the accepted theories. The most valuable overall conclusion is that the mean thermal vibration amplitude of the atoms in a crytical determines the critical approach distance to the channel walls at which an ion can remain channelled, even when this distance is much smaller than the Thomas-Fermi screening distance of the atomic potential, as is the case in diamond. A brief study was made of the radiation damage caused by α-particle bombardment, via its effect on the channelling phenomenon. It was possible to hold damage down to negligible levels during the

  6. Expression, purification and functional reconstitution of slack sodium-activated potassium channels.

    Science.gov (United States)

    Yan, Yangyang; Yang, Youshan; Bian, Shumin; Sigworth, Fred J

    2012-11-01

    The slack (slo2.2) gene codes for a potassium-channel α-subunit of the 6TM voltage-gated channel family. Expression of slack results in Na(+)-activated potassium channel activity in various cell types. We describe the purification and reconstitution of Slack protein and show that the Slack α-subunit alone is sufficient for potassium channel activity activated by sodium ions as assayed in planar bilayer membranes and in membrane vesicles.

  7. Functional characterization of a prokaryotic Kir channel.

    Science.gov (United States)

    Enkvetchakul, Decha; Bhattacharyya, Jaya; Jeliazkova, Iana; Groesbeck, Darcy K; Cukras, Catherine A; Nichols, Colin G

    2004-11-05

    The Kir gene family encodes inward rectifying K+ (Kir) channels that are widespread and critical regulators of excitability in eukaryotic cells. A related gene family (KirBac) has recently been identified in prokaryotes. While a crystal structure of one member, Kir-Bac1.1, has been solved, there has been no functional characterization of any KirBac gene products. Here we present functional characterization of KirBac1.1 reconstituted in liposomes. Utilizing a 86Rb+ uptake assay, we demonstrate that KirBac1.1 generates a K+ -selective permeation path that is inhibited by extraliposomal Ba2+ and Ca2+ ions. In contrast to KcsA (an acid-activated bacterial potassium channel), KirBac1.1 is inhibited by extraliposomal acid (pKa approximately 6). This characterization of KirBac1.1 activity now paves the way for further correlation of structure and function in this model Kir channel.

  8. Optical Communications Channel Combiner

    Science.gov (United States)

    Quirk, Kevin J.; Quirk, Kevin J.; Nguyen, Danh H.; Nguyen, Huy

    2012-01-01

    NASA has identified deep-space optical communications links as an integral part of a unified space communication network in order to provide data rates in excess of 100 Mb/s. The distances and limited power inherent in a deep-space optical downlink necessitate the use of photon-counting detectors and a power-efficient modulation such as pulse position modulation (PPM). For the output of each photodetector, whether from a separate telescope or a portion of the detection area, a communication receiver estimates a log-likelihood ratio for each PPM slot. To realize the full effective aperture of these receivers, their outputs must be combined prior to information decoding. A channel combiner was developed to synchronize the log-likelihood ratio (LLR) sequences of multiple receivers, and then combines these into a single LLR sequence for information decoding. The channel combiner synchronizes the LLR sequences of up to three receivers and then combines these into a single LLR sequence for output. The channel combiner has three channel inputs, each of which takes as input a sequence of four-bit LLRs for each PPM slot in a codeword via a XAUI 10 Gb/s quad optical fiber interface. The cross-correlation between the channels LLR time series are calculated and used to synchronize the sequences prior to combining. The output of the channel combiner is a sequence of four-bit LLRs for each PPM slot in a codeword via a XAUI 10 Gb/s quad optical fiber interface. The unit is controlled through a 1 Gb/s Ethernet UDP/IP interface. A deep-space optical communication link has not yet been demonstrated. This ground-station channel combiner was developed to demonstrate this capability and is unique in its ability to process such a signal.

  9. Channel Choice: A Literature Review

    DEFF Research Database (Denmark)

    Østergaard Madsen, Christian; Kræmmergaard, Pernille

    2015-01-01

    The channel choice branch of e-government studies citizens’ and businesses’ choice of channels for interacting with government, and how government organizations can integrate channels and migrate users towards the most cost-efficient channels. In spite of the valuable contributions offered...

  10. Channel Identification Machines

    Directory of Open Access Journals (Sweden)

    Aurel A. Lazar

    2012-01-01

    Full Text Available We present a formal methodology for identifying a channel in a system consisting of a communication channel in cascade with an asynchronous sampler. The channel is modeled as a multidimensional filter, while models of asynchronous samplers are taken from neuroscience and communications and include integrate-and-fire neurons, asynchronous sigma/delta modulators and general oscillators in cascade with zero-crossing detectors. We devise channel identification algorithms that recover a projection of the filter(s onto a space of input signals loss-free for both scalar and vector-valued test signals. The test signals are modeled as elements of a reproducing kernel Hilbert space (RKHS with a Dirichlet kernel. Under appropriate limiting conditions on the bandwidth and the order of the test signal space, the filter projection converges to the impulse response of the filter. We show that our results hold for a wide class of RKHSs, including the space of finite-energy bandlimited signals. We also extend our channel identification results to noisy circuits.

  11. Channel identification machines.

    Science.gov (United States)

    Lazar, Aurel A; Slutskiy, Yevgeniy B

    2012-01-01

    We present a formal methodology for identifying a channel in a system consisting of a communication channel in cascade with an asynchronous sampler. The channel is modeled as a multidimensional filter, while models of asynchronous samplers are taken from neuroscience and communications and include integrate-and-fire neurons, asynchronous sigma/delta modulators and general oscillators in cascade with zero-crossing detectors. We devise channel identification algorithms that recover a projection of the filter(s) onto a space of input signals loss-free for both scalar and vector-valued test signals. The test signals are modeled as elements of a reproducing kernel Hilbert space (RKHS) with a Dirichlet kernel. Under appropriate limiting conditions on the bandwidth and the order of the test signal space, the filter projection converges to the impulse response of the filter. We show that our results hold for a wide class of RKHSs, including the space of finite-energy bandlimited signals. We also extend our channel identification results to noisy circuits.

  12. Cryogenic microwave channelized receiver

    International Nuclear Information System (INIS)

    Rauscher, C.; Pond, J.M.; Tait, G.B.

    1996-01-01

    The channelized receiver being presented demonstrates the use of high temperature superconductor technology in a microwave system setting where superconductor, microwave-monolithic-integrated-circuit, and hybrid-integrated-circuit components are united in one package and cooled to liquid-nitrogen temperatures. The receiver consists of a superconducting X-band four-channel demultiplexer with 100-MHz-wide channels, four commercial monolithically integrated mixers, and four custom-designed hybrid-circuit detectors containing heterostructure ramp diodes. The composite receiver unit has been integrated into the payload of the second-phase NRL high temperature superconductor space experiment (HTSSE-II). Prior to payload assembly, the response characteristics of the receiver were measured as functions of frequency, temperature, and drive levels. The article describes the circuitry, discusses the key issues related to design and implementation, and summarizes the experimental results

  13. Chaos in quantum channels

    Energy Technology Data Exchange (ETDEWEB)

    Hosur, Pavan; Qi, Xiao-Liang [Department of Physics, Stanford University,476 Lomita Mall, Stanford, California 94305 (United States); Roberts, Daniel A. [Center for Theoretical Physics and Department of Physics, Massachusetts Institute of Technology,77 Massachusetts Ave, Cambridge, Massachusetts 02139 (United States); Yoshida, Beni [Perimeter Institute for Theoretical Physics,31 Caroline Street North, Waterloo, Ontario N2L 2Y5 (Canada); Walter Burke Institute for Theoretical Physics, California Institute of Technology,1200 E California Blvd, Pasadena CA 91125 (United States)

    2016-02-01

    We study chaos and scrambling in unitary channels by considering their entanglement properties as states. Using out-of-time-order correlation functions to diagnose chaos, we characterize the ability of a channel to process quantum information. We show that the generic decay of such correlators implies that any input subsystem must have near vanishing mutual information with almost all partitions of the output. Additionally, we propose the negativity of the tripartite information of the channel as a general diagnostic of scrambling. This measures the delocalization of information and is closely related to the decay of out-of-time-order correlators. We back up our results with numerics in two non-integrable models and analytic results in a perfect tensor network model of chaotic time evolution. These results show that the butterfly effect in quantum systems implies the information-theoretic definition of scrambling.

  14. Distribution Channels Conflict and Management

    OpenAIRE

    Kiran, Dr Vasanth; Majumdar, Dr Mousumi; Kishore, Dr Krishna

    2012-01-01

    Relationships in distribution channels tend to be long-term oriented and members of the channel rely on each other to jointly realize their goals by serving buyers. Despite the channels focus on serving buyers, conflicts often arise between channel members because of each members self-interest. When conflicts arise, the perceptions of a channel member based on normative, rational/instrumental, or emotional reasoning will influence relational norms like trust and commitment that characterize t...

  15. Fuel channel refilling

    International Nuclear Information System (INIS)

    Shoukri, M.; Abdul-Razzak, A.

    1992-11-01

    This report extends the work reported in document INFO-0370 on fuel channel refilling by providing analysis of the refilling tests conducted using the RD-14 and RD-14M test facilities. The analysis focuses on the general thermal-hydraulic characteristics of the facilities following various small and large inlet and outlet header breaks with emergency coolant injection. The two-fluid model thermal-hydraulic computer code CATHENA was tested against results obtained from selected experiments carried out in the two facilities. Conclusions related to the effect of break size, mode of emergency core injection, primary pump operation and parallel channels are presented. (Author) (116 figs., 17 tabs., 53 refs.)

  16. Ion channels in glioblastoma.

    Science.gov (United States)

    Molenaar, Remco J

    2011-01-01

    Glioblastoma is the most common primary brain tumor with the most dismal prognosis. It is characterized by extensive invasion, migration, and angiogenesis. Median survival is only 15 months due to this behavior, rendering focal surgical resection ineffective and adequate radiotherapy impossible. At this moment, several ion channels have been implicated in glioblastoma proliferation, migration, and invasion. This paper summarizes studies on potassium, sodium, chloride, and calcium channels of glioblastoma. It provides an up-to-date overview of the literature that could ultimately lead to new therapeutic targets.

  17. Fuel channel refilling

    International Nuclear Information System (INIS)

    Shoukri, M.; Abdul-Razzak, A.

    1990-04-01

    Analysis of existing data on fuel channel refilling is presented. The analysis focuses on the data obtained using the Stern Laboratories Cold Water Injection Test (CWIT) Facility. The two-fluid model thermal-hydraulics computer code CATHENA is also used to simulate experimental results on fuel channel refilling from both the CWIT and RD-14 facilities. Conclusions related to single and double break tests, including the effect of non-condensible gases, are presented. A set of recommendations is given for further analysis and separate effect experiments. (67 figs., 5 tabs., 24 refs.)

  18. Genetic Variations in the Kir6.2 Subunit (KCNJ11 of Pancreatic ATP-Sensitive Potassium Channel Gene Are Associated with Insulin Response to Glucose Loading and Early Onset of Type 2 Diabetes in Childhood and Adolescence in Taiwan

    Directory of Open Access Journals (Sweden)

    Yi-Der Jiang

    2014-01-01

    Full Text Available To investigate the role of E23K polymorphism of the KCNJ11 gene on early onset of type 2 diabetes in school-aged children/adolescents in Taiwan, we recruited 38 subjects with type 2 diabetes (ages 18.6 ± 6.6 years; body mass index percentiles 83.3 ± 15.4 and 69 normal controls (ages 17.3 ± 3.8 years; body mass index percentiles 56.7 ± 29.0 from a national surveillance for childhood/adolescent diabetes in Taiwan. We searched for the E23K polymorphism of the KCNJ11 gene. We found that type 2 diabetic subjects had higher carrier rate of E23K polymorphism of KCNJ11 gene than control subjects (P = 0.044. After adjusting for age, gender, body mass index percentiles, and fasting plasma insulin, the E23K polymorphism contributed to an increased risk for type 2 diabetes (P = 0.047. K23-allele-containing genotypes conferring increased plasma insulin level during OGTT in normal subjects. However, the diabetic subjects with the K23-allele-containing genotypes had lower fasting plasma insulin levels after adjustment of age and BMI percentiles. In conclusion, the E23K variant of the KCNJ11 gene conferred higher susceptibility to type 2 diabetes in children/adolescents. Furthermore, in normal glucose-tolerant children/adolescents, K23 allele carriers had a higher insulin response to oral glucose loading.

  19. Potassium channels in brain mitochondria.

    Science.gov (United States)

    Bednarczyk, Piotr

    2009-01-01

    Potassium channels are the most widely distributed class of ion channels. These channels are transmembrane proteins known to play important roles in both normal and pathophysiological functions in all cell types. Various potassium channels are recognised as potential therapeutic targets in the treatment of Parkinson's disease, Alzheimer's disease, brain/spinal cord ischaemia and sepsis. In addition to their importance as therapeutic targets, certain potassium channels are known for their beneficial roles in anaesthesia, cardioprotection and neuroprotection. Some types of potassium channels present in the plasma membrane of various cells have been found in the inner mitochondrial membrane as well. Potassium channels have been proposed to regulate mitochondrial membrane potential, respiration, matrix volume and Ca(+) ion homeostasis. It has been proposed that mitochondrial potassium channels mediate ischaemic preconditioning in various tissues. However, the specificity of a pharmacological agents and the mechanisms underlying their effects on ischaemic preconditioning remain controversial. The following potassium channels from various tissues have been identified in the inner mitochondrial membrane: ATP-regulated (mitoK(ATP)) channel, large conductance Ca(2+)-regulated (mitoBK(Ca)) channel, intermediate conductance Ca(2+)-regulated (mitoIK(Ca)) channel, voltage-gated (mitoKv1.3 type) channel, and twin-pore domain (mitoTASK-3) channel. It has been shown that increased potassium flux into brain mitochondria induced by either the mitoK(ATP) channel or mitoBK(Ca) channel affects the beneficial effects on neuronal cell survival under pathological conditions. Recently, differential distribution of mitoBK(Ca) channels has been observed in neuronal mitochondria. These findings may suggest a neuroprotective role for the mitoBK(Ca) channel in specific brain structures. This minireview summarises current data on brain mitochondrial potassium channels and the efforts to identify

  20. Sodium Channel Mutations and Pyrethroid Resistance in Aedes aegypti

    Directory of Open Access Journals (Sweden)

    Yuzhe Du

    2016-10-01

    Full Text Available Pyrethroid insecticides are widely used to control insect pests and human disease vectors. Voltage-gated sodium channels are the primary targets of pyrethroid insecticides. Mutations in the sodium channel have been shown to be responsible for pyrethroid resistance, known as knockdown resistance (kdr, in various insects including mosquitoes. In Aedes aegypti mosquitoes, the principal urban vectors of dengue, zika, and yellow fever viruses, multiple single nucleotide polymorphisms in the sodium channel gene have been found in pyrethroid-resistant populations and some of them have been functionally confirmed to be responsible for kdr in an in vitro expression system, Xenopus oocytes. This mini-review aims to provide an update on the identification and functional characterization of pyrethroid resistance-associated sodium channel mutations from Aedes aegypti. The collection of kdr mutations not only helped us develop molecular markers for resistance monitoring, but also provided valuable information for computational molecular modeling of pyrethroid receptor sites on the sodium channel.

  1. Slack, Slick, and Sodium-Activated Potassium Channels

    Science.gov (United States)

    Kaczmarek, Leonard K.

    2013-01-01

    The Slack and Slick genes encode potassium channels that are very widely expressed in the central nervous system. These channels are activated by elevations in intracellular sodium, such as those that occur during trains of one or more action potentials, or following activation of nonselective cationic neurotransmitter receptors such as AMPA receptors. This review covers the cellular and molecular properties of Slack and Slick channels and compares them with findings on the properties of sodium-activated potassium currents (termed KNa currents) in native neurons. Human mutations in Slack channels produce extremely severe defects in learning and development, suggesting that KNa channels play a central role in neuronal plasticity and intellectual function. PMID:24319675

  2. Evolving regulatory paradigm for proarrhythmic risk assessment for new drugs.

    Science.gov (United States)

    Vicente, Jose; Stockbridge, Norman; Strauss, David G

    Fourteen drugs were removed from the market worldwide because their potential to cause torsade de pointes (torsade), a potentially fatal ventricular arrhythmia. The observation that most drugs that cause torsade block the potassium channel encoded by the human ether-à-go-go related gene (hERG) and prolong the heart rate corrected QT interval (QTc) on the ECG, led to a focus on screening new drugs for their potential to block the hERG potassium channel and prolong QTc. This has been a successful strategy keeping torsadogenic drugs off the market, but has resulted in drugs being dropped from development, sometimes inappropriately. This is because not all drugs that block the hERG potassium channel and prolong QTc cause torsade, sometimes because they block other channels. The regulatory paradigm is evolving to improve proarrhythmic risk prediction. ECG studies can now use exposure-response modeling for assessing the effect of a drug on the QTc in small sample size first-in-human studies. Furthermore, the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is developing and validating a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential. Under CiPA, the prediction of proarrhythmic potential will come from in vitro ion channel assessments coupled with an in silico model of the human ventricular myocyte. The preclinical assessment will be checked with an assessment of human phase 1 ECG data to determine if there are unexpected ion channel effects in humans compared to preclinical ion channel data. While there is ongoing validation work, the heart rate corrected J-T peak interval is likely to be assessed under CiPA to detect inward current block in presence of hERG potassium channel block. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. Downregulation of Kv7.4 channel activity in primary and secondary hypertension

    DEFF Research Database (Denmark)

    Jepps, Thomas Andrew; Chadha, Preet S; Davis, Alison J

    2011-01-01

    Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of...... structurally different activators of Kv7.2 through Kv7.5 channels (BMS-204352, S-1, and retigabine) on blood vessels from normotensive and hypertensive animals.......Voltage-gated potassium (K(+)) channels encoded by KCNQ genes (Kv7 channels) have been identified in various rodent and human blood vessels as key regulators of vascular tone; however, nothing is known about the functional impact of these channels in vascular disease. We ascertained the effect of 3...

  4. Chemistry in Microfluidic Channels

    Science.gov (United States)

    Chia, Matthew C.; Sweeney, Christina M.; Odom, Teri W.

    2011-01-01

    General chemistry introduces principles such as acid-base chemistry, mixing, and precipitation that are usually demonstrated in bulk solutions. In this laboratory experiment, we describe how chemical reactions can be performed in a microfluidic channel to show advanced concepts such as laminar fluid flow and controlled precipitation. Three sets of…

  5. Workshop on Gas Channels

    Science.gov (United States)

    2013-02-07

    Effect of pressure on gas permeability. In Fish … Different channels or splice variants at different depth.  HRE (hypoxia-response elements): which...proteins unexpectedly have HREs . HIF-1.  Shear stress:  expression of NOS  Are different splice variants used under different conditions?  Size

  6. Chloride channels as tools for developing selective insecticides.

    Science.gov (United States)

    Bloomquist, Jeffrey R

    2003-12-01

    Ligand-gated chloride channels underlie inhibition in excitable membranes and are proven target sites for insecticides. The gamma-aminobutyric acid (GABA(1)) receptor/chloride ionophore complex is the primary site of action for a number of currently used insecticides, such as lindane, endosulfan, and fipronil. These compounds act as antagonists by stabilizing nonconducting conformations of the chloride channel. Blockage of the GABA-gated chloride channel reduces neuronal inhibition, which leads to hyperexcitation of the central nervous system, convulsions, and death. We recently investigated the mode of action of the silphinenes, plant-derived natural compounds that structurally resemble picrotoxinin. These materials antagonize the action of GABA on insect neurons and block GABA-mediated chloride uptake into mouse brain synaptoneurosomes in a noncompetitive manner. In mammals, avermectins have a blocking action on the GABA-gated chloride channel consistent with a coarse tremor, whereas at longer times and higher concentrations, activation of the channel suppresses neuronal activity. Invertebrates display ataxia, paralysis, and death as the predominant signs of poisoning, with a glutamate-gated chloride channel playing a major role. Additional target sites for the avermectins or other chloride channel-directed compounds might include receptors gated by histamine, serotonin, or acetylcholine.The voltage-sensitive chloride channels form another large gene family of chloride channels. Voltage-dependent chloride channels are involved in a number of physiological processes including: maintenance of electrical excitability, chloride ion secretion and resorption, intravesicular acidification, and cell volume regulation. A subset of these channels is affected by convulsants and insecticides in mammals, although the role they play in acute lethality in insects is unclear. Given the wide range of functions that they mediate, these channels are also potential targets for

  7. Cardiac Delayed Rectifier Potassium Channels in Health and Disease.

    Science.gov (United States)

    Chen, Lei; Sampson, Kevin J; Kass, Robert S

    2016-06-01

    Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Involvement of the putative Ca²⁺-permeable mechanosensitive channels, NtMCA1 and NtMCA2, in Ca²⁺ uptake, Ca²⁺-dependent cell proliferation and mechanical stress-induced gene expression in tobacco (Nicotiana tabacum) BY-2 cells.

    Science.gov (United States)

    Kurusu, Takamitsu; Yamanaka, Takuya; Nakano, Masataka; Takiguchi, Akiko; Ogasawara, Yoko; Hayashi, Teruyuki; Iida, Kazuko; Hanamata, Shigeru; Shinozaki, Kazuo; Iida, Hidetoshi; Kuchitsu, Kazuyuki

    2012-07-01

    To gain insight into the cellular functions of the mid1-complementing activity (MCA) family proteins, encoding putative Ca²⁺-permeable mechanosensitive channels, we isolated two MCA homologs of tobacco (Nicotiana tabacum) BY-2 cells, named NtMCA1 and NtMCA2. NtMCA1 and NtMCA2 partially complemented the lethality and Ca²⁺ uptake defects of yeast mutants lacking mechanosensitive Ca²⁺ channel components. Furthermore, in yeast cells overexpressing NtMCA1 and NtMCA2, the hypo-osmotic shock-induced Ca²⁺ influx was enhanced. Overexpression of NtMCA1 or NtMCA2 in BY-2 cells enhanced Ca²⁺ uptake, and significantly alleviated growth inhibition under Ca²⁺ limitation. NtMCA1-overexpressing BY-2 cells showed higher sensitivity to hypo-osmotic shock than control cells, and induced the expression of the touch-inducible gene, NtERF4. We found that both NtMCA1-GFP and NtMCA2-GFP were localized at the plasma membrane and its interface with the cell wall, Hechtian strands, and at the cell plate and perinuclear vesicles of dividing cells. NtMCA2 transcript levels fluctuated during the cell cycle and were highest at the G1 phase. These results suggest that NtMCA1 and NtMCA2 play roles in Ca²⁺-dependent cell proliferation and mechanical stress-induced gene expression in BY-2 cells, by regulating the Ca²⁺ influx through the plasma membrane.

  9. Reconstruction of Cell Surface Densities of Ion Pumps, Exchangers, and Channels from mRNA Expression, Conductance Kinetics, Whole-Cell Calcium, and Current-Clamp Voltage Recordings, with an Application to Human Uterine Smooth Muscle Cells.

    Directory of Open Access Journals (Sweden)

    Jolene Atia

    2016-04-01

    Full Text Available Uterine smooth muscle cells remain quiescent throughout most of gestation, only generating spontaneous action potentials immediately prior to, and during, labor. This study presents a method that combines transcriptomics with biophysical recordings to characterise the conductance repertoire of these cells, the 'conductance repertoire' being the total complement of ion channels and transporters expressed by an electrically active cell. Transcriptomic analysis provides a set of potential electrogenic entities, of which the conductance repertoire is a subset. Each entity within the conductance repertoire was modeled independently and its gating parameter values were fixed using the available biophysical data. The only remaining free parameters were the surface densities for each entity. We characterise the space of combinations of surface densities (density vectors consistent with experimentally observed membrane potential and calcium waveforms. This yields insights on the functional redundancy of the system as well as its behavioral versatility. Our approach couples high-throughput transcriptomic data with physiological behaviors in health and disease, and provides a formal method to link genotype to phenotype in excitable systems. We accurately predict current densities and chart functional redundancy. For example, we find that to evoke the observed voltage waveform, the BK channel is functionally redundant whereas hERG is essential. Furthermore, our analysis suggests that activation of calcium-activated chloride conductances by intracellular calcium release is the key factor underlying spontaneous depolarisations.

  10. Modulation of voltage-gated Na+ and K+ channels by pumiliotoxin 251D: a "joint venture" alkaloid from arthropods and amphibians.

    Science.gov (United States)

    Vandendriessche, Thomas; Abdel-Mottaleb, Yousra; Maertens, Chantal; Cuypers, Eva; Sudau, Alexander; Nubbemeyer, Udo; Mebs, Dietrich; Tytgat, Jan

    2008-03-01

    Certain amphibians provide themselves with a chemical defense by accumulating lipophilic alkaloids into skin glands from dietary arthropods. Examples of such alkaloids are pumiliotoxins (PTXs). In general, PTXs are known as positive modulators of voltage-gated sodium channels (VGSCs). Unlike other PTXs, PTX 251D does not share this characteristic. However, mice and insect studies showed that PTX 251D is highly toxic and to date the basis of its toxicity remains unknown. In this work, we searched for the possible target of PTX 251D. The toxin was therefore made synthetically and tested on four VGSCs (mammalian rNa(v)1.2/beta(1), rNa(v)1.4/beta(1), hNa(v)1.5/beta(1) and insect Para/tipE) and five voltage-gated potassium channels (VGPCs) (mammalian rK(v)1.1-1.2, hK(v)1.3, hK(v)11.1 (hERG) and insect Shaker IR) expressed heterologously in Xenopus laevis oocytes, using the two-electrode voltage clamp technique. PTX 251D not only inhibited the Na(+) influx through the mammalian VGSCs but also affected the steady-state activation and inactivation. Interestingly, in the insect ortholog, the inactivation process was dramatically affected. Additionally, PTX 251D inhibited the K(+) efflux through all five tested VGPCs and slowed down the deactivation kinetics of the mammalian VGPCs. hK(v)1.3 was the most sensitive channel, with an IC(50) value 10.8+/-0.5 microM. To the best of our knowledge this is the first report of a PTX affecting VGPCs.

  11. TRESK potassium channel in human T lymphoblasts

    Energy Technology Data Exchange (ETDEWEB)

    Sánchez-Miguel, Dénison Selene, E-mail: amurusk@hotmail.com [Center for Biomedical Research, University of Colima, Av. 25 de Julio 965, Villa San Sebastian, C.P. 28045 Colima (Mexico); García-Dolores, Fernando, E-mail: garciaddf@yahoo.com [Department of Pathology, Institute of Forensic Sciences, Av. Niños Héroes 130, Col. Doctores, C.P. 06720 Mexico, DF (Mexico); Rosa Flores-Márquez, María, E-mail: mariafo31@yahoo.com.mx [National Medical Center of Occident (CMNO) IMSS, Belisario Dominguez 735, Col. Independencia Oriente, C.P. 44340 Guadalajara, Jalisco (Mexico); Delgado-Enciso, Iván [University of Colima, School of Medicine, Av. Universidad 333, Col. Las Viboras, C.P. 28040 Colima (Mexico); Pottosin, Igor, E-mail: pottosin@ucol.mx [Center for Biomedical Research, University of Colima, Av. 25 de Julio 965, Villa San Sebastian, C.P. 28045 Colima (Mexico); Dobrovinskaya, Oxana, E-mail: oxana@ucol.mx [Center for Biomedical Research, University of Colima, Av. 25 de Julio 965, Villa San Sebastian, C.P. 28045 Colima (Mexico)

    2013-05-03

    Highlights: • TRESK (KCNK18) mRNA is present in different T lymphoblastic cell lines. • KCNK18 mRNA was not found in resting peripheral blood lymphocytes. • Clinical samples of T lymphoblastic leukemias and lymphomas were positive for TRESK. • TRESK in T lymphoblasts has dual localization, in plasma membrane and intracellular. -- Abstract: TRESK (TWIK-related spinal cord K{sup +}) channel, encoded by KCNK18 gene, belongs to the double-pore domain K{sup +} channel family and in normal conditions is expressed predominantly in the central nervous system. In our previous patch-clamp study on Jurkat T lymphoblasts we have characterized highly selective K{sup +} channel with pharmacological profile identical to TRESK. In the present work, the presence of KCNK18 mRNA was confirmed in T lymphoblastic cell lines (Jurkat, JCaM, H9) but not in resting peripheral blood lymphocytes of healthy donors. Positive immunostaining for TRESK was demonstrated in lymphoblastic cell lines, in germinal centers of non-tumoral lymph nodes, and in clinical samples of T acute lymphoblastic leukemias/lymphomas. Besides detection in the plasma membrane, intracellular TRESK localization was also revealed. Possible involvement of TRESK channel in lymphocyte proliferation and tumorigenesis is discussed.

  12. TRESK potassium channel in human T lymphoblasts

    International Nuclear Information System (INIS)

    Sánchez-Miguel, Dénison Selene; García-Dolores, Fernando; Rosa Flores-Márquez, María; Delgado-Enciso, Iván; Pottosin, Igor; Dobrovinskaya, Oxana

    2013-01-01

    Highlights: • TRESK (KCNK18) mRNA is present in different T lymphoblastic cell lines. • KCNK18 mRNA was not found in resting peripheral blood lymphocytes. • Clinical samples of T lymphoblastic leukemias and lymphomas were positive for TRESK. • TRESK in T lymphoblasts has dual localization, in plasma membrane and intracellular. -- Abstract: TRESK (TWIK-related spinal cord K + ) channel, encoded by KCNK18 gene, belongs to the double-pore domain K + channel family and in normal conditions is expressed predominantly in the central nervous system. In our previous patch-clamp study on Jurkat T lymphoblasts we have characterized highly selective K + channel with pharmacological profile identical to TRESK. In the present work, the presence of KCNK18 mRNA was confirmed in T lymphoblastic cell lines (Jurkat, JCaM, H9) but not in resting peripheral blood lymphocytes of healthy donors. Positive immunostaining for TRESK was demonstrated in lymphoblastic cell lines, in germinal centers of non-tumoral lymph nodes, and in clinical samples of T acute lymphoblastic leukemias/lymphomas. Besides detection in the plasma membrane, intracellular TRESK localization was also revealed. Possible involvement of TRESK channel in lymphocyte proliferation and tumorigenesis is discussed

  13. Quantum communication under channel uncertainty

    International Nuclear Information System (INIS)

    Noetzel, Janis Christian Gregor

    2012-01-01

    This work contains results concerning transmission of entanglement and subspaces as well as generation of entanglement in the limit of arbitrary many uses of compound- and arbitrarily varying quantum channels (CQC, AVQC). In both cases, the channel is described by a set of memoryless channels. Only forward communication between one sender and one receiver is allowed. A code is said to be ''good'' only, if it is ''good'' for every channel out of the set. Both settings describe a scenario, in which sender and receiver have only limited channel knowledge. For different amounts of information about the channel available to sender or receiver, coding theorems are proven for the CQC. For the AVQC, both deterministic and randomised coding schemes are considered. Coding theorems are proven, as well as a quantum analogue of the Ahlswede-dichotomy. The connection to zero-error capacities of stationary memoryless quantum channels is investigated. The notion of symmetrisability is defined and used for both classes of channels.

  14. VAX CAMAC channel

    International Nuclear Information System (INIS)

    Nelson, D.J.; Breidenbach, M.; Granieri, C.D.; Grund, J.E.; Patrick, J.F.; Weaver, L.J.

    1980-10-01

    A new generation CAMAC System has been developed for the Mark II Detector at SLAC's PEP storage ring. This flexible system can efficiently transfer data between a host computer and a very large set of CAMAC data acquisition and control modules. A bipolar microprocessor operates as a Channel interface by supervising the CAMAC system and minimizing the host computer's work. This programmable channel couples the host to a set of System Crates; each System Crate houses Branch Drivers that can directly control a set of crates or communicate over differential parallel highways to Branch Receivers for control of distant crates. A coherent software package integrates the high level programs, system driver level programs, and microcode control of the system

  15. Geysering in boiling channels

    Energy Technology Data Exchange (ETDEWEB)

    Aritomi, Masanori; Takemoto, Takatoshi [Tokyo Institute of Technology, Tokyo (Japan); Chiang, Jing-Hsien [Japan NUS Corp. Ltd., Toyko (Japan)] [and others

    1995-09-01

    A concept of natural circulation BWRs such as the SBWR has been proposed and seems to be promising in that the primary cooling system can be simplified. The authors have been investigating thermo-hydraulic instabilities which may appear during the start-up in natural circulation BWRs. In our previous works, geysering was investigated in parallel boiling channels for both natural and forced circulations, and its driving mechanism and the effect of system pressure on geysering occurrence were made clear. In this paper, geysering is investigated in a vertical column and a U-shaped vertical column heated in the lower parts. It is clarified from the results that the occurrence mechanism of geysering and the dependence of system pressure on geysering occurrence coincide between parallel boiling channels in circulation systems and vertical columns in non-circulation systems.

  16. Coolant channel module CCM

    International Nuclear Information System (INIS)

    Hoeld, Alois

    2007-01-01

    A complete and detailed description of the theoretical background of an '(1D) thermal-hydraulic drift-flux based mixture-fluid' coolant channel model and its resulting module CCM will be presented. The objective of this module is to simulate as universally as possible the steady state and transient behaviour of the key characteristic parameters of a single- or two-phase fluid flowing within any type of heated or non-heated coolant channel. Due to the possibility that different flow regimes can appear along any channel, such a 'basic (BC)' 1D channel is assumed to be subdivided into a number of corresponding sub-channels (SC-s). Each SC can belong to only two types of flow regime, an SC with just a single-phase fluid, containing exclusively either sub-cooled water or superheated steam, or an SC with a two-phase mixture flow. After an appropriate nodalisation of such a BC (and therefore also its SC-s) a 'modified finite volume method' has been applied for the spatial discretisation of the partial differential equations (PDE-s) which represent the basic conservation equations of thermal-hydraulics. Special attention had to be given to the possibility of variable SC entrance or outlet positions (which describe boiling boundaries or mixture levels) and thus the fact that an SC can even disappear or be created anew. The procedure yields for each SC type (and thus the entire BC), a set of non-linear ordinary 1st order differential equations (ODE-s). To link the resulting mean nodal with the nodal boundary function values, both of which are present in the discretised differential equations, a special quadratic polygon approximation procedure (PAX) had to be constructed. Together with the very thoroughly tested packages for drift-flux, heat transfer and single- and two-phase friction factors this procedure represents the central part of the here presented 'Separate-Region' approach, a theoretical model which provides the basis to the very effective working code package CCM

  17. Physiology and pathophysiology of ClC-K/barttin channels.

    Science.gov (United States)

    Fahlke, Christoph; Fischer, Martin

    2010-01-01

    ClC-K channels form a subgroup of anion channels within the ClC family of anion transport proteins. They are expressed predominantly in the kidney and in the inner ear, and are necessary for NaCl resorption in the loop of Henle and for K+ secretion by the stria vascularis. Subcellular distribution as well as the function of these channels are tightly regulated by an accessory subunit, barttin. Barttin improves the stability of ClC-K channel protein, stimulates the exit from the endoplasmic reticulum and insertion into the plasma membrane and changes its function by modifying voltage-dependent gating processes. The importance of ClC-K/barttin channels is highlighted by several genetic diseases. Dysfunctions of ClC-K channels result in Bartter syndrome, an inherited human condition characterized by impaired urinary concentration. Mutations in the gene encoding barttin, BSND, affect the urinary concentration as well as the sensory function of the inner ear. Surprisingly, there is one BSND mutation that causes deafness without affecting renal function, indicating that kidney function tolerates a reduction of anion channel activity that is not sufficient to support normal signal transduction in inner hair cells. This review summarizes recent work on molecular mechanisms, physiology, and pathophysiology of ClC-K/barttin channels.

  18. Physiology and pathophysiology of ClC-K/barttin channels

    Directory of Open Access Journals (Sweden)

    Christoph eFahlke

    2010-11-01

    Full Text Available ClC-K channels form a subgroup of anion channels within the ClC family of anion transport proteins. They are expressed predominantly in the kidney and in the inner ear, and are necessary for NaCl resorption in the loop of Henle and for K+ secretion by the stria vascularis. Subcellular distribution as well as the function of these channels are tightly regulated by an accessory subunit, barttin. Barttin improves the stability of ClC-K channel protein, stimulates the exit from the endoplasmic reticulum and insertion into the plasma membrane and changes its function by modifying voltage-dependent gating processes. The importance of ClC-K/barttin channels is highlighted by several genetic diseases. Dysfunctions of ClC-K channels result in Bartter syndrome, an inherited human condition characterized by impaired urinary concentration. Mutations in the gene encoding barttin, BSND, affect the urinary concentration as well as the sensory function of the inner ear. Surprisingly, there is one BSND mutation that causes deafness without affecting renal function, indicating that kidney function tolerates a reduction of anion channel activity that is not sufficient to support normal signal transduction in inner hair cells. This review summarizes recent work on molecular mechanisms, physiology and pathophysiology of ClC-K/barttin channels.

  19. Tourism distribution channels

    OpenAIRE

    Camilleri, Mark Anthony

    2017-01-01

    The distribution channels link the customers with the businesses. For many years, the tourism businesses may have distributed their products and services through intermediaries. However, the latest advances in technology have brought significant changes in this regard. More individuals and corporate customers are increasingly benefiting of ubiquitous technologies, including digital media. The development of mobile devices and their applications, are offering a wide range of possibilities to t...

  20. Athermal channeled spectropolarimeter

    Science.gov (United States)

    Jones, Julia Craven

    2015-12-08

    A temperature insensitive (athermal) channeled spectropolarimeter (CSP) is described. The athermal CSP includes a crystal retarder formed of a biaxial crystal. The crystal retarder has three crystal axes, wherein each axis has its own distinct index of refraction. The axes are oriented in a particular manner, causing an amplitude modulating carrier frequency induced by the crystal retarder to be thermally invariant. Accordingly, a calibration beam technique can be used over a relatively wide range of ambient temperatures, with a common calibration data set.

  1. Nuclear reactor coolant channels

    International Nuclear Information System (INIS)

    Macbeth, R.V.

    1978-01-01

    A nuclear reactor coolant channel is described that is suitable for sub-cooled reactors as in pressurised water reactors as well as for bulk boiling, as in boiling water reactors and steam generating nuclear reactors. The arrangement aims to improve heat transfer between the fuel elements and the coolant. Full constructional details are given. See also other similar patents by the author. (U.K.)

  2. The M2 Channel

    DEFF Research Database (Denmark)

    Santner, Paul

    Drug resistance of Influenza A against antivirals is an increasing problem. No effective Influenza A drugs targeting the crucial viral protein, the proton transporter M2 are available anymore due to widespread resistance. Thanks to research efforts elucidating M2 protein structure, function and i...... resistance escape routes from drug inhibition. We thereby were hopefully able to provide a platform for the large-scale evaluation of M2 channel activity, inhibitors and resistance....

  3. Aquaglyceroporins: generalized metalloid channels

    Science.gov (United States)

    Mukhopadhyay, Rita; Bhattacharjee, Hiranmoy; Rosen, Barry P.

    2014-01-01

    Background: Aquaporins (AQPs), members of a superfamily of transmembrane channel proteins, are ubiquitous in all domains of life. They fall into a number of branches that can be functionally categorized into two major sub-groups: i) orthodox aquaporins, which are water-specific channels, and ii) aquaglyceroporins, which allow the transport of water, non-polar solutes, such as urea or glycerol, the reactive oxygen species hydrogen peroxide, and gases such as ammonia, carbon dioxide and nitric oxide and, as described in this review, metalloids. Scope of Review: This review summarizes the key findings that AQP channels conduct bidirectional movement of metalloids into and out of cells. Major Conclusions: As(OH)3 and Sb(OH)3 behave as inorganic molecular mimics of glycerol, a property that allows their passage through AQP channels. Plant AQPs also allow the passage of boron and silicon as their hydroxyacids, boric acid (B(OH)3) and orthosilicic acid (Si(OH)4), respectively. Genetic analysis suggests that germanic acid (GeO2) is also a substrate. While As(III), Sb(III) and Ge(IV) are toxic metalloids, borate (B(III)) and silicate (Si(IV)) are essential elements in higher plants. General Significance: The uptake of environmental metalloids by aquaporins provides an understanding of (i) how toxic elements such as arsenic enter the food chain; (ii) the delivery of arsenic and antimony containing drugs in the treatment of certain forms of leukemia and chemotherapy of diseases caused by pathogenic protozoa; and (iii) the possibility that food plants such as rice could be made safer by genetically modifying them to exclude arsenic while still accumulating boron and silicon. PMID:24291688

  4. Matching Dyadic Distributions to Channels

    OpenAIRE

    Böcherer, Georg; Mathar, Rudolf

    2010-01-01

    Many communication channels with discrete input have non-uniform capacity achieving probability mass functions (PMF). By parsing a stream of independent and equiprobable bits according to a full prefix-free code, a modu-lator can generate dyadic PMFs at the channel input. In this work, we show that for discrete memoryless channels and for memoryless discrete noiseless channels, searching for good dyadic input PMFs is equivalent to minimizing the Kullback-Leibler distance between a dyadic PMF ...

  5. Radar channel balancing with commutation

    Energy Technology Data Exchange (ETDEWEB)

    Doerry, Armin Walter

    2014-02-01

    When multiple channels are employed in a pulse-Doppler radar, achieving and maintaining balance between the channels is problematic. In some circumstances the channels may be commutated to achieve adequate balance. Commutation is the switching, trading, toggling, or multiplexing of the channels between signal paths. Commutation allows modulating the imbalance energy away from the balanced energy in Doppler, where it can be mitigated with filtering.

  6. Microstructural information from channeling measurements

    International Nuclear Information System (INIS)

    Quere, Y.

    1984-09-01

    Channeling is sensitive to nearly all structural changes in solids. One briefly recalls how particles are dechanneled by lattice defects and describes the main applications of channeling to materials science: detection of radiation damage, location of impurity atoms, precipitations in alloys... Channeling being a phenomenon characteristic of perfect crystals, any type of lattice imperfection (phonons, crystal defects, precipitation etc.) is expected to produce dechanneling. Consequently channeling and its opposite, dechanneling, have both been used to study structure and structural changes of materials

  7. Ion channeling revisited

    Energy Technology Data Exchange (ETDEWEB)

    Doyle, Barney Lee [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Corona, Aldo [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Nguyen, Anh [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2014-09-01

    A MS Excel program has been written that calculates accidental, or unintentional, ion channeling in cubic bcc, fcc and diamond lattice crystals or polycrystalline materials. This becomes an important issue when simulating the creation by energetic neutrons of point displacement damage and extended defects using beams of ions. All of the tables and graphs in the three Ion Beam Analysis Handbooks that previously had to be manually looked up and read from were programed into Excel in handy lookup tables, or parameterized, for the case of the graphs, using rather simple exponential functions with different powers of the argument. The program then offers an extremely convenient way to calculate axial and planar half-angles and minimum yield or dechanneling probabilities, effects on half-angles of amorphous overlayers, accidental channeling probabilities for randomly oriented crystals or crystallites, and finally a way to automatically generate stereographic projections of axial and planar channeling half-angles. The program can generate these projections and calculate these probabilities for axes and [hkl] planes up to (555).

  8. The alpha channeling effect

    Science.gov (United States)

    Fisch, N. J.

    2015-12-01

    Alpha particles born through fusion reactions in a tokamak reactor tend to slow down on electrons, but that could take up to hundreds of milliseconds. Before that happens, the energy in these alpha particles can destabilize on collisionless timescales toroidal Alfven modes and other waves, in a way deleterious to energy confinement. However, it has been speculated that this energy might be instead be channeled into useful energy, so as to heat fuel ions or to drive current. Such a channeling needs to be catalyzed by waves Waves can produce diffusion in energy of the alpha particles in a way that is strictly coupled to diffusion in space. If these diffusion paths in energy-position space point from high energy in the center to low energy on the periphery, then alpha particles will be cooled while forced to the periphery. The energy from the alpha particles is absorbed by the wave. The amplified wave can then heat ions or drive current. This process or paradigm for extracting alpha particle energy collisionlessly has been called alpha channeling. While the effect is speculative, the upside potential for economical fusion is immense. The paradigm also operates more generally in other contexts of magnetically confined plasma.

  9. Phycodnavirus potassium ion channel proteins question the virus molecular piracy hypothesis.

    Directory of Open Access Journals (Sweden)

    Kay Hamacher

    Full Text Available Phycodnaviruses are large dsDNA, algal-infecting viruses that encode many genes with homologs in prokaryotes and eukaryotes. Among the viral gene products are the smallest proteins known to form functional K(+ channels. To determine if these viral K(+ channels are the product of molecular piracy from their hosts, we compared the sequences of the K(+ channel pore modules from seven phycodnaviruses to the K(+ channels from Chlorella variabilis and Ectocarpus siliculosus, whose genomes have recently been sequenced. C. variabilis is the host for two of the viruses PBCV-1 and NY-2A and E. siliculosus is the host for the virus EsV-1. Systematic phylogenetic analyses consistently indicate that the viral K(+ channels are not related to any lineage of the host channel homologs and that they are more closely related to each other than to their host homologs. A consensus sequence of the viral channels resembles a protein of unknown function from a proteobacterium. However, the bacterial protein lacks the consensus motif of all K(+ channels and it does not form a functional channel in yeast, suggesting that the viral channels did not come from a proteobacterium. Collectively, our results indicate that the viruses did not acquire their K(+ channel-encoding genes from their current algal hosts by gene transfer; thus alternative explanations are required. One possibility is that the viral genes arose from ancient organisms, which served as their hosts before the viruses developed their current host specificity. Alternatively the viral proteins could be the origin of K(+ channels in algae and perhaps even all cellular organisms.

  10. TRP channels in kidney disease.

    NARCIS (Netherlands)

    Hsu, Y.J.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2007-01-01

    Mammalian TRP channel proteins form six-transmembrane cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Recent studies of TRP channels indicate that they are involved in numerous fundamental cell

  11. Parallel inter channel interaction mechanisms

    International Nuclear Information System (INIS)

    Jovic, V.; Afgan, N.; Jovic, L.

    1995-01-01

    Parallel channels interactions are examined. For experimental researches of nonstationary regimes flow in three parallel vertical channels results of phenomenon analysis and mechanisms of parallel channel interaction for adiabatic condition of one-phase fluid and two-phase mixture flow are shown. (author)

  12. Voltage-Gated Calcium Channels

    Science.gov (United States)

    Zamponi, Gerald Werner

    Voltage Gated Calcium Channels is the first comprehensive book in the calcium channel field, encompassing over thirty years of progress towards our understanding of calcium channel structure, function, regulation, physiology, pharmacology, and genetics. This book balances contributions from many of the leading authorities in the calcium channel field with fresh perspectives from risings stars in the area, taking into account the most recent literature and concepts. This is the only all-encompassing calcium channel book currently available, and is an essential resource for academic researchers at all levels in the areas neuroscience, biophysics, and cardiovascular sciences, as well as to researchers in the drug discovery area.

  13. The KCNE genes in hypertrophic cardiomyopathy: a candidate gene study

    DEFF Research Database (Denmark)

    Hedley, Paula L; Haundrup, Ole; Andersen, Paal S

    2011-01-01

    The gene family KCNE1-5, which encode modulating β-subunits of several repolarising K+-ion channels, has been associated with genetic cardiac diseases such as long QT syndrome, atrial fibrillation and Brugada syndrome. The minK peptide, encoded by KCNE1, is attached to the Z-disc of the sarcomere...... as well as the T-tubules of the sarcolemma. It has been suggested that minK forms part of an "electro-mechanical feed-back" which links cardiomyocyte stretching to changes in ion channel function. We examined whether mutations in KCNE genes were associated with hypertrophic cardiomyopathy (HCM), a genetic...

  14. Beyond the Manual Channel

    DEFF Research Database (Denmark)

    , the main focus there is on spoken languages in their written and spoken forms. This series of workshops, however, offers a forum for researchers focussing on sign languages. For the fourth time, the workshop had sign language corpora as its main topic. This time, the focus was on any aspect beyond...... the manual channel. Not surprisingly, most papers deal with non-manuals on the face. Once again, the papers at this workshop clearly identify the potentials of even closer cooperation between sign linguists and sign language engineers, and we think it is events like this that contribute a lot to a better...

  15. Ion Channels in Leukocytes

    Science.gov (United States)

    1991-07-01

    muscle k142), heart muscle (80), bo- are released. In recent years much has been learned vine pulmonar arter endothelial cells (251), and rat about the...b3 Zn or cytes from cystic fibrosis patients lack a Cl current that Ni (1 mM)-added to the cytoplasmic side of the mem- can be acti% ated b3 the...that at37’C hu- to be defectiv.- in cystic fibrosis (55, 277), and Chen et al. man T-cell CiL channels are active at rest, implies that (25) have shown

  16. A Micromechanical RF Channelizer

    Science.gov (United States)

    Akgul, Mehmet

    The power consumption of a radio generally goes as the number and strength of the RF signals it must process. In particular, a radio receiver would consume much less power if the signal presented to its electronics contained only the desired signal in a tiny percent bandwidth frequency channel, rather than the typical mix of signals containing unwanted energy outside the desired channel. Unfortunately, a lack of filters capable of selecting single channel bandwidths at RF forces the front-ends of contemporary receivers to accept unwanted signals, and thus, to operate with sub-optimal efficiency. This dissertation focuses on the degree to which capacitive-gap transduced micromechanical resonators can achieve the aforementioned RF channel-selecting filters. It aims to first show theoretically that with appropriate scaling capacitive-gap transducers are strong enough to meet the needed coupling requirements; and second, to fully detail an architecture and design procedure needed to realize said filters. Finally, this dissertation provides an actual experimentally demonstrated RF channel-select filter designed using the developed procedures and confirming theoretical predictions. Specifically, this dissertation introduces four methods that make possible the design and fabrication of RF channel-select filters. The first of these introduces a small-signal equivalent circuit for parallel-plate capacitive-gap transduced micromechanical resonators that employs negative capacitance to model the dependence of resonance frequency on electrical stiffness in a way that facilitates the analysis of micromechanical circuits loaded with arbitrary electrical impedances. The new circuit model not only correctly predicts the dependence of electrical stiffness on the impedances loading the input and output electrodes of parallel-plate capacitive-gap transduced micromechanical device, but does so in a visually intuitive way that identifies current drive as most appropriate for

  17. A sodium-channel mutation causes isolated cardiac conduction disease

    NARCIS (Netherlands)

    Tan, HL; Bink-Boelkens, MTE; Bezzina, CR; Viswanathan, PC; Beaufort-Krol, GCM; van Tintelen, PJ; van den Berg, MP; Wilde, AAM; Balser, [No Value

    2001-01-01

    Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening(1-3); however, a

  18. A sodium-channel mutation causes isolated cardiac conduction disease

    NARCIS (Netherlands)

    Tan, H. L.; Bink-Boelkens, M. T.; Bezzina, C. R.; Viswanathan, P. C.; Beaufort-Krol, G. C.; van Tintelen, P. J.; van den Berg, M. P.; Wilde, A. A.; Balser, J. R.

    2001-01-01

    Cardiac conduction disorders slow the heart rhythm and cause disability in millions of people worldwide. Inherited mutations in SCN5A, the gene encoding the human cardiac sodium (Na+) channel, have been associated with rapid heart rhythms that occur suddenly and are life-threatening; however, a

  19. Voltage-gated calcium channels of Paramecium cilia.

    Science.gov (United States)

    Lodh, Sukanya; Yano, Junji; Valentine, Megan S; Van Houten, Judith L

    2016-10-01

    Paramecium cells swim by beating their cilia, and make turns by transiently reversing their power stroke. Reversal is caused by Ca 2+ entering the cilium through voltage-gated Ca 2+ (Ca V ) channels that are found exclusively in the cilia. As ciliary Ca 2+ levels return to normal, the cell pivots and swims forward in a new direction. Thus, the activation of the Ca V channels causes cells to make a turn in their swimming paths. For 45 years, the physiological characteristics of the Paramecium ciliary Ca V channels have been known, but the proteins were not identified until recently, when the P. tetraurelia ciliary membrane proteome was determined. Three Ca V α1 subunits that were identified among the proteins were cloned and confirmed to be expressed in the cilia. We demonstrate using RNA interference that these channels function as the ciliary Ca V channels that are responsible for the reversal of ciliary beating. Furthermore, we show that Pawn (pw) mutants of Paramecium that cannot swim backward for lack of Ca V channel activity do not express any of the three Ca V 1 channels in their ciliary membrane, until they are rescued from the mutant phenotype by expression of the wild-type PW gene. These results reinforce the correlation of the three Ca V channels with backward swimming through ciliary reversal. The PwB protein, found in endoplasmic reticulum fractions, co-immunoprecipitates with the Ca V 1c channel and perhaps functions in trafficking. The PwA protein does not appear to have an interaction with the channel proteins but affects their appearance in the cilia. © 2016. Published by The Company of Biologists Ltd.

  20. Mimicking multi-channel scattering with single-channel approaches

    OpenAIRE

    Grishkevich, Sergey; Schneider, Philipp-Immanuel; Vanne, Yulian V.; Saenz, Alejandro

    2009-01-01

    The collision of two atoms is an intrinsic multi-channel (MC) problem as becomes especially obvious in the presence of Feshbach resonances. Due to its complexity, however, single-channel (SC) approximations, which reproduce the long-range behavior of the open channel, are often applied in calculations. In this work the complete MC problem is solved numerically for the magnetic Feshbach resonances (MFRs) in collisions between generic ultracold 6Li and 87Rb atoms in the ground state and in the ...

  1. Multiplicative properties of quantum channels

    Science.gov (United States)

    Rahaman, Mizanur

    2017-08-01

    In this paper, we study the multiplicative behaviour of quantum channels, mathematically described by trace preserving, completely positive maps on matrix algebras. It turns out that the multiplicative domain of a unital quantum channel has a close connection to its spectral properties. A structure theorem (theorem 2.5), which reveals the automorphic property of an arbitrary unital quantum channel on a subalgebra, is presented. Various classes of quantum channels (irreducible, primitive, etc) are then analysed in terms of this stabilising subalgebra. The notion of the multiplicative index of a unital quantum channel is introduced, which measures the number of times a unital channel needs to be composed with itself for the multiplicative algebra to stabilise. We show that the maps that have trivial multiplicative domains are dense in completely bounded norm topology in the set of all unital completely positive maps. Some applications in quantum information theory are discussed.

  2. Gene Therapy

    Science.gov (United States)

    Gene therapy Overview Gene therapy involves altering the genes inside your body's cells in an effort to treat or stop disease. Genes contain your ... that don't work properly can cause disease. Gene therapy replaces a faulty gene or adds a new ...

  3. Upgrading a marketing channels role

    Directory of Open Access Journals (Sweden)

    Tišma-Borota Ankica

    2002-01-01

    Full Text Available As one of the marketing mix instruments, marketing channels were usually behind other instruments (product, price and promotion. Many companies regarded marketing channels as something that was 'left' after more important strategies of price, product and promotion were created. In recent past, things have changed and marketing channels became more interesting for research. This change came as a result of change in global market functioning especially in competitive advantage, distributors' strength and increasing technology.

  4. Single-channel kinetics of BK (Slo1 channels

    Directory of Open Access Journals (Sweden)

    Yanyan eGeng

    2015-01-01

    Full Text Available Single-channel kinetics has proven a powerful tool to reveal information about the gating mechanisms that control the opening and closing of ion channels. This introductory review focuses on the gating of large conductance Ca2+- and voltage-activated K+ (BK or Slo1 channels at the single-channel level. It starts with single-channel current records and progresses to presentation and analysis of single-channel data and the development of gating mechanisms in terms of discrete state Markov (DSM models. The DSM models are formulated in terms of the tetrameric modular structure of BK channels, consisting of a central transmembrane pore-gate domain (PGD attached to four surrounding transmembrane voltage sensing domains (VSD and a large intracellular cytosolic domain (CTD, also referred to as the gating ring. The modular structure and data analysis shows that the Ca2+ and voltage dependent gating considered separately can each be approximated by 10-state two-tiered models with 5 closed states on the upper tier and 5 open states on the lower tier. The modular structure and joint Ca2+ and voltage dependent gating are consistent with a 50 state two-tiered model with 25 closed states on the upper tier and 25 open states on the lower tier. Adding an additional tier of brief closed (flicker states to the 10-state or 50-state models improved the description of the gating. For fixed experimental conditions a channel would gate in only a subset of the potential number of states. The detected number of states and the correlations between adjacent interval durations are consistent with the tiered models. The examined models can account for the single-channel kinetics and the bursting behavior of gating. Ca2+ and voltage activate BK channels by predominantly increasing the effective opening rate of the channel with a smaller decrease in the effective closing rate. Ca2+ and depolarization thus activate by mainly destabilizing the closed states.

  5. UMTS Common Channel Sensitivity Analysis

    DEFF Research Database (Denmark)

    Pratas, Nuno; Rodrigues, António; Santos, Frederico

    2006-01-01

    and as such it is necessary that both channels be available across the cell radius. This requirement makes the choice of the transmission parameters a fundamental one. This paper presents a sensitivity analysis regarding the transmission parameters of two UMTS common channels: RACH and FACH. Optimization of these channels...... is performed and values for the key transmission parameters in both common channels are obtained. On RACH these parameters are the message to preamble offset, the initial SIR target and the preamble power step while on FACH it is the transmission power offset....

  6. Demystifying Mechanosensitive Piezo Ion Channels.

    Science.gov (United States)

    Xu, X Z Shawn

    2016-06-01

    Mechanosensitive channels mediate touch, hearing, proprioception, and blood pressure regulation. Piezo proteins, including Piezo1 and Piezo2, represent a new class of mechanosensitive channels that have been reported to play key roles in most, if not all, of these modalities. The structural architecture and molecular mechanisms by which Piezos act as mechanosensitive channels, however, remain mysterious. Two new studies have now provided critical insights into the atomic structure and molecular basis of the ion permeation and mechano-gating properties of the Piezo1 channel.

  7. Defect Distributions in Channeling Experiments

    DEFF Research Database (Denmark)

    Andersen, Hans Henrik; Sigmund, P.

    1965-01-01

    A simple collision model allows to calculate energy losses of perfectly channeled particles. The maximum energy loss is related in a simple way to the displacement energy of lattice atoms perpendicular to the channel. From that, one obtains rather definite predictions on the possibility...... of radiation damage by channeled particles. As an application, one gets a necessary criterion for the occurence of super tails in channeling experiments. The theory involves some assumptions on the behaviour of Born-Mayer potentials which are verified by comparison to experimental displacement energies....

  8. Preservation of meandering river channels in uniformly aggrading channel belts

    NARCIS (Netherlands)

    Lageweg, W.I. van de; Schuurman, F.; Cohen, K.M.; Dijk, W.M. van; Shimizu, Y.; Kleinhans, M.G.

    2016-01-01

    Channel belt deposits from meandering river systems commonly display an internal architecture of stacked depositional features with scoured basal contacts due to channel and bedform migration across a range of scales. Recognition and correct interpretation of these bounding surfaces is essential to

  9. MONETARY TRANSMISSION CHANNELS IN ROMANIA – THE CREDIT CHANNEL

    Directory of Open Access Journals (Sweden)

    Magdalena RĂDULESCU

    2009-12-01

    Full Text Available The theoretical – intuitive analysis applied to the segment of monetary transmission evidences the fact that forming the traditional monetary impulses transmission channels are in a starting phase due to the long financial non – intermediary process which Romanian economy had known. In these conditions, the exchange rate channel, and also NBR currency purchases was, for a long time, an important way through which monetary authorities actions influenced macro economical behaviors. But starting with 2000, it is observed a credit channel reactivation and, especially, interest rate channel. Anyhow, the credit channel continues to be undermined by the existence of liquidity surplus within the system, by the phenomena of substitution of national currency credit with currency credits, and also moral hazardous displays. Albeit some of these phenomena also affect the interest rate channel, its role in sending monetary policy impulses is in a continuous progress. Apparently, it acts by way of nominal interest rates, their real level seeming less relevant. Once with remaking the two traditional channels, the companies and households balance is configured and consolidated, which shall potentate in the future the efficiency of the monetary policy. This paper analyses the credit channel in Romania, through an unrestricted VAR analysis.. It shows the responses of exchange rate, inflation rate, GDP, interest rate, imports and exports to a shock on non-governmental credit

  10. ZnO-channel thin-film transistors: Channel mobility

    International Nuclear Information System (INIS)

    Hoffman, R.L.

    2004-01-01

    ZnO-channel thin-film transistor (TFT) test structures are fabricated using a bottom-gate structure on thermally oxidized Si; ZnO is deposited via RF sputtering from an oxide target, with an unheated substrate. Electrical characteristics are evaluated, with particular attention given to the extraction and interpretation of transistor channel mobility. ZnO-channel TFT mobility exhibits severe deviation from that assumed by ideal TFT models; mobility extraction methodology must accordingly be recast so as to provide useful insight into device operation. Two mobility metrics, μ avg and μ inc , are developed and proposed as relevant tools in the characterization of nonideal TFTs. These mobility metrics are employed to characterize the ZnO-channel TFTs reported herein; values for μ inc as high as 25 cm2/V s are measured, comprising a substantial increase in ZnO-channel TFT mobility as compared to previously reported performance for such devices

  11. An improved channel assessment scheme

    KAUST Repository

    Bader, Ahmed

    2014-01-01

    A source node in a multihop network determines whether to transmit in a channel based on whether the channel is occupied by a packet transmission with a large number of relays; whether the source node is in the data tones back-off zone; and the source node is in the busy tone back-off zone.

  12. Quantum communication under channel uncertainty

    Energy Technology Data Exchange (ETDEWEB)

    Noetzel, Janis Christian Gregor

    2012-09-06

    This work contains results concerning transmission of entanglement and subspaces as well as generation of entanglement in the limit of arbitrary many uses of compound- and arbitrarily varying quantum channels (CQC, AVQC). In both cases, the channel is described by a set of memoryless channels. Only forward communication between one sender and one receiver is allowed. A code is said to be ''good'' only, if it is ''good'' for every channel out of the set. Both settings describe a scenario, in which sender and receiver have only limited channel knowledge. For different amounts of information about the channel available to sender or receiver, coding theorems are proven for the CQC. For the AVQC, both deterministic and randomised coding schemes are considered. Coding theorems are proven, as well as a quantum analogue of the Ahlswede-dichotomy. The connection to zero-error capacities of stationary memoryless quantum channels is investigated. The notion of symmetrisability is defined and used for both classes of channels.

  13. Perceived quality of channel zapping

    NARCIS (Netherlands)

    Kooij, R.E.; Ahmed, K.; Brunnström, K.

    2006-01-01

    The end user experience of service quality is critical to the success of a service provider's IPTV deployment program. A key element involved in validating IPTV quality of experience (QoE) is how quickly and reliably users can change TV channels, often referred to as channel zapping. Currently there

  14. Channel's Concurrence and Quantum Teleportation

    Institute of Scientific and Technical Information of China (English)

    LING Yin-Sheng

    2005-01-01

    Concurrence can measure the entanglement property of a system. If the channel is a pure state, positive concurrence state can afford the good performance in the teleportation process. If the channel ia a mixed state, positive concurrence state cannot assure the good performance in the teleportation. The conditions of the positive concurrence and the quantum teleportation in the Heisenberg spin ring is derived.

  15. An improved channel assessment scheme

    KAUST Repository

    Bader, Ahmed

    2014-05-01

    A source node in a multihop network determines whether to transmit in a channel based on whether the channel is occupied by a packet transmission with a large number of relays; whether the source node is in the data tones back-off zone; and the source node is in the busy tone back-off zone.

  16. Decreasing vortex flux in channels

    International Nuclear Information System (INIS)

    Migaj, V.K.; Nosova, I.S.

    1979-01-01

    A new method for reducing vortex flow losses in power plant channels is suggested. The method is based on vortex splitting in vortex flow areas with transverse barriers placed on the channel walls. The upper barrier ends are at the level of the upper boundary of the vortex area and don't protrude to the active flow beyond this boundary. The effectiveness of the method suggested is illustrated taking as an example the investigation of square and flat channels with abrupt widening in one plane, diffusers with widening in one plane, or a rectangualr bend. It is shown that splitting the vortex areas with transverse barriers in the channels results in reduction of hydraulic losses by 10-25%. The above method is characteristic of an extreme simplicity, its application doesn't require changes in the channel shape nor installation of any devices in the flow

  17. Channel box dimension measuring method

    International Nuclear Information System (INIS)

    Oshima, Hirotake; Jo, Hiroto.

    1994-01-01

    The present invention provides a method for measuring the entire length of a channel box of a fuel assembly of a BWR type reactor. Namely, four sensors are used as one set that generate ultrasonic waves from oblique upper portion, oblique lower portion, upper portion and lower portion of the channel box respectively. The distances between the four sensors and each of the portions of the channel box are measured respectively for both of a reference member and a member to be measured. The entire length of the channel box is measured by calculating the measured values and the angles of the obliquely disposed sensors according to a predetermined formula. According to the method of the present invention, the inclination of the channel box to be measured can be corrected. In addition, accuracy of the measurement is improved and the measuring time is saved as well as the measuring device and operation can be simplified. (I.S.)

  18. Marketing channels and competitive advantage

    Directory of Open Access Journals (Sweden)

    Jovičić Dragoljub

    2005-01-01

    Full Text Available Issue that can already be seen and will be very clear in the future is that the central problem in the market of tube caps will not be the product or the price or promotion, but marketing channels. Therefore, the competitive advantage will most probably be built on marketing channels and not the production - as it has been so far, so, the questions of choice functioning and modification of marketing channels, as well as selection of the most appropriate members of channels will become more and more important. Accordingly, it may freely be said that the choice, i.e. the movement of marketing channels represents one of the strategic decisions which has to be made by a company management and which will subsequently very significantly influence the functioning and efficacy of not only the system of distribution, but also the entire business transactions.

  19. Methods of channeling simulation

    International Nuclear Information System (INIS)

    Barrett, J.H.

    1989-06-01

    Many computer simulation programs have been used to interpret experiments almost since the first channeling measurements were made. Certain aspects of these programs are important in how accurately they simulate ions in crystals; among these are the manner in which the structure of the crystal is incorporated, how any quantity of interest is computed, what ion-atom potential is used, how deflections are computed from the potential, incorporation of thermal vibrations of the lattice atoms, correlations of thermal vibrations, and form of stopping power. Other aspects of the programs are included to improve the speed; among these are table lookup, importance sampling, and the multiparameter method. It is desirable for programs to facilitate incorporation of special features of interest in special situations; examples are relaxations and enhanced vibrations of surface atoms, easy substitution of an alternate potential for comparison, change of row directions from layer to layer in strained-layer lattices, and different vibration amplitudes for substitutional solute or impurity atoms. Ways of implementing all of these aspects and features and the consequences of them will be discussed. 30 refs., 3 figs

  20. Based on Channel Characteristics

    Directory of Open Access Journals (Sweden)

    Zhuo Hao

    2013-01-01

    Full Text Available A number of key agreement schemes based on wireless channel characteristics have been proposed recently. However, previous key agreement schemes require that two nodes which need to agree on a key are within the communication range of each other. Hence, they are not suitable for multihop wireless networks, in which nodes do not always have direct connections with each other. In this paper, we first propose a basic multihop key agreement scheme for wireless ad hoc networks. The proposed basic scheme is resistant to external eavesdroppers. Nevertheless, this basic scheme is not secure when there exist internal eavesdroppers or Man-in-the-Middle (MITM adversaries. In order to cope with these adversaries, we propose an improved multihop key agreement scheme. We show that the improved scheme is secure against internal eavesdroppers and MITM adversaries in a single path. Both performance analysis and simulation results demonstrate that the improved scheme is efficient. Consequently, the improved key agreement scheme is suitable for multihop wireless ad hoc networks.

  1. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Directory of Open Access Journals (Sweden)

    Julia Pollak

    Full Text Available Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  2. Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.

    Science.gov (United States)

    Pollak, Julia; Rai, Karan G; Funk, Cory C; Arora, Sonali; Lee, Eunjee; Zhu, Jun; Price, Nathan D; Paddison, Patrick J; Ramirez, Jan-Marino; Rostomily, Robert C

    2017-01-01

    Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.

  3. Information geometry of Gaussian channels

    International Nuclear Information System (INIS)

    Monras, Alex; Illuminati, Fabrizio

    2010-01-01

    We define a local Riemannian metric tensor in the manifold of Gaussian channels and the distance that it induces. We adopt an information-geometric approach and define a metric derived from the Bures-Fisher metric for quantum states. The resulting metric inherits several desirable properties from the Bures-Fisher metric and is operationally motivated by distinguishability considerations: It serves as an upper bound to the attainable quantum Fisher information for the channel parameters using Gaussian states, under generic constraints on the physically available resources. Our approach naturally includes the use of entangled Gaussian probe states. We prove that the metric enjoys some desirable properties like stability and covariance. As a by-product, we also obtain some general results in Gaussian channel estimation that are the continuous-variable analogs of previously known results in finite dimensions. We prove that optimal probe states are always pure and bounded in the number of ancillary modes, even in the presence of constraints on the reduced state input in the channel. This has experimental and computational implications. It limits the complexity of optimal experimental setups for channel estimation and reduces the computational requirements for the evaluation of the metric: Indeed, we construct a converging algorithm for its computation. We provide explicit formulas for computing the multiparametric quantum Fisher information for dissipative channels probed with arbitrary Gaussian states and provide the optimal observables for the estimation of the channel parameters (e.g., bath couplings, squeezing, and temperature).

  4. Channel Simulation in Quantum Metrology

    Directory of Open Access Journals (Sweden)

    Laurenza Riccardo

    2018-04-01

    Full Text Available In this review we discuss how channel simulation can be used to simplify the most general protocols of quantum parameter estimation, where unlimited entanglement and adaptive joint operations may be employed. Whenever the unknown parameter encoded in a quantum channel is completely transferred in an environmental program state simulating the channel, the optimal adaptive estimation cannot beat the standard quantum limit. In this setting, we elucidate the crucial role of quantum teleportation as a primitive operation which allows one to completely reduce adaptive protocols over suitable teleportation-covariant channels and derive matching upper and lower bounds for parameter estimation. For these channels,wemay express the quantum Cramér Rao bound directly in terms of their Choi matrices. Our review considers both discrete- and continuous-variable systems, also presenting some new results for bosonic Gaussian channels using an alternative sub-optimal simulation. It is an open problem to design simulations for quantum channels that achieve the Heisenberg limit.

  5. 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.

  6. Molecular studies of BKCa channels in intracranial arteries

    DEFF Research Database (Denmark)

    Wulf, Helle; Hay-Schmidt, Anders; Poulsen, Asser Nyander

    2008-01-01

    expression of the BK(Ca) channel in rat basilar, middle cerebral, and middle meningeal arteries by reverse transcription polymerase chain reaction (RT-PCR), quantitative real-time PCR, and Western blotting. Distribution patterns were investigated using in situ hybridization and immunofluorescence studies. RT......  Large conductance calcium-activated potassium channels (BK(ca)) are crucial for the regulation of cerebral vascular basal tone and might be involved in cerebral vasodilation relevant to migraine and stroke. We studied the differential gene expression of mRNA transcript levels and protein......-PCR and quantitative real-time PCR detected the expression of the BK(Ca) channel mRNA transcript in rat basilar, middle cerebral, and middle meningeal arteries, with the transcript being expressed more abundantly in rat basilar arteries than in middle cerebral and middle meningeal arteries. Western blotting detected...

  7. Hydraulic jumps in a channel

    DEFF Research Database (Denmark)

    Bonn, D.; Andersen, Anders Peter; Bohr, Tomas

    2009-01-01

    We present a study of hydraulic jumps with flow predominantly in one direction, created either by confining the flow to a narrow channel with parallel walls or by providing an inflow in the form of a narrow sheet. In the channel flow, we find a linear height profile upstream of the jump as expected......'s mixing-length theory with a mixing length that is proportional to the height of the fluid layer. Using averaged boundary-layer equations, taking into account the friction with the channel walls and the eddy viscosity, the flow both upstream and downstream of the jump can be understood. For the downstream...... subcritical flow, we assume that the critical height is attained close to the channel outlet. We use mass and momentum conservation to determine the position of the jump and obtain an estimate which is in rough agreement with our experiment. We show that the averaging method with a varying velocity profile...

  8. Green channel cargo inspection system

    International Nuclear Information System (INIS)

    Shi Yuanping; Yu Jingsheng; Sun Hongqiang; Hao Pu; Cai Wenxia

    2011-01-01

    A radiation detection device was installed in the lanes of a highway toll station, radioactive rays which was collimated emitted through the measured, and arrived the detector. The average density of the fresh agricultural products belonged to Green channel and other prohibited items vary greatly, the absorption of radiation are different between the Green Channel Cargo and other substances. Prior to the experimental group, different standard samples which represent different models and goods were measured, the different standard samples were stored in a computer database. When the trucks get through the Green Channel, the detector will detect the radiation signal and bring to the computer, the computer will process the measured data, and make a conclusion whether the goods are Green Channel cargo. (authors)

  9. Flooding correlations in narrow channel

    International Nuclear Information System (INIS)

    Kim, S. H.; Baek, W. P.; Chang, S. H.

    1999-01-01

    Heat transfer in narrow gap is considered as important phenomena in severe accidents in nuclear power plants. Also in heat removal of electric chip. Critical heat flux(CHF) in narrow gap limits the maximum heat transfer rate in narrow channel. In case of closed bottom channel, flooding limited CHF occurrence is observed. Flooding correlations will be helpful to predict the CHF in closed bottom channel. In present study, flooding data for narrow channel geometry were collected and the work to recognize the effect of the span, w and gap size, s were performed. And new flooding correlations were suggested for high-aspect-ratio geometry. Also, flooding correlation was applied to flooding limited CHF data

  10. Multi-channel Kondo necklace

    International Nuclear Information System (INIS)

    Fazekas, P.; Kee Haeyoung.

    1993-06-01

    A multi-channel generalization of Doniach's Kondo necklace model is formulated, and its phase diagram studied in the mean-field approximation. Our intention is to introduce the possible simplest model which displays some of the features expected from the overscreened Kondo lattice. The N conduction electron channels are represented by N sets of pseudospins τ J , j = 1 1,..., N which are all antiferromagnetically coupled to a periodic array of modul S = 1/2 spins. Exploiting permutation symmetry in the channel index j allows us to write down the self-consistency equation for general N. For N > 2, we find that the critical temperature is rising with increasing Kondo interaction; we interpret this effect by pointing out that the Kondo coupling creates the composite pseudospin objects which undergo an ordering transition. The relevance of our findings to the underlying fermionic multi-channel problem is discussed. (author). 33 refs, 1 fig

  11. Experimentation with PEC channel prototype

    International Nuclear Information System (INIS)

    Caponetti, R.; Iacovelli, M.

    1984-01-01

    Experimentation on prototypes of PEC components is presently being carried out at Casaccia CRE. This report shows the results of the first cycle of experimentation of the central channel, concerning the aspects of sodium removal after experimentation

  12. Multi-channel Kondo necklace

    Energy Technology Data Exchange (ETDEWEB)

    Fazekas, P; Haeyoung, Kee

    1993-06-01

    A multi-channel generalization of Doniach`s Kondo necklace model is formulated, and its phase diagram studied in the mean-field approximation. Our intention is to introduce the possible simplest model which displays some of the features expected from the overscreened Kondo lattice. The N conduction electron channels are represented by N sets of pseudospins {tau}{sub J}, j = 1 1,..., N which are all antiferromagnetically coupled to a periodic array of modul S = 1/2 spins. Exploiting permutation symmetry in the channel index j allows us to write down the self-consistency equation for general N. For N > 2, we find that the critical temperature is rising with increasing Kondo interaction; we interpret this effect by pointing out that the Kondo coupling creates the composite pseudospin objects which undergo an ordering transition. The relevance of our findings to the underlying fermionic multi-channel problem is discussed. (author). 33 refs, 1 fig.

  13. FMCG companies specific distribution channels

    Directory of Open Access Journals (Sweden)

    Ioana Barin

    2009-12-01

    Full Text Available Distribution includes all activities undertaken by the producer, alone or in cooperation, since the end of the final finished products or services until they are in possession of consumers. The distribution consists of the following major components: distribution channels or marketing channels, which together form a distribution network; logistics o rphysical distribution. In order to effective achieve, distribution of goods requires an amount of activities and operational processes related to transit of goods from producer to consumer, the best conditions, using existing distribution channels and logistics system. One of the essential functions of a distribution is performing acts of sale, through which, with the actual movement of goods, their change of ownership takes place, that the successive transfer of ownership from producer to consumer. This is an itinerary in the economic cycle of goods, called the distribution channel.

  14. Evolutionary conservation and changes in insect TRP channels.

    Science.gov (United States)

    Matsuura, Hironori; Sokabe, Takaaki; Kohno, Keigo; Tominaga, Makoto; Kadowaki, Tatsuhiko

    2009-09-10

    TRP (Transient Receptor Potential) channels respond to diverse stimuli and thus function as the primary integrators of varied sensory information. They are also activated by various compounds and secondary messengers to mediate cell-cell interactions as well as to detect changes in the local environment. Their physiological roles have been primarily characterized only in mice and fruit flies, and evolutionary studies are limited. To understand the evolution of insect TRP channels and the mechanisms of integrating sensory inputs in insects, we have identified and compared TRP channel genes in Drosophila melanogaster, Bombyx mori, Tribolium castaneum, Apis mellifera, Nasonia vitripennis, and Pediculus humanus genomes as part of genome sequencing efforts. All the insects examined have 2 TRPV, 1 TRPN, 1 TRPM, 3 TRPC, and 1 TRPML subfamily members, demonstrating that these channels have the ancient origins in insects. The common pattern also suggests that the mechanisms for detecting mechanical and visual stimuli and maintaining lysosomal functions may be evolutionarily well conserved in insects. However, a TRPP channel, the most ancient TRP channel, is missing in B. mori, A. mellifera, and N. vitripennis. Although P. humanus and D. melanogaster contain 4 TRPA subfamily members, the other insects have 5 TRPA subfamily members. T. castaneum, A. mellifera, and N. vitripennis contain TRPA5 channels, which have been specifically retained or gained in Coleoptera and Hymenoptera. Furthermore, TRPA1, which functions for thermotaxis in Drosophila, is missing in A. mellifera and N. vitripennis; however, they have other Hymenoptera-specific TRPA channels (AmHsTRPA and NvHsTRPA). NvHsTRPA expressed in HEK293 cells is activated by temperature increase, demonstrating that HsTRPAs function as novel thermal sensors in Hymenoptera. The total number of insect TRP family members is 13-14, approximately half that of mammalian TRP family members. As shown for mammalian TRP channels, this

  15. Evolutionary conservation and changes in insect TRP channels

    Directory of Open Access Journals (Sweden)

    Tominaga Makoto

    2009-09-01

    Full Text Available Abstract Background TRP (Transient Receptor Potential channels respond to diverse stimuli and thus function as the primary integrators of varied sensory information. They are also activated by various compounds and secondary messengers to mediate cell-cell interactions as well as to detect changes in the local environment. Their physiological roles have been primarily characterized only in mice and fruit flies, and evolutionary studies are limited. To understand the evolution of insect TRP channels and the mechanisms of integrating sensory inputs in insects, we have identified and compared TRP channel genes in Drosophila melanogaster, Bombyx mori, Tribolium castaneum, Apis mellifera, Nasonia vitripennis, and Pediculus humanus genomes as part of genome sequencing efforts. Results All the insects examined have 2 TRPV, 1 TRPN, 1 TRPM, 3 TRPC, and 1 TRPML subfamily members, demonstrating that these channels have the ancient origins in insects. The common pattern also suggests that the mechanisms for detecting mechanical and visual stimuli and maintaining lysosomal functions may be evolutionarily well conserved in insects. However, a TRPP channel, the most ancient TRP channel, is missing in B. mori, A. mellifera, and N. vitripennis. Although P. humanus and D. melanogaster contain 4 TRPA subfamily members, the other insects have 5 TRPA subfamily members. T. castaneum, A. mellifera, and N. vitripennis contain TRPA5 channels, which have been specifically retained or gained in Coleoptera and Hymenoptera. Furthermore, TRPA1, which functions for thermotaxis in Drosophila, is missing in A. mellifera and N. vitripennis; however, they have other Hymenoptera-specific TRPA channels (AmHsTRPA and NvHsTRPA. NvHsTRPA expressed in HEK293 cells is activated by temperature increase, demonstrating that HsTRPAs function as novel thermal sensors in Hymenoptera. Conclusion The total number of insect TRP family members is 13-14, approximately half that of mammalian TRP

  16. Marketing channel behaviour and performance

    OpenAIRE

    Duarte, Margarida

    2000-01-01

    Thesis submitted to University of Manchester for the degree of Doctor of Philosophy in the Faculty of Business Administration. A major aim of this study is to offer a relatively comprehensive picture of marketing channel behaviour and performance. Given the statistical difficulties in testing a very large, comprehensive model to achieve this aim, two separate but overlapping models are proposed. One model specifically addresses behaviour in marketing channels, while the other integrates k...

  17. Channel coincidence counter: version 1

    International Nuclear Information System (INIS)

    Krick, M.S.; Menlove, H.O.

    1980-06-01

    A thermal neutron coincidence counter has been designed for the assay of fast critical assembly fuel drawers and plutonium-bearing fuel rods. The principal feature of the detector is a 7-cm by 7-cm by 97-cm detector channel, which provides a uniform neutron detection efficiency of 16% along the central 40 cm of the channel. The electronics system is identical to that used for the High-Level Neutron Coincidence Counter

  18. TRP Channels in Human Prostate

    Directory of Open Access Journals (Sweden)

    Carl Van Haute

    2010-01-01

    Full Text Available This review gives an overview of morphological and functional characteristics in the human prostate. It will focus on the current knowledge about transient receptor potential (TRP channels expressed in the human prostate, and their putative role in normal physiology and prostate carcinogenesis. Controversial data regarding the expression pattern and the potential impact of TRP channels in prostate function, and their involvement in prostate cancer and other prostate diseases, will be discussed.

  19. Voltage-gated sodium channels in taste bud cells.

    Science.gov (United States)

    Gao, Na; Lu, Min; Echeverri, Fernando; Laita, Bianca; Kalabat, Dalia; Williams, Mark E; Hevezi, Peter; Zlotnik, Albert; Moyer, Bryan D

    2009-03-12

    Taste bud cells transmit information regarding the contents of food from taste receptors embedded in apical microvilli to gustatory nerve fibers innervating basolateral membranes. In particular, taste cells depolarize, activate voltage-gated sodium channels, and fire action potentials in response to tastants. Initial cell depolarization is attributable to sodium influx through TRPM5 in sweet, bitter, and umami cells and an undetermined cation influx through an ion channel in sour cells expressing PKD2L1, a candidate sour taste receptor. The molecular identity of the voltage-gated sodium channels that sense depolarizing signals and subsequently initiate action potentials coding taste information to gustatory nerve fibers is unknown. We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore. SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.

  20. Electrophysiological characterisation of KCNQ channel modulators

    DEFF Research Database (Denmark)

    Schrøder, R.L

    Potassium (K+) ion channels are ubiquitously expressed in mammalian cells, and each channel serves a precise physiological role due to its specific biophysical characteristics and expression pattern. A few K+ channels are targets for certain drugs, and in this thesis it is suggested that the KCNQ K......+ channels may be targets for neuroprotective, anti-epileptic and anti-nociceptive compounds. The importance of these channels is underscored by the fact that four out of five KCNQ channel subtypes are involved in severe human diseases. However, the pharmacology of the KCNQ channels is yet poorly understood...... as these channels were identified only recently. Therefore, there is a need for understanding the biophysical behavior and pharmacology of these ion channels. KCNQ channels belong to the group of voltage-activated K+ channels. The subfamily consists of KCNQ1-5, which is primarily expressed in the CNS, heart, ear...

  1. Different protein kinase C isoenzymes mediate inhibition of cardiac rapidly activating delayed rectifier K+ current by different G-protein coupled receptors.

    Science.gov (United States)

    Liu, Xueli; Wang, Yuhong; Zhang, Hua; Shen, Li; Xu, Yanfang

    2017-12-01

    Elevated angiotensin II (Ang II) and sympathetic activity contributes to a high risk of ventricular arrhythmias in heart disease. The rapidly activating delayed rectifier K + current (I Kr ) carried by the hERG channels plays a critical role in cardiac repolarization, and decreased I Kr is involved in increased cardiac arrhythmogenicity. Stimulation of α 1A -adrenoreceptors or angiotensin II AT 1 receptors is known to inhibit I Kr via PKC. Here, we have identified the PKC isoenzymes mediating the inhibition of I Kr by activation of these two different GPCRs. The whole-cell patch-clamp technique was used to record I Kr in guinea pig cardiomyocytes and HEK293 cells co-transfected with hERG and α 1A -adrenoreceptor or AT 1 receptor genes. A broad spectrum PKC inhibitor Gö6983 (not inhibiting PKCε), a selective cPKC inhibitor Gö6976 and a PKCα-specific inhibitor peptide, blocked the inhibition of I Kr by the α 1A -adrenoreceptor agonist A61603. However, these inhibitors did not affect the reduction of I Kr by activation of AT 1 receptors, whereas the PKCε-selective inhibitor peptide did block the effect. The effects of angiotensin II and the PKCε activator peptide were inhibited in mutant hERG channels in which 17 of the 18 PKC phosphorylation sites were deleted, whereas a deletion of the N-terminus of the hERG channels selectively prevented the inhibition elicited by A61603 and the cPKC activator peptide. Our results indicated that inhibition of I Kr by activation of α 1A -adrenoreceptors or AT 1 receptors were mediated by PKCα and PKCε isoforms respectively, through different molecular mechanisms. © 2017 The British Pharmacological Society.

  2. Uncertainty analysis for hot channel

    International Nuclear Information System (INIS)

    Panka, I.; Kereszturi, A.

    2006-01-01

    The fulfillment of the safety analysis acceptance criteria is usually evaluated by separate hot channel calculations using the results of neutronic or/and thermo hydraulic system calculations. In case of an ATWS event (inadvertent withdrawal of control assembly), according to the analysis, a number of fuel rods are experiencing DNB for a longer time and must be regarded as failed. Their number must be determined for a further evaluation of the radiological consequences. In the deterministic approach, the global power history must be multiplied by different hot channel factors (kx) taking into account the radial power peaking factors for each fuel pin. If DNB occurs it is necessary to perform a few number of hot channel calculations to determine the limiting kx leading just to DNB and fuel failure (the conservative DNBR limit is 1.33). Knowing the pin power distribution from the core design calculation, the number of failed fuel pins can be calculated. The above procedure can be performed by conservative assumptions (e.g. conservative input parameters in the hot channel calculations), as well. In case of hot channel uncertainty analysis, the relevant input parameters (k x, mass flow, inlet temperature of the coolant, pin average burnup, initial gap size, selection of power history influencing the gap conductance value) of hot channel calculations and the DNBR limit are varied considering the respective uncertainties. An uncertainty analysis methodology was elaborated combining the response surface method with the one sided tolerance limit method of Wilks. The results of deterministic and uncertainty hot channel calculations are compared regarding to the number of failed fuel rods, max. temperature of the clad surface and max. temperature of the fuel (Authors)

  3. Planar channeling in superlattices: Theory

    International Nuclear Information System (INIS)

    Ellison, J.A.; Picraux, S.T.; Allen, W.R.; Chu, W.K.

    1988-01-01

    The well-known continuum model theory for planar channeled energetic particles in perfect crystals is extended to layered crystalline structures and applied to superlattices. In a strained-layer structure, the planar channels with normals which are not perpendicular to the growth direction change their direction at each interface, and this dramatically influences the channeling behavior. The governing equation of motion for a planar channeled ion in a strained-layer superlattice with equal layer thicknesses is a one degree of freedom nonlinear oscillator which is periodically forced with a sequence of δ functions. These δ functions, which are of equal spacing and amplitude with alternating sign, represent the tilts at each of the interfaces. Thus upon matching an effective channeled particle wavelength, corresponding to a natural period of the nonlinear oscillator, to the period of the strained-layer superlattice, corresponding to the periodic forcing, strong resonance effects are expected. The condition of one effective wavelength per period corresponds to a rapid dechanneling at a well-defined depth (catastrophic dechanneling), whereas two wavelengths per period corresponds to no enhanced dechanneling after the first one or two layers (resonance channeling). A phase plane analysis is used to characterize the channeled particle motion. Detailed calculations using the Moliere continuum potential are compared with our previously described modified harmonic model, and new results are presented for the phase plane evolution, as well as the dechanneling as a function of depth, incident angle, energy, and layer thickness. General scaling laws are developed and nearly universal curves are obtained for the dechanneling versus depth under catastrophic dechanneling

  4. Volume of the space of qubit-qubit channels and state transformations under random quantum channels

    OpenAIRE

    Lovas, Attila; Andai, Attila

    2017-01-01

    The simplest building blocks for quantum computations are the qubit-qubit quantum channels. In this paper, we analyze the structure of these channels via their Choi representation. The restriction of a quantum channel to the space of classical states (i.e. probability distributions) is called the underlying classical channel. The structure of quantum channels over a fixed classical channel is studied, the volume of general and unital qubit channels with respect to the Lebesgue measure is comp...

  5. Information transfer through quantum channels

    International Nuclear Information System (INIS)

    Kretschmann, D.

    2007-01-01

    This PhD thesis represents work done between Aug. 2003 and Dec. 2006 in Reinhard F. Werner's quantum information theory group at Technische Universitaet Braunschweig, and Artur Ekert's Centre for Quantum Computation at the University of Cambridge. My thesis falls into the field of abstract quantum information theory. This work investigates both fundamental properties of quantum channels and their asymptotic capacities for classical as well as quantum information transfer. Stinespring's theorem is the basic structure theorem for quantum channels. It implies that every quantum channel can be represented as a unitary evolution on an enlarged system. In Ch. 3 we present a continuity theorem for Stinespring's representation: two quantum channels are similar if and only if it is possible to find unitary implementations that are likewise similar, with dimension-independent norm bounds. The continuity theorem allows to derive a formulation of the information-disturbance tradeoff in terms of quantum channels, and a continuity estimate for the no-broadcasting principle. In Ch. 4 we then apply the continuity theorem to give a strengthened no-go proof for quantum bit commitment, an important cryptographic primitive. This result also provides a natural characterization of those protocols that fall outside the standard setting of unconditional security, and thus may allow secure bit commitment. We present a new such protocol whose security relies on decoherence in the receiver's lab. Ch. 5 reviews the capacities of quantum channels for the transfer of both classical and quantum information, and investigates several variations in the notion of channel capacity. Memory effects are then investigated in detail in Ch. 6. We advertise a model which is sufficiently general to encompass all causal automata: every quantum process in which the outputs up to any given time t do not depend on the inputs at times t'>t can be represented as a concatenated memory channel. We then explain how

  6. Information transfer through quantum channels

    Energy Technology Data Exchange (ETDEWEB)

    Kretschmann, D.

    2007-03-12

    This PhD thesis represents work done between Aug. 2003 and Dec. 2006 in Reinhard F. Werner's quantum information theory group at Technische Universitaet Braunschweig, and Artur Ekert's Centre for Quantum Computation at the University of Cambridge. My thesis falls into the field of abstract quantum information theory. This work investigates both fundamental properties of quantum channels and their asymptotic capacities for classical as well as quantum information transfer. Stinespring's theorem is the basic structure theorem for quantum channels. It implies that every quantum channel can be represented as a unitary evolution on an enlarged system. In Ch. 3 we present a continuity theorem for Stinespring's representation: two quantum channels are similar if and only if it is possible to find unitary implementations that are likewise similar, with dimension-independent norm bounds. The continuity theorem allows to derive a formulation of the information-disturbance tradeoff in terms of quantum channels, and a continuity estimate for the no-broadcasting principle. In Ch. 4 we then apply the continuity theorem to give a strengthened no-go proof for quantum bit commitment, an important cryptographic primitive. This result also provides a natural characterization of those protocols that fall outside the standard setting of unconditional security, and thus may allow secure bit commitment. We present a new such protocol whose security relies on decoherence in the receiver's lab. Ch. 5 reviews the capacities of quantum channels for the transfer of both classical and quantum information, and investigates several variations in the notion of channel capacity. Memory effects are then investigated in detail in Ch. 6. We advertise a model which is sufficiently general to encompass all causal automata: every quantum process in which the outputs up to any given time t do not depend on the inputs at times t'>t can be represented as a concatenated memory

  7. A Crash Course in Calcium Channels.

    Science.gov (United States)

    Zamponi, Gerald W

    2017-12-20

    Much progress has been made in understanding the molecular physiology and pharmacology of calcium channels. Recently, there have been tremendous advances in learning about calcium channel structure and function through crystallography and cryo-electron microscopy studies. Here, I will give an overview of our knowledge about calcium channels, and highlight two recent studies that give important insights into calcium channel structure.

  8. Transient receptor potential channels in essential hypertension

    DEFF Research Database (Denmark)

    Liu, Daoyan; Scholze, Alexandra; Zhu, Zhiming

    2006-01-01

    The role of nonselective cation channels of the transient receptor potential channel (TRPC) family in essential hypertension has not yet been investigated.......The role of nonselective cation channels of the transient receptor potential channel (TRPC) family in essential hypertension has not yet been investigated....

  9. The hitchhiker’s guide to the voltage-gated sodium channel galaxy

    Science.gov (United States)

    2016-01-01

    Eukaryotic voltage-gated sodium (Nav) channels contribute to the rising phase of action potentials and served as an early muse for biophysicists laying the foundation for our current understanding of electrical signaling. Given their central role in electrical excitability, it is not surprising that (a) inherited mutations in genes encoding for Nav channels and their accessory subunits have been linked to excitability disorders in brain, muscle, and heart; and (b) Nav channels are targeted by various drugs and naturally occurring toxins. Although the overall architecture and behavior of these channels are likely to be similar to the more well-studied voltage-gated potassium channels, eukaryotic Nav channels lack structural and functional symmetry, a notable difference that has implications for gating and selectivity. Activation of voltage-sensing modules of the first three domains in Nav channels is sufficient to open the channel pore, whereas movement of the domain IV voltage sensor is correlated with inactivation. Also, structure–function studies of eukaryotic Nav channels show that a set of amino acids in the selectivity filter, referred to as DEKA locus, is essential for Na+ selectivity. Structures of prokaryotic Nav channels have also shed new light on mechanisms of drug block. These structures exhibit lateral fenestrations that are large enough to allow drugs or lipophilic molecules to gain access into the inner vestibule, suggesting that this might be the passage for drug entry into a closed channel. In this Review, we will synthesize our current understanding of Nav channel gating mechanisms, ion selectivity and permeation, and modulation by therapeutics and toxins in light of the new structures of the prokaryotic Nav channels that, for the time being, serve as structural models of their eukaryotic counterparts. PMID:26712848

  10. The minimum yield in channeling

    International Nuclear Information System (INIS)

    Uguzzoni, A.; Gaertner, K.; Lulli, G.; Andersen, J.U.

    2000-01-01

    A first estimate of the minimum yield was obtained from Lindhard's theory, with the assumption of a statistical equilibrium in the transverse phase-space of channeled particles guided by a continuum axial potential. However, computer simulations have shown that this estimate should be corrected by a fairly large factor, C (approximately equal to 2.5), called the Barrett factor. We have shown earlier that the concept of a statistical equilibrium can be applied to understand this result, with the introduction of a constraint in phase-space due to planar channeling of axially channeled particles. Here we present an extended test of these ideas on the basis of computer simulation of the trajectories of 2 MeV α particles in Si. In particular, the gradual trend towards a full statistical equilibrium is studied. We also discuss the introduction of this modification of standard channeling theory into descriptions of the multiple scattering of channeled particles (dechanneling) by a master equation and show that the calculated minimum yields are in very good agreement with the results of a full computer simulation

  11. Generic theory for channel sinuosity.

    Science.gov (United States)

    Lazarus, Eli D; Constantine, José Antonio

    2013-05-21

    Sinuous patterns traced by fluid flows are a ubiquitous feature of physical landscapes on Earth, Mars, the volcanic floodplains of the Moon and Venus, and other planetary bodies. Typically discussed as a consequence of migration processes in meandering rivers, sinuosity is also expressed in channel types that show little or no indication of meandering. Sinuosity is sometimes described as "inherited" from a preexisting morphology, which still does not explain where the inherited sinuosity came from. For a phenomenon so universal as sinuosity, existing models of channelized flows do not explain the occurrence of sinuosity in the full variety of settings in which it manifests, or how sinuosity may originate. Here we present a generic theory for sinuous flow patterns in landscapes. Using observations from nature and a numerical model of flow routing, we propose that flow resistance (representing landscape roughness attributable to topography or vegetation density) relative to surface slope exerts a fundamental control on channel sinuosity that is effectively independent of internal flow dynamics. Resistance-dominated surfaces produce channels with higher sinuosity than those of slope-dominated surfaces because increased resistance impedes downslope flow. Not limited to rivers, the hypothesis we explore pertains to sinuosity as a geomorphic pattern. The explanation we propose is inclusive enough to account for a wide variety of sinuous channel types in nature, and can serve as an analytical tool for determining the sinuosity a landscape might support.

  12. Charged and Neutral Particles Channeling Phenomena Channeling 2008

    Science.gov (United States)

    Dabagov, Sultan B.; Palumbo, Luigi

    2010-04-01

    On the discovery of coherent Bremsstrahlung in a single crystal at the Frascati National Laboratories / C. Barbiellini, G. P. Murtas and S. B. Dabagov -- Advances in coherent Bremsstrahlung and LPM-effect studies (to the lOOth anniversary from the birth of L. D. Landau) / N. F. Shul'ga -- Spectra of radiation and created particles at intermediate energy in oriented crystal taking into account energy loss / V. N. Baier and V. M. Katkov -- The coherent Bremsstrahlung beam at MAX-lab facility / K. Fissum ... [et al.] -- Radiation from thin, structured targets (CERN NA63) / A. Dizdar -- Hard incoherent radiation in thick crystals / N. F. Shul'ga, V. V. Syshchenko and A. I. Tarnovsky -- Coherent Bremsstrahlung in periodically deformed crystals with a complex base / A. R. Mkrtchyan, A. A. Saharian and V. V. Parazian -- Induction of coherent x-ray Bremsstrahlung in crystals under the influence of acoustic waves / A. R. Mkrtchyan and V. V. Parazian -- Coherent processes in bent single crystals / V. A. Maisheev -- Experimental and theoretical investigation of complete transfer phenomenon for media with various heat exchange coefficients / A. R. Mkrtchyan, A. E. Movsisyan and V. R. Kocharyan -- Coherent pair production in crystals / A. R. Mkrtchyan, A. A. Saharian and V. V. Parazian -- Negative particle planar and axial channeling and channeling collimation / R. A. Carrigan, Jr. -- CERN crystal-based collimation in modern hadron colliders / W. Scandale -- Studies and application of bent crystals for beam steering at 70 GeV IHEP accelerator / A. G. Afonin ... [et al.] -- Crystal collimation studies at the Tevatron (T-980) / N. V. Mokhov ... [et al.] -- Fabrication of crystals for channeling of particles in accellerators / A. Mazzolari ... [et al.] -- New possibilities to facilitate collimation of both positively and negatively charged particle beams by crystals / V. Guidi, A. Mazzolari and V. V. Tikhomirov -- Increase of probability of particle capture into the channeling

  13. Arrhythmogenic KCNE gene variants: current knowledge and future challenges

    Directory of Open Access Journals (Sweden)

    Shawn M Crump

    2014-01-01

    Full Text Available There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE-associated cardiac rhythm disturbances.

  14. CLC channel function and dysfunction in health and disease

    Directory of Open Access Journals (Sweden)

    Gabriel eStölting

    2014-10-01

    Full Text Available CLC channels and transporters are expressed in most tissues and fulfill diverse functions. There are four human CLC channels, ClC-1, ClC-2, ClC-Ka and ClC-Kb, and five CLC transporters, ClC-3 through -7. Some of the CLC channels additionally associate with accessory subunits. Whereas barttin is mandatory for the functional expression of CLC-K, GlialCam is a facultative subunit of ClC-2 which modifies gating and thus increases the functional variability within the CLC family. Isoform-specific ion conduction and gating properties optimize distinct CLC channels for their cellular tasks. ClC-1 preferentially conducts at negative voltages, and the resulting inward rectification provides a large resting chloride conductance without interference with the muscle action potential. Exclusive opening at voltages negative to the chloride reversal potential allows for ClC-2 to regulate intracellular chloride concentrations. ClC-Ka and ClC-Kb are equally suited for inward and outward currents to support transcellular chloride fluxes. Every human CLC channel gene has been linked to a genetic disease, and studying these mutations has provided much information about the physiological roles and the molecular basis of CLC channel function. Mutations in the gene encoding ClC-1 cause myotonia congenita, a disease characterized by sarcolemmal hyperexcitability and muscle stiffness. Loss-of-function of ClC-Kb/barttin channels in patients suffering from Bartter syndrome identified the determinants of chloride conductances in the limb of Henle. Mutations in CLCN2 were found in patients with CNS disorders but the functional role of this isoform is still not understood. Recent links between ClC-1 and epilepsy and ClC-Ka and heart failure suggested novel cellular functions of these proteins. This review aims to survey the knowledge about physiological and pathophysiological functions of human CLC channels in the light of recent discoveries from biophysical, physiological

  15. Pannexin-1 channels in epilepsy.

    Science.gov (United States)

    Aquilino, Mark S; Whyte-Fagundes, Paige; Zoidl, Georg; Carlen, Peter L

    2017-09-05

    Pannexin-1 (Panx1) expression is raised in several animal seizure models and in resected human epileptic brain tissue, suggesting relevance to epilepsy. Multiple factors that are characteristic of seizures are thought to regulate Panx1 channel opening, including elevated levels of extracellular K + . Panx1, when open, 1) releases ATP, glutamate, and other metabolites into the extracellular medium, and 2) may depolarize the membrane due to a channel reversal potential around 0mV. Resultant ATP release from stimulated Panx1 can activate purinergic receptors, including P2X7 receptors. Glutamate and other signaling molecules released by Panx1 opening may have both excitatory and inhibitory actions on seizure generation. This review examines the critical and complex roles of Panx1 channels in epilepsy, which could provide a basis for future therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Axial channeling of uttrarelativistic electrons

    Energy Technology Data Exchange (ETDEWEB)

    Telegin, V.I.; Khokonov, M.Kh. (Moskovskij Gosudarstvennyj Univ. (USSR). Nauchno-Issledovatel' skij Inst. Yadernoj Fiziki)

    1982-07-01

    The dynamics of motion of ultrarelativistic electrons under axial channeling conditions is investigated. The analysis is based on the solution of the kinetic equation obtained recently by Beloshitsky and Kumakhov. The particle dechanneling function is investigated as depending on the type of a crystal, particle energy and angle of entrance into the single crystal. It is found that for most of the beam the major diffusion mechanism is scattering by electrons. It is shown that an optimal depth range exists for which the fraction of channeled particles sharply increases at the expense of the quasi-channeled particles. In a number of cases the dechanneling length for crystals with high atomic numbers may be greater than that of light elements.

  17. Axial channeling of uttrarelativistic electrons

    International Nuclear Information System (INIS)

    Telegin, V.I.; Khokonov, M.Kh.

    1982-01-01

    The dynamics of motion of ultrarelativistic electrons under axial channeling conditions is investigated. The analysis is based on the solution of the kinetic equation obtained recently by Beloshitsky and Kumakhov. The particle dechanneling function is investigated as depending on the type of a crystal, particle energy and angle of entrance into the single crystal. It is found that for most of the beam the major diffusion mechanism is scattering by electrons. It is shown that an optimal depth range exists for which the fraction of channeled particles sharply increases at the expense of the quasi-channeled particles. In a number of cases the dechanneling length for crystals with high atomic numbers may be greater than that of light elements

  18. Pharmacological modulation of SK3 channels

    DEFF Research Database (Denmark)

    Grunnet, M; Jespersen, Thomas; Angelo, K

    2001-01-01

    Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adapt...... at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6)....

  19. Local quantum channels preserving classical correlations

    International Nuclear Information System (INIS)

    Guo Zhihua; Cao Huaixin

    2013-01-01

    The aim of this paper is to discuss local quantum channels that preserve classical correlations. First, we give two equivalent characterizations of classical correlated states. Then we obtain the relationships among classical correlation-preserving local quantum channels, commutativity-preserving local quantum channels and commutativity-preserving quantum channels on each subsystem. Furthermore, for a two-qubit system, we show the general form of classical correlation-preserving local quantum channels. (paper)

  20. The ion-channel laser

    International Nuclear Information System (INIS)

    Whittum, D.H.; Sessler, A.M.; Dawson, J.M.

    1990-01-01

    A relativistic electron beam propagating through a plasma in the ion-focused regime exhibits an electromagnetic instability at a resonant frequency ω ∼ 2γ 2 ω β . Growth is enhanced by optical guiding in the ion channel, which acts as dielectric waveguide, with fiber parameter V ∼ 2 (I/I A ) 1/2 . A 1-D theory for such an ''ion-channel laser'' is formulated, scaling laws are derived and numerical examples are given. Possible experimental evidence is noted. 23 refs., 1 fig., 1 tab

  1. Electron angular distribution axial channeling

    International Nuclear Information System (INIS)

    Khokonov, A.Kh.; Khokonov, M.Kh.

    1989-01-01

    Angular distributions of ultra-relativistic electrons are calculated in the assumption about presence of statistical equilibrium. Analysis is based on numerical solution of Fokker-Planck type kinetic equation. It is shown that in contrast to case of amorphous medium, the multiple scattering at axial channeling of negative particles results in self-focusing of the initial beam particles and due to it number of electrons moving at an angles to the chain, which are smaller, than critical angle of channeling, may increase by several times as compared to the initial one

  2. Antenna for Ultrawideband Channel Sounding

    DEFF Research Database (Denmark)

    Zhekov, Stanislav Stefanov; Tatomirescu, Alexandru; Pedersen, Gert F.

    2016-01-01

    A novel compact antenna for ultrawideband channel sounding is presented. The antenna is composed of a symmetrical biconical antenna modified by adding a cylinder and a ring to each cone. A feeding coaxial cable is employed during the simulations in order to evaluate and reduce its impact on the a......A novel compact antenna for ultrawideband channel sounding is presented. The antenna is composed of a symmetrical biconical antenna modified by adding a cylinder and a ring to each cone. A feeding coaxial cable is employed during the simulations in order to evaluate and reduce its impact...

  3. EPICS: Channel Access security design

    International Nuclear Information System (INIS)

    Kraimer, M.; Hill, J.

    1994-05-01

    This document presents the design for implementing the requirements specified in: EPICS -- Channel Access Security -- functional requirements, Ned. D. Arnold, 03/09/92. Use of the access security system is described along with a summary of the functional requirements. The programmer's interface is given. Security protocol is described and finally aids for reading the access security code are provided

  4. Improved Ion-Channel Biosensors

    Science.gov (United States)

    Nadeau, Jay; White, Victor; Dougherty, Dennis; Maurer, Joshua

    2004-01-01

    An effort is underway to develop improved biosensors of a type based on ion channels in biomimetic membranes. These sensors are microfabricated from silicon and other materials compatible with silicon. As described, these sensors offer a number of advantages over prior sensors of this type.

  5. Single top t-channel

    CERN Document Server

    Faltermann, Nils

    2017-01-01

    The production of single top quarks allows to study the interplay of top quark physics and the electroweak sector of the standard model. Deviations from predictions can be a hint for physics beyond the standard model. The t-channel is the dominant production mode for single top quarks at the LHC. This talk presents the latest measurements from the ATLAS and CMS collaborations.

  6. Visualizing multi-channel networks

    DEFF Research Database (Denmark)

    Antemijczuk, Paweł; Magiera, Marta; Jørgensen, Sune Lehmann

    2014-01-01

    In this paper, we propose a visualization to illustrate social interactions, built from multiple distinct channels of communication. The visualization displays a summary of dense personal information in a compact graphical notation. The starting point is an abstract drawing of a spider’s web. Below...

  7. CHANNELING IN QUASI-CRYSTALS

    NARCIS (Netherlands)

    VANVOORTHUYSEN, EHD; SMULDERS, PJM; WERKMAN, RD; DEBOER, JL; VANSMAALEN, S

    Ion-beam channeling has been observed in quasicrystals. For 1 MeV He-4+ ions in icosahedral AlCuFe the maximum effect found is 36%. The full width at half maximum of the observed dips is 1.3-degrees. The effect persists up to great depths (> 200 nm), thus showing a high degree of ordering in this

  8. Sorting out river channel patterns

    NARCIS (Netherlands)

    Kleinhans, M.G.

    2010-01-01

    Rivers self-organize their pattern/planform through feedbacks between bars, channels, floodplain and vegetation, which emerge as a result of the basic spatial sorting process of wash load sediment and bed sediment. The balance between floodplain formation and destruction determines the width and

  9. Aquaglyceroporins: ancient channels for metalloids

    Science.gov (United States)

    Bhattacharjee, Hiranmoy; Mukhopadhyay, Rita; Thiyagarajan, Saravanamuthu; Rosen, Barry P

    2008-01-01

    The identification of aquaglyceroporins as uptake channels for arsenic and antimony shows how these toxic elements can enter the food chain, and suggests that food plants could be genetically modified to exclude arsenic while still accumulating boron and silicon. PMID:19014407

  10. Sales promotions and channel coordination

    NARCIS (Netherlands)

    B. Wierenga (Berend); H. Soethoudt (Han)

    2009-01-01

    textabstractConsumer sales promotions are usually the result of the decisions of two marketing channel parties, the manufacturer and the retailer. In making these decisions, each party normally follows its own interest: i.e. maximizes its own profit. Unfortunately, this results in a suboptimal

  11. Sales promotion and channel coordination

    NARCIS (Netherlands)

    Wierenga, B.; Soethoudt, J.M.

    2010-01-01

    Consumer sales promotions are usually the result of the decisions of two marketing channel parties, the manufacturer and the retailer. In making these decisions, each party normally follows its own interest: i.e. maximizes its own profit. Unfortunately, this results in a suboptimal outcome for the

  12. CONDUCTIVE CHANNEL FOR ENERGY TRANSMISSION

    Directory of Open Access Journals (Sweden)

    V. V. Apollonov

    2014-01-01

    Full Text Available Laser spark obtained by using a conical optics is much more appropriate to form conducting channels in atmosphere. Only two types of lasers are actively considered to be used in forming high-conductivity channels in atmosphere, controlled by laser spark: pulsed sub-microsecond gas and chemical lasers (CO2, DF and short pulse solid-state and UV lasers. Main advantage of short pulse lasers is their ability in forming of super long ionized channels with a characteristic diameter of ~100  µ  in atmosphere along the  beam propagation direction. At estimated electron densities below  10 ⋅ 16 cm–3 in these filaments and laser wavelengths in the range of 0,5–1,0 mm, the plasma barely absorbs laser radiation.  In this case, the length of the track composed of many filaments is determined by the laser intensity and may reach many kilometers at a femtosecond pulse energy of ~100 mJ. However, these lasers could not be used to form high-conductivity long channels in atmosphere. The ohmic resistance of this type a conducting channels turned out to be very high, and the gas in the channels could not be strongly heated (< 1 J. An electric breakdown controlled by radiation of femtosecond solid-state laser was implemented in only at a length of 3 m with a voltage of 2 MV across the discharge gap (670 kV/m.Not so long ago scientific group from P. N. Lebedev has improved that result, the discharge gap – 1 m had been broken under KrF laser irradiation when switching high-voltage (up to 390 kV/m electric discharge by 100-ns UV pulses. Our previous result  –  16 m long conducting channel controlled by a  laser spark at the voltage  –  3 MV  – was obtained more than 20 years ago in Russia and Japan by using pulsed CO2  laser with energy  –  0,5 kJ. An average electric field strength  was < 190 kV/m. It is still too much for efficient applications.

  13. Molecular cloning of a K+ channel from the malaria parasite Plasmodium falciparum

    DEFF Research Database (Denmark)

    Ellekvist, Peter; Ricke, Christina Høier; Litman, Thomas

    2004-01-01

    In most living cells, K(+) channels are important for the generation of the membrane potential and for volume regulation. The parasite Plasmodium falciparum, which causes malignant malaria, must be able to deal with large variations in the ambient K(+) concentration: it is exposed to high...... concentrations of K(+) when inside the erythrocyte and low concentrations when in plasma. In the recently published genome of P. falciparum, we have identified a gene, pfkch1, encoding a potential K(+) channel, which to some extent resembles the big-conductance (BK) K(+) channel. We have cloned the approximately...

  14. Parallel Evolution of Sperm Hyper-Activation Ca2+ Channels.

    Science.gov (United States)

    Cooper, Jacob C; Phadnis, Nitin

    2017-07-01

    Sperm hyper-activation is a dramatic change in sperm behavior where mature sperm burst into a final sprint in the race to the egg. The mechanism of sperm hyper-activation in many metazoans, including humans, consists of a jolt of Ca2+ into the sperm flagellum via CatSper ion channels. Surprisingly, all nine CatSper genes have been independently lost in several animal lineages. In Drosophila, sperm hyper-activation is performed through the cooption of the polycystic kidney disease 2 (pkd2) Ca2+ channel. The parallels between CatSpers in primates and pkd2 in Drosophila provide a unique opportunity to examine the molecular evolution of the sperm hyper-activation machinery in two independent, nonhomologous calcium channels separated by > 500 million years of divergence. Here, we use a comprehensive phylogenomic approach to investigate the selective pressures on these sperm hyper-activation channels. First, we find that the entire CatSper complex evolves rapidly under recurrent positive selection in primates. Second, we find that pkd2 has parallel patterns of adaptive evolution in Drosophila. Third, we show that this adaptive evolution of pkd2 is driven by its role in sperm hyper-activation. These patterns of selection suggest that the evolution of the sperm hyper-activation machinery is driven by sexual conflict with antagonistic ligands that modulate channel activity. Together, our results add sperm hyper-activation channels to the class of fast evolving reproductive proteins and provide insights into the mechanisms used by the sexes to manipulate sperm behavior. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  15. Transmembrane helical interactions in the CFTR channel pore.

    Directory of Open Access Journals (Sweden)

    Jhuma Das

    2017-06-01

    Full Text Available Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR gene affect CFTR protein biogenesis or its function as a chloride channel, resulting in dysregulation of epithelial fluid transport in the lung, pancreas and other organs in cystic fibrosis (CF. Development of pharmaceutical strategies to treat CF requires understanding of the mechanisms underlying channel function. However, incomplete 3D structural information on the unique ABC ion channel, CFTR, hinders elucidation of its functional mechanism and correction of cystic fibrosis causing mutants. Several CFTR homology models have been developed using bacterial ABC transporters as templates but these have low sequence similarity to CFTR and are not ion channels. Here, we refine an earlier model in an outward (OWF and develop an inward (IWF facing model employing an integrated experimental-molecular dynamics simulation (200 ns approach. Our IWF structure agrees well with a recently solved cryo-EM structure of a CFTR IWF state. We utilize cysteine cross-linking to verify positions and orientations of residues within trans-membrane helices (TMHs of the OWF conformation and to reconstruct a physiologically relevant pore structure. Comparison of pore profiles of the two conformations reveal a radius sufficient to permit passage of hydrated Cl- ions in the OWF but not the IWF model. To identify structural determinants that distinguish the two conformations and possible rearrangements of TMHs within them responsible for channel gating, we perform cross-linking by bifunctional reagents of multiple predicted pairs of cysteines in TMH 6 and 12 and 6 and 9. To determine whether the effects of cross-linking on gating observed are the result of switching of the channel from open to close state, we also treat the same residue pairs with monofunctional reagents in separate experiments. Both types of reagents prevent ion currents indicating that pore blockage is primarily responsible.

  16. Gene expression

    International Nuclear Information System (INIS)

    Hildebrand, C.E.; Crawford, B.D.; Walters, R.A.; Enger, M.D.

    1983-01-01

    We prepared probes for isolating functional pieces of the metallothionein locus. The probes enabled a variety of experiments, eventually revealing two mechanisms for metallothionein gene expression, the order of the DNA coding units at the locus, and the location of the gene site in its chromosome. Once the switch regulating metallothionein synthesis was located, it could be joined by recombinant DNA methods to other, unrelated genes, then reintroduced into cells by gene-transfer techniques. The expression of these recombinant genes could then be induced by exposing the cells to Zn 2+ or Cd 2+ . We would thus take advantage of the clearly defined switching properties of the metallothionein gene to manipulate the expression of other, perhaps normally constitutive, genes. Already, despite an incomplete understanding of how the regulatory switch of the metallothionein locus operates, such experiments have been performed successfully

  17. Molecular Evolution of Slow and Quick Anion Channels (SLACs and QUACs/ALMTs).

    Science.gov (United States)

    Dreyer, Ingo; Gomez-Porras, Judith Lucia; Riaño-Pachón, Diego Mauricio; Hedrich, Rainer; Geiger, Dietmar

    2012-01-01

    Electrophysiological analyses conducted about 25 years ago detected two types of anion channels in the plasma membrane of guard cells. One type of channel responds slowly to changes in membrane voltage while the other responds quickly. Consequently, they were named SLAC, for SLow Anion Channel, and QUAC, for QUick Anion Channel. Recently, genes SLAC1 and QUAC1/ALMT12, underlying the two different anion current components, could be identified in the model plant Arabidopsis thaliana. Expression of the gene products in Xenopus oocytes confirmed the quick and slow current kinetics. In this study we provide an overview on our current knowledge on slow and quick anion channels in plants and analyze the molecular evolution of ALMT/QUAC-like and SLAC-like channels. We discovered fingerprints that allow screening databases for these channel types and were able to identify 192 (177 non-redundant) SLAC-like and 422 (402 non-redundant) ALMT/QUAC-like proteins in the fully sequenced genomes of 32 plant species. Phylogenetic analyses provided new insights into the molecular evolution of these channel types. We also combined sequence alignment and clustering with predictions of protein features, leading to the identification of known conserved phosphorylation sites in SLAC1-like channels along with potential sites that have not been yet experimentally confirmed. Using a similar strategy to analyze the hydropathicity of ALMT/QUAC-like channels, we propose a modified topology with additional transmembrane regions that integrates structure and function of these membrane proteins. Our results suggest that cross-referencing phylogenetic analyses with position-specific protein properties and functional data could be a very powerful tool for genome research approaches in general.

  18. Molecular evolution of slow and quick anion channels (SLACs and QUACs/ALMTs

    Directory of Open Access Journals (Sweden)

    Ingo eDreyer

    2012-11-01

    Full Text Available Electrophysiological analyses conducted about 25 years ago detected two types of anion channels in the plasma membrane of guard cells. One type of channel responds slowly to changes in membrane voltage while the other responds quickly. Consequently, they were named SLAC, for SLow Anion Channel, and QUAC, for QUick Anion Channel. Recently, genes SLAC1 and QUAC1/ALMT12, underlying the two different anion current components, could be identified in the model plant Arabidopsis thaliana. Expression of the gene products in Xenopus oocytes confirmed the quick and slow current kinetics. In this study we provide an overview on our current knowledge on slow and quick anion channels in plants and analyze the molecular evolution of ALMT/QUAC-like and SLAC-like channels. We discovered fingerprints that allow screening databases for these channel types and were able to identify 192 (177 non-redundant SLAC-like and 422 (402 non-redundant ALMT/QUAC-like proteins in the fully sequenced genomes of 32 plant species. Phylogenetic analyses provided new insights into the molecular evolution of these channel types. We also combined sequence alignment and clustering with predictions of protein features, leading to the identification of known conserved phosphorylation sites in SLAC1-like channels along with potential sites that have not been yet experimentally confirmed. Using a similar strategy to analyze the hydropathicity of ALMT/QUAC-like channels, we propose a modified topology with additional transmembrane regions that integrates structure and function of these membrane proteins. Our results suggest that cross-referencing phylogenetic analyses with position-specific protein properties and functional data could be a very powerful tool for genome research approaches in general.

  19. Interior point decoding for linear vector channels

    International Nuclear Information System (INIS)

    Wadayama, T

    2008-01-01

    In this paper, a novel decoding algorithm for low-density parity-check (LDPC) codes based on convex optimization is presented. The decoding algorithm, called interior point decoding, is designed for linear vector channels. The linear vector channels include many practically important channels such as inter-symbol interference channels and partial response channels. It is shown that the maximum likelihood decoding (MLD) rule for a linear vector channel can be relaxed to a convex optimization problem, which is called a relaxed MLD problem

  20. Interior point decoding for linear vector channels

    Energy Technology Data Exchange (ETDEWEB)

    Wadayama, T [Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya, Aichi, 466-8555 (Japan)], E-mail: wadayama@nitech.ac.jp

    2008-01-15

    In this paper, a novel decoding algorithm for low-density parity-check (LDPC) codes based on convex optimization is presented. The decoding algorithm, called interior point decoding, is designed for linear vector channels. The linear vector channels include many practically important channels such as inter-symbol interference channels and partial response channels. It is shown that the maximum likelihood decoding (MLD) rule for a linear vector channel can be relaxed to a convex optimization problem, which is called a relaxed MLD problem.

  1. The transient receptor potential, TRP4, cation channel is a novel member of the family of calmodulin binding proteins.

    OpenAIRE

    Trost, C; Bergs, C; Himmerkus, N; Flockerzi, V

    2001-01-01

    The mammalian gene products, transient receptor potential (trp)1 to trp7, are related to the Drosophila TRP and TRP-like ion channels, and are candidate proteins underlying agonist-activated Ca(2+)-permeable ion channels. Recently, the TRP4 protein has been shown to be part of native store-operated Ca(2+)-permeable channels. These channels, most likely, are composed of other proteins in addition to TRP4. In the present paper we report the direct interaction of TRP4 and calmodulin (CaM) by: (1...

  2. The MISO wiretap channel with channel uncertainty: Asymptotic perspectives

    KAUST Repository

    Chaaban, Anas; Rezki, Zouheir; Alomair, Basel; Alouini, Mohamed-Slim

    2017-01-01

    The N-antenna MISO Gaussian wiretap channel with imperfect channel-state information at the transmitter (CSIT) is studied in terms of secrecy rate scaling versus the signal-to-noise ratio (SNR) and N. Two schemes are considered, beamforming (BF) and artificial noise injection (AN). It is shown that if the CSIT error is independent of SNR, then both schemes do not achieve scaling versus SNR. However, if this error vanishes as SNR increases, then AN achieves the optimal scaling versus SNR, contrary to BF. Scaling can be achieved in BF by increasing N. In fact, BF achieves the optimal scaling versus N. In the AN scheme however, injecting noise in multiple direction deteriorates its scaling versus N. Nevertheless, AN can achieve the optimal scaling if noise is sent in only one direction. This leads to better performance than BF if the CSIT error is smaller than a threshold which is also derived.

  3. The MISO wiretap channel with channel uncertainty: Asymptotic perspectives

    KAUST Repository

    Chaaban, Anas

    2017-05-12

    The N-antenna MISO Gaussian wiretap channel with imperfect channel-state information at the transmitter (CSIT) is studied in terms of secrecy rate scaling versus the signal-to-noise ratio (SNR) and N. Two schemes are considered, beamforming (BF) and artificial noise injection (AN). It is shown that if the CSIT error is independent of SNR, then both schemes do not achieve scaling versus SNR. However, if this error vanishes as SNR increases, then AN achieves the optimal scaling versus SNR, contrary to BF. Scaling can be achieved in BF by increasing N. In fact, BF achieves the optimal scaling versus N. In the AN scheme however, injecting noise in multiple direction deteriorates its scaling versus N. Nevertheless, AN can achieve the optimal scaling if noise is sent in only one direction. This leads to better performance than BF if the CSIT error is smaller than a threshold which is also derived.

  4. An Effective Channel Allocation Scheme to Reduce Co-Channel and Adjacent Channel Interference for WMN Backhaul

    International Nuclear Information System (INIS)

    Abbasi, S.; Ismaili, I.A.; Khuhawar, F.Y.

    2016-01-01

    Two folded work presents channel allocation scheme sustaining channel orthogonality and channel spacing to reduce CCI (Co-Channel Interference) and ACI (Adjacent Channel Interference) for inter flow of an intra-flow link. Proposed scheme as a part of radio resource allocation is applied on infrastructure based backhaul of wireless mesh network using directional antennas. The proposed approach is applied separately on 2.4 and 5GHz bands. Interference of connectivity graph is modelled by strongly connected directed graph and greedy algorithms are used for channel allocation. We have used OPNET Modeller suite to simulate network models for this research. The proposed arrangement reduces the channel interference and increases system throughput. In this research, the influence of channel is computed in terms of network throughput and delay. (author)

  5. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease.

    Science.gov (United States)

    Jentsch, Thomas J; Pusch, Michael

    2018-07-01

    CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl - channels, whereas ClC-3 through ClC-7 are 2Cl - /H + -exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl - channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.

  6. Chloride channels regulate chondrogenesis in chicken mandibular mesenchymal cells.

    Science.gov (United States)

    Tian, Meiyu; Duan, Yinzhong; Duan, Xiaohong

    2010-12-01

    Voltage gated chloride channels (ClCs) play an important role in the regulation of intracellular pH and cell volume homeostasis. Mutations of these genes result in genetic diseases with abnormal bone deformation and body size, indicating that ClCs may have a role in chondrogenesis. In the present study, we isolated chicken mandibular mesenchymal cells (CMMC) from Hamburg-Hamilton (HH) stage 26 chick embryos and induced chondrocyte maturation by using ascorbic acid and β-glycerophosphate (AA-BGP). We also determined the effect of the chloride channel inhibitor NPPB [5-nitro-2-(3-phenylpropylamino) benzoic acid] on regulation of growth, differentiation, and gene expression in these cells using MTT and real-time PCR assays. We found that CLCN1 and CLCN3-7 mRNA were expressed in CMMC and NPPB reduced expression of CLCN3, CLCN5, and CLCN7 mRNA in these cells. At the same time, NPPB inhibited the growth of the CMMC, but had no effect on the mRNA level of cyclin D1 and cyclin E (P>0.05) with/without AA-BGP treatment. AA-BGP increased markers for early chondrocyte differentiation including type II collagen, aggrecan (Ptype X collagen. NPPB antagonized AA-BGP-induced expression of type II collagen and aggrecan (Ptype X collagen (PType X collagen might function as a target of chloride channel inhibitors during the differentiation process. Copyright © 2010 Elsevier Ltd. All rights reserved.

  7. Defective channels lead to an impaired skin barrier.

    Science.gov (United States)

    Blaydon, Diana C; Kelsell, David P

    2014-10-15

    Channels are integral membrane proteins that form a pore, allowing the passive movement of ions or molecules across a membrane (along a gradient), either between compartments within a cell, between intracellular and extracellular environments or between adjacent cells. The ability of cells to communicate with one another and with their environment is a crucial part of the normal physiology of a tissue that allows it to carry out its function. Cell communication is particularly important during keratinocyte differentiation and formation of the skin barrier. Keratinocytes in the skin epidermis undergo a programme of apoptosis-driven terminal differentiation, whereby proliferating keratinocytes in the basal (deepest) layer of the epidermis stop proliferating, exit the basal layer and move up through the spinous and granular layers of the epidermis to form the stratum corneum, the external barrier. Genes encoding different families of channel proteins have been found to harbour mutations linked to a variety of rare inherited monogenic skin diseases. In this Commentary, we discuss how human genetic findings in aquaporin (AQP) and transient receptor potential (TRP) channels reveal different mechanisms by which these channel proteins function to ensure the proper formation and maintenance of the skin barrier. © 2014. Published by The Company of Biologists Ltd.

  8. Clofilium inhibits Slick and Slack potassium channels.

    Science.gov (United States)

    de Los Angeles Tejada, Maria; Stolpe, Kathleen; Meinild, Anne-Kristine; Klaerke, Dan A

    2012-01-01

    Slick and Slack high-conductance potassium channels have been recently discovered, and are found in the central nervous system and in the heart. Both channels are activated by Na(+) and Cl(-), and Slick channels are also inhibited by adenosine triphospate (ATP). An important role of setting the resting membrane potential and controlling the basal excitability of neurons has been suggested for these channels. In addition, no specific blockers for these channels are known up to the present. With the purpose of studying the pharmacological characteristics of Slick and Slack channels, the effects of exposure to the antiarrhythmic compound clofilium were evaluated. Clofilium was able to modulate the activity of Slick and Slack channels effectively, with a stronger effect on Slack than Slick channels. In order to evaluate the pharmacological behavior of Slick and Slack channels further, 38 commonly used potassium channel blockers were tested. Screening of these compounds did not reveal any modulators of Slick and Slack channels, except for clofilium. The present study provides a first approach towards elucidating the pharmacological characteristics of Slick and Slack channels and could be the basis for future studies aimed at developing potent and specific blockers and activators for these channels.

  9. Search after new agents for hyperpolarization-activated and cyclic nucleotide-gated ion channels; Suche nach neuen Wirkstoffen fuer Hyperpolarisationsaktivierte und zyklisch Nukleotid-gesteuerte Ionenkanaele

    Energy Technology Data Exchange (ETDEWEB)

    Struenker, T.

    2005-12-01

    Rhythmic activity of single cells or cellular networks is a common feature of most organisms. Cellular rhythms govern the beating of the heart, cycles of sleep and wakefulness, breathing, and the release of hormones. The endogenous rhythmic activity of many neurons and cardiac relies on a complex interplay between several distinct ion channels. In particular, one type of ion channel plays a prominent role in the control of rhythmic electrical activity because it determines the frequency of the oscillations. The activity of the channels is thus setting the ''pace'' of the activity; therefore, these channels are often referred to as ''pacemaker'' channels. Despite their obvious physiological importance it hasn't been until a few years ago that the genes encoding pacemaker channels have been identified. Because both hyperpolarization and cyclic nucleotides are key elements that control their activity, pacemaker channels have now been designated hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels. From a scientific as well as medical point of view, HCN channels are interesting drug targets. Only a few substances are known that specifically affect HCN channels. In the present study, a microtiter plate-based high throughput screening assay for HCN1 and HCN4 channels was developed. With this assay, known drugs for HCN channels were characterized. Subsequently, venoms of snails, spiders, scorpions, and snakes were screened for toxins affecting HCN channel activity. A few venoms were identified that possibly contain drugs that act on HCN channels. (orig.)

  10. Targeting sodium channels in cardiac arrhythmia

    NARCIS (Netherlands)

    Remme, Carol Ann; Wilde, Arthur A. M.

    2014-01-01

    Cardiac voltage-gated sodium channels are responsible for proper electrical conduction in the heart. During acquired pathological conditions and inherited sodium channelopathies, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. Although the clinical,

  11. Matagorda Ship Channel, Texas: Jetty Stability Study

    National Research Council Canada - National Science Library

    Kraus, Nicholas C; Lin, Lihwa; Batten, Brian K; Brown, Gary L

    2006-01-01

    .... The current has produced a large area of scour on the bay side of the inlet adjacent to the west jetty, and vessels encountering a strong along-channel and cross-channel current at the entrance...

  12. Quantum Correlations Evolution Asymmetry in Quantum Channels

    International Nuclear Information System (INIS)

    Li Meng; Huang Yun-Feng; Guo Guang-Can

    2017-01-01

    It was demonstrated that the entanglement evolution of a specially designed quantum state in the bistochastic channel is asymmetric. In this work, we generalize the study of the quantum correlations, including entanglement and quantum discord, evolution asymmetry to various quantum channels. We found that the asymmetry of entanglement and quantum discord only occurs in some special quantum channels, and the behavior of the entanglement evolution may be quite different from the behavior of the quantum discord evolution. To quantum entanglement, in some channels it decreases monotonously with the increase of the quantum channel intensity. In some other channels, when we increase the intensity of the quantum channel, it decreases at first, then keeps zero for some time, and then rises up. To quantum discord, the evolution becomes more complex and you may find that it evolutes unsmoothly at some points. These results illustrate the strong dependence of the quantum correlations evolution on the property of the quantum channels. (paper)

  13. Coastal Maintained Channels in US waters

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — This layer shows coastal channels and waterways that are maintained and surveyed by the U.S. Army Corps of Engineers (USACE). These channels are necessary...

  14. Channel Estimation in DCT-Based OFDM

    Science.gov (United States)

    Wang, Yulin; Zhang, Gengxin; Xie, Zhidong; Hu, Jing

    2014-01-01

    This paper derives the channel estimation of a discrete cosine transform- (DCT-) based orthogonal frequency-division multiplexing (OFDM) system over a frequency-selective multipath fading channel. Channel estimation has been proved to improve system throughput and performance by allowing for coherent demodulation. Pilot-aided methods are traditionally used to learn the channel response. Least square (LS) and mean square error estimators (MMSE) are investigated. We also study a compressed sensing (CS) based channel estimation, which takes the sparse property of wireless channel into account. Simulation results have shown that the CS based channel estimation is expected to have better performance than LS. However MMSE can achieve optimal performance because of prior knowledge of the channel statistic. PMID:24757439

  15. Channel CAT: A Tactical Link Analysis Tool

    National Research Council Canada - National Science Library

    Coleman, Michael

    1997-01-01

    .... This thesis produced an analysis tool, the Channel Capacity Analysis Tool (Channel CAT), designed to provide an automated tool for the analysis of design decisions in developing client-server software...

  16. Investigation Of Information Sources And Communication Channels ...

    African Journals Online (AJOL)

    Investigation Of Information Sources And Communication Channels In Ipm Rice ... the information accessibility of farmer groups seems as empowerment strategy. ... information sources and communication channels, in order of importance, ...

  17. The KATP channel in migraine pathophysiology

    DEFF Research Database (Denmark)

    Al-Karagholi, Mohammad Al-Mahdi; Hansen, Jakob Møller; Severinsen, Johanne

    2017-01-01

    BACKGROUND: To review the distribution and function of KATP channels, describe the use of KATP channels openers in clinical trials and make the case that these channels may play a role in headache and migraine. DISCUSSION: KATP channels are widely present in the trigeminovascular system and play...... an important role in the regulation of tone in cerebral and meningeal arteries. Clinical trials using synthetic KATP channel openers report headache as a prevalent-side effect in non-migraine sufferers, indicating that KATP channel opening may cause headache, possibly due to vascular mechanisms. Whether KATP...... channel openers can provoke migraine in migraine sufferers is not known. CONCLUSION: We suggest that KATP channels may play an important role in migraine pathogenesis and could be a potential novel therapeutic anti-migraine target....

  18. Optimization of Communication in Noisy Quantum Channels

    National Research Council Canada - National Science Library

    Ruskai, Mary

    2002-01-01

    .... This project has been concerned with the analysis of mathematical models of noise for qubit channels, with the capacity of qubit channels used to transmit classical information, and with exchange...

  19. Four-channel delay generator model 5740

    International Nuclear Information System (INIS)

    Baumatz, D.; Milner, M.

    1978-01-01

    The 4-channel delay generator model 5740 generates 4-pulse groups in independent channels. The device offers the possibility of controlling both the time intervals between the pulses of a group and the rate of generation of groups

  20. Channelling of flow through fractures in rock

    International Nuclear Information System (INIS)

    Bourke, P.J.

    1987-05-01

    A method of mapping the channelling of flow in rock fractures formed by contacts between rock faces and of measuring the effective apertures of channels has been developed. Some typical results are given. (author)

  1. Consolidation equipment for irradiated nuclear fuel channels

    International Nuclear Information System (INIS)

    Taguchi, M.; Komatsu, Y.; Ose, T.

    1989-01-01

    The authors have developed and put into use a new type of mechanical consolidation equipment for irradiated nuclear fuel channels. This includes round-slice cutting of the top 100mm of the fuel channel with a guillotine cutter, and press cutting of the two corners of the remaining length of the fuel channel. Four guillotine blades work in combination with receiving blades arranged inside the fuel channel to cut the top 100mm, including the clips and spacers, of the fuel channel into a round slice. A press assembled in the consolidation equipment then presses the slice to achieve volume reduction. The press cutting operation uses two press cutting blades arranged inside the fuel channel and the receiving blades outside the fuel channel. The remaining length of fuel channel is cut off into L-shaped pieces by press cutting. This consolidation equipment is highly efficient because the round-slice cutting, pressing, and press cutting are all achieved by one unit

  2. Channeling experiments at IPNE Cyclotron

    Energy Technology Data Exchange (ETDEWEB)

    Constantin, F; Dumitru, M; Ivan, A [Cyclotron Laboratory, Institute of Atomic Physics, Institute of Physics and Nuclear Engineering, R-76900 Bucharest, P.O.Box MG-6, (Romania)

    1992-01-01

    Channeling experiments have been performed at the I.P.N.E Cyclotron using a 3 MeV alpha beam. A slide system cut the beam up to 5 minutes spatial resolution with a maximum 60 nA beam current on the target. The two-axis goniometer, fully computer-controlled, moves the target, a silicon wafer, with 2.5 minute resolution, while an alpha particle sensitive solid state detector, monitors the backscattered particle fluence. In the first stage, channeling appears to be a simple, fast and reliable method for precise monocrystal orientation. A reduction of the host yield by a factor of two allowed impurities and defects to be studied. (Author).

  3. Thermoelectricity in Heterogeneous Nanofluidic Channels.

    Science.gov (United States)

    Li, Long; Wang, Qinggong

    2018-05-01

    Ionic fluids are essential to energy conversion, water desalination, drug delivery, and lab-on-a-chip devices. Ionic transport in nanoscale confinements and complex physical fields still remain elusive. Here, a nanofluidic system is developed using nanochannels of heterogeneous surface properties to investigate transport properties of ions under different temperatures. Steady ionic currents are observed under symmetric temperature gradients, which is equivalent to generating electricity using waste heat (e.g., electronic chips and solar panels). The currents increase linearly with temperature gradient and nonlinearly with channel size. Contributions to ion motion from temperatures and channel properties are evaluated for this phenomenon. The findings provide insights into the study of confined ionic fluids in multiphysical fields, and suggest applications in thermal energy conversion, temperature sensors, and chip-level thermal management. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. Improving Channel Coordination Through Franchising

    OpenAIRE

    Rajiv Lal

    1990-01-01

    In this paper, we explore the role of franchising arrangements in improving coordination between channel members. In particular we focus on two elements of the franchising contract, namely, the royalty structure and the monitoring technology. We begin with a simple analysis where a manufacturer distributes its product through a retailer and the retail demand is affected by the retail price and the service provided by the retailer. In this context we show that neither royalty payments nor moni...

  5. Digital Multi Channel Analyzer Enhancement

    International Nuclear Information System (INIS)

    Gonen, E.; Marcus, E.; Wengrowicz, U.; Beck, A.; Nir, J.; Sheinfeld, M.; Broide, A.; Tirosh, D.

    2002-01-01

    A cement analyzing system based on radiation spectroscopy had been developed [1], using novel digital approach for real-time, high-throughput and low-cost Multi Channel Analyzer. The performance of the developed system had a severe problem: the resulted spectrum suffered from lack of smoothness, it was very noisy and full of spikes and surges, therefore it was impossible to use this spectrum for analyzing the cement substance. This paper describes the work carried out to improve the system performance

  6. Trafficking of neuronal calcium channels

    Czech Academy of Sciences Publication Activity Database

    Weiss, Norbert; Zamponi, G. W.

    2017-01-01

    Roč. 1, č. 1 (2017), č. článku NS20160003. ISSN 2059-6553 R&D Projects: GA ČR GA15-13556S; GA MŠk 7AMB15FR015 Institutional support: RVO:61388963 Keywords : calcium channel * neuron * trafficing Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) http://www.neuronalsignaling.org/content/1/1/NS20160003

  7. Spark channel propagation in a microbubble liquid

    Energy Technology Data Exchange (ETDEWEB)

    Panov, V. A.; Vasilyak, L. M., E-mail: vasilyak@ihed.ras.ru; Vetchinin, S. P.; Pecherkin, V. Ya.; Son, E. E. [Russian Academy of Sciences, Joint Institute for High Temperatures (Russian Federation)

    2016-11-15

    Experimental study on the development of the spark channel from the anode needle under pulsed electrical breakdown of isopropyl alcohol solution in water with air microbubbles has been performed. The presence of the microbubbles increases the velocity of the spark channel propagation and increases the current in the discharge gap circuit. The observed rate of spark channel propagation in microbubble liquid ranges from 4 to 12 m/s, indicating the thermal mechanism of the spark channel development in a microbubble liquid.

  8. Assessing the Consequences of a Channel Switch

    OpenAIRE

    Xinlei (Jack) Chen; George John; Om Narasimhan

    2008-01-01

    Switching marketing channels is an expensive and sticky decision. While a number of theories suggest efficiency and strategic differences between channels, there is virtually no work on combining these ideas into an empirically workable methodology to assess the impact of a channel switch. In this study, we undertake to close this gap with an empirical study of the sports drink market, featuring competing producers and heterogeneous channels. We estimate demand and cost parameters for a numbe...

  9. Degenerate RFID Channel Modeling for Positioning Applications

    Directory of Open Access Journals (Sweden)

    A. Povalac

    2012-12-01

    Full Text Available This paper introduces the theory of channel modeling for positioning applications in UHF RFID. It explains basic parameters for channel characterization from both the narrowband and wideband point of view. More details are given about ranging and direction finding. Finally, several positioning scenarios are analyzed with developed channel models. All the described models use a degenerate channel, i.e. combined signal propagation from the transmitter to the tag and from the tag to the receiver.

  10. Channel CAT: A Tactical Link Analysis Tool

    Science.gov (United States)

    1997-09-01

    NAVAL POSTGRADUATE SCHOOL Monterey, California THESIS CHANNEL CAT : A TACTICAL LINK ANALYSIS TOOL by Michael Glenn Coleman September 1997 Thesis...REPORT TYPE AND DATES COVERED September 1997 Master’s Thesis 4. TITLE AND SUBTITLE CHANNEL CAT : A TACTICAL LINK ANALYSIS TOOL 5. FUNDING NUMBERS 6...tool, the Channel Capacity Analysis Tool (Channel CAT ), designed to provide an automated tool for the anlysis of design decisions in developing client

  11. Optimal super dense coding over memory channels

    OpenAIRE

    Shadman, Zahra; Kampermann, Hermann; Macchiavello, Chiara; Bruß, Dagmar

    2011-01-01

    We study the super dense coding capacity in the presence of quantum channels with correlated noise. We investigate both the cases of unitary and non-unitary encoding. Pauli channels for arbitrary dimensions are treated explicitly. The super dense coding capacity for some special channels and resource states is derived for unitary encoding. We also provide an example of a memory channel where non-unitary encoding leads to an improvement in the super dense coding capacity.

  12. Radio propagation measurement and channel modelling

    CERN Document Server

    Salous, Sana

    2013-01-01

    While there are numerous books describing modern wireless communication systems that contain overviews of radio propagation and radio channel modelling, there are none that contain detailed information on the design, implementation and calibration of radio channel measurement equipment, the planning of experiments and the in depth analysis of measured data. The book would begin with an explanation of the fundamentals of radio wave propagation and progress through a series of topics, including the measurement of radio channel characteristics, radio channel sounders, measurement strategies

  13. Spin chain model for correlated quantum channels

    Energy Technology Data Exchange (ETDEWEB)

    Rossini, Davide [International School for Advanced Studies SISSA/ISAS, via Beirut 2-4, I-34014 Trieste (Italy); Giovannetti, Vittorio; Montangero, Simone [NEST-CNR-INFM and Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa (Italy)], E-mail: monta@sns.it

    2008-11-15

    We analyze the quality of the quantum information transmission along a correlated quantum channel by studying the average fidelity between input and output states and the average output purity, giving bounds for the entropy of the channel. Noise correlations in the channel are modeled by the coupling of each channel use with an element of a one-dimensional interacting quantum spin chain. Criticality of the environment chain is seen to emerge in the changes of the fidelity and of the purity.

  14. Subunit Stoichiometry of Human Muscle Chloride Channels

    OpenAIRE

    Fahlke, Christoph; Knittle, Timothy; Gurnett, Christina A.; Campbell, Kevin P.; George, Alfred L.

    1997-01-01

    Voltage-gated Cl? channels belonging to the ClC family appear to function as homomultimers, but the number of subunits needed to form a functional channel is controversial. To determine subunit stoichiometry, we constructed dimeric human skeletal muscle Cl? channels in which one subunit was tagged by a mutation (D136G) that causes profound changes in voltage-dependent gating. Sucrose-density gradient centrifugation experiments indicate that both monomeric and dimeric hClC-1 channels in their ...

  15. Engineering of metabolic pathways by artificial enzyme channels

    Directory of Open Access Journals (Sweden)

    Marlene ePröschel

    2015-10-01

    Full Text Available Application of industrial enzymes for production of valuable chemical compounds has greatly benefited from recent developments in Systems and Synthetic Biology. Both, in vivo and in vitro systems have been established, allowing conversion of simple into complex compounds. Metabolic engineering in living cells needs to be balanced which is achieved by controlling gene expression levels, translation, scaffolding, compartmentation and flux control. In vitro applications are often hampered by limited protein stability/half-life and insufficient rates of substrate conversion. To improve stability and catalytic activity, proteins are post-translationally modified and arranged in artificial metabolic channels. Within the review article we will first discuss the supramolecular organization of enzymes in living systems and secondly summarize current and future approaches to design artificial metabolic channels by additive manufacturing for the efficient production of desired products.

  16. Hollow core plasma channel generation

    International Nuclear Information System (INIS)

    Quast, Heinrich Martin

    2018-03-01

    The use of a hollow plasma channel in plasma-based acceleration has beneficial properties for the acceleration of electron and positron bunches. In the scope of the FLASHForward facility at DESY, the generation of such a plasma structure is examined. Therefore, the generation of a ring-shaped laser intensity profile with different techniques is analyzed. From the obtained intensity profiles the electron density of a hollow plasma channel is simulated in the focal region. Different parameters are scanned to understand their influence on the electron density distribution - an important parameter being, for example, the radius of the central region of the channel. In addition to the simulations, experiments are presented, during which a laser pulse is transformed into a hollow beam with a spiral phase plate. Subsequently, it forms a plasma during the interaction with hydrogen, where the plasma is imaged with interferometry. For energies above 0.9 mJ a hollow plasma structure can be observed at the location of first plasma formation.

  17. Local Transfer Coefficient, Smooth Channel

    Directory of Open Access Journals (Sweden)

    R. T. Kukreja

    1998-01-01

    Full Text Available Naphthalene sublimation technique and the heat/mass transfer analogy are used to determine the detailed local heat/mass transfer distributions on the leading and trailing walls of a twopass square channel with smooth walls that rotates about a perpendicular axis. Since the variation of density is small in the flow through the channel, buoyancy effect is negligible. Results show that, in both the stationary and rotating channel cases, very large spanwise variations of the mass transfer exist in he turn and in the region immediately downstream of the turn in the second straight pass. In the first straight pass, the rotation-induced Coriolis forces reduce the mass transfer on the leading wall and increase the mass transfer on the trailing wall. In the turn, rotation significantly increases the mass transfer on the leading wall, especially in the upstream half of the turn. Rotation also increases the mass transfer on the trailing wall, more in the downstream half of the turn than in the upstream half of the turn. Immediately downstream of the turn, rotation causes the mass transfer to be much higher on the trailing wall near the downstream corner of the tip of the inner wall than on the opposite leading wall. The mass transfer in the second pass is higher on the leading wall than on the trailing wall. A slower flow causes higher mass transfer enhancement in the turn on both the leading and trailing walls.

  18. Study of material properties using channeling radiation

    International Nuclear Information System (INIS)

    Pantell, R.H.; Kephart, J.O.; Klein, R.K.; Park, H.; Berman, B.L.; Datz, S.

    1986-01-01

    A possible application for channeling radiation is for investigating the properties of crystals in which the channeling occurs. In this paper we present some general considerations concerning channeling radiation as a measurement technique, and then we proceed to describe several specific examples

  19. Square root approximation to the poisson channel

    NARCIS (Netherlands)

    Tsiatmas, A.; Willems, F.M.J.; Baggen, C.P.M.J.

    2013-01-01

    Starting from the Poisson model we present a channel model for optical communications, called the Square Root (SR) Channel, in which the noise is additive Gaussian with constant variance. Initially, we prove that for large peak or average power, the transmission rate of a Poisson Channel when coding

  20. The Marketing Channels of China Auto Industry

    Institute of Scientific and Technical Information of China (English)

    our reporter

    2001-01-01

    <正> After the 1990’s, the multi-channel structure of sales has still existed although the market mechanism is playing a main role in Chinese auto marketing circulation. Now, the channels of automobile marketing in China are as follows: 1. Manufacturer-established marketing channels

  1. Molecular determinants in TRPV5 channel assembly.

    NARCIS (Netherlands)

    Chang, Q.; Gyftogianni, E.; Graaf, K.F.J. van de; Hoefs, S.J.G.; Weidema, A.F.; Bindels, R.J.M.; Hoenderop, J.G.J.

    2004-01-01

    The epithelial Ca(2+) channels TRPV5 and TRPV6 mediate the Ca(2+) influx in 1,25-dihydroxyvitamin D(3)-responsive epithelia and are therefore essential in the maintenance of the body Ca(2+) balance. These Ca(2+) channels assemble in (hetero)tetrameric channel complexes with different functional

  2. Molecular determinants in TRPV5 channel assembly

    NARCIS (Netherlands)

    Chang, Qing; Gyftogianni, Emmanouela; van de Graaf, Stan F. J.; Hoefs, Susan; Weidema, Freek A.; Bindels, René J. M.; Hoenderop, Joost G. J.

    2004-01-01

    The epithelial Ca(2+) channels TRPV5 and TRPV6 mediate the Ca(2+) influx in 1,25-dihydroxyvitamin D(3)-responsive epithelia and are therefore essential in the maintenance of the body Ca(2+) balance. These Ca(2+) channels assemble in (hetero)tetrameric channel complexes with different functional

  3. Electronic Commerce and Retail Channel Substitution

    NARCIS (Netherlands)

    M.C.W. Janssen (Maarten); R. van der Noll

    2002-01-01

    textabstractWe analyze a market where firms compete in a conventional and an electronic retail channel. Consumers easily compare prices online, but some incur purchase uncertainties on the online channel. We investigate the market shares of the two retail channels and the prices that are charged. We

  4. 47 CFR 95.29 - Channels available.

    Science.gov (United States)

    2010-10-01

    ... with no more than 5 watts ERP. (g) Fixed stations in GMRS systems authorized before March 18, 1968... transmission of another GMRS station on a different channel or channels), the licensee of the GMRS system must... GMRS system from the following 462 MHz channels: 462.5500, 462.5750, 462.6000, 462.6250, 462.6500, 462...

  5. Mechanosensitive Channels: In Touch with Piezo

    OpenAIRE

    Xiao, Rui; Xu, X.Z. Shawn

    2010-01-01

    Mechanosensory transduction underlies touch, hearing and proprioception and requires mechanosensitive channels that are directly gated by forces; however, the molecular identities of these channels remain largely elusive. A new study has identified Piezo1 and Piezo2 as a novel class of mechanosensitive channels.

  6. Language Planning, Channel Management, and ESP.

    Science.gov (United States)

    Kennedy, Chris

    Channel management, a concept developed in marketing to refer to the process by which a product is moved from production to consumption, uses a channel of distribution operating at several levels, each responsible for one or more of the activities of moving the product forward to the consumer. The function of channel management is to select the…

  7. Increase of ATP-sensitive potassium (KATP channels in the heart of type-1 diabetic rats

    Directory of Open Access Journals (Sweden)

    Chen Zhih-Cherng

    2012-01-01

    Full Text Available Abstract Background An impairment of cardiovascular function in streptozotocin (STZ-diabetic rats has been mentioned within 5 days-to-3 months of induction. ATP-sensitive potassium (KATP channels are expressed on cardiac sarcolemmal membranes. It is highly responsive to metabolic fluctuations and can have effects on cardiac contractility. The present study attempted to clarify the changes of cardiac KATP channels in diabetic disorders. Methods Streptozotocin-induced diabetic rats and neonatal rat cardiomyocytes treated with a high concentration of glucose (a D-glucose concentration of 30 mM was used and cells were cultured for 24 hr were used to examine the effect of hyperglycemia on cardiac function and the expression of KATP channels. KATP channels expression was found to be linked to cardiac tonic dysfunction, and we evaluated the expression levels of KATP channels by Western blot and Northern blot analysis. Results The result shows diazoxide produced a marked reduction of heart rate in control group. Furthermore, the methods of Northern blotting and Western blotting were employed to identify the gene expression of KATP channel. Two subunits of cardiac KATP channel (SUR2A and kir 6.2 were purchased as indicators and showed significantly decreased in both diabetic rats and high glucose treated rat cardiac myocytes. Correction of hyperglycemia by insulin or phlorizin restored the gene expression of cardiac KATP in these diabetic rats. Conclusions Both mRNA and protein expression of cardiac KATP channels are decreased in diabetic rats induced by STZ for 8 weeks. This phenomenon leads to result in desensitization of some KATP channel drugs.

  8. Trichoderma genes

    Science.gov (United States)

    Foreman, Pamela [Los Altos, CA; Goedegebuur, Frits [Vlaardingen, NL; Van Solingen, Pieter [Naaldwijk, NL; Ward, Michael [San Francisco, CA

    2012-06-19

    Described herein are novel gene sequences isolated from Trichoderma reesei. Two genes encoding proteins comprising a cellulose binding domain, one encoding an arabionfuranosidase and one encoding an acetylxylanesterase are described. The sequences, CIP1 and CIP2, contain a cellulose binding domain. These proteins are especially useful in the textile and detergent industry and in pulp and paper industry.

  9. Voltage-gated sodium channels in taste bud cells

    Directory of Open Access Journals (Sweden)

    Williams Mark E

    2009-03-01

    Full Text Available Abstract Background Taste bud cells transmit information regarding the contents of food from taste receptors embedded in apical microvilli to gustatory nerve fibers innervating basolateral membranes. In particular, taste cells depolarize, activate voltage-gated sodium channels, and fire action potentials in response to tastants. Initial cell depolarization is attributable to sodium influx through TRPM5 in sweet, bitter, and umami cells and an undetermined cation influx through an ion channel in sour cells expressing PKD2L1, a candidate sour taste receptor. The molecular identity of the voltage-gated sodium channels that sense depolarizing signals and subsequently initiate action potentials coding taste information to gustatory nerve fibers is unknown. Results We describe the molecular and histological expression profiles of cation channels involved in electrical signal transmission from apical to basolateral membrane domains. TRPM5 was positioned immediately beneath tight junctions to receive calcium signals originating from sweet, bitter, and umami receptor activation, while PKD2L1 was positioned at the taste pore. Using mouse taste bud and lingual epithelial cells collected by laser capture microdissection, SCN2A, SCN3A, and SCN9A voltage-gated sodium channel transcripts were expressed in taste tissue. SCN2A, SCN3A, and SCN9A were expressed beneath tight junctions in subsets of taste cells. SCN3A and SCN9A were expressed in TRPM5 cells, while SCN2A was expressed in TRPM5 and PKD2L1 cells. HCN4, a gene previously implicated in sour taste, was expressed in PKD2L1 cells and localized to cell processes beneath the taste pore. Conclusion SCN2A, SCN3A and SCN9A voltage-gated sodium channels are positioned to sense initial depolarizing signals stemming from taste receptor activation and initiate taste cell action potentials. SCN2A, SCN3A and SCN9A gene products likely account for the tetrodotoxin-sensitive sodium currents in taste receptor cells.

  10. Heteromeric ASIC channels composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death

    Science.gov (United States)

    Sherwood, Thomas W.; Lee, Kirsten G.; Gormley, Matthew G.; Askwith, Candice C.

    2011-01-01

    Acid-sensing ion channel (ASIC) subunits associate to form homomeric or heteromeric proton-gated ion channels in neurons throughout the nervous system. The ASIC1a subunit plays an important role in establishing the kinetics of proton-gated currents in the central nervous system and activation of ASIC1a homomeric channels induces neuronal death following local acidosis that accompanies cerebral ischemia. The ASIC2b subunit is expressed in the brain in a pattern that overlaps ASIC1a, yet the contribution of ASIC2b has remained elusive. We find that co-expression of ASIC2b with ASIC1a in Xenopus oocytes results in novel proton-gated currents with properties distinct from ASIC1a homomeric channels. In particular, ASIC2b/1a heteromeric channels are inhibited by the non-selective potassium channel blockers tetraethylammonium (TEA) and barium. In addition, steady-state desensitization is induced at more basic pH values and Big Dynorphin sensitivity is enhanced in these unique heteromeric channels. Cultured hippocampal neurons show proton-gated currents consistent with ASIC2b contribution and these currents are lacking in neurons from mice with an ACCN1 (ASIC2) gene disruption. Finally, we find that these ASIC2b/1a heteromeric channels contribute to acidosis-induced neuronal death. Together, our results show that ASIC2b confers unique properties to heteromeric channels in central neurons. Further, these data indicate that ASIC2, like ASIC1, plays a role in acidosis-induced neuronal death and implicate the ASIC2b/1a subtype as a novel pharmacological target to prevent neuronal injury following stroke. PMID:21715637

  11. Separation of Particles in Channels Rotary Engine

    Directory of Open Access Journals (Sweden)

    Zyatikov Pavel

    2015-01-01

    Full Text Available The article considers the separation of particles in channels with different relative length. It is shown that the intensity of turbulence at the inlet section of the channel varies considerably in its length. The dependence of the turbulence damping along the channel expressing by fraction of the distance is shown. The ratio of the particle separation efficiency out the gas flow in the rotor channel is defined. The values of particle separation efficiency in the channel for the angle α=π/4 in turbulent aerosol flow is shows, including without mixing the particles.

  12. CHANNEL EVOLUTION IN MODIFIED ALLUVIAL STREAMS.

    Science.gov (United States)

    Simon, Andrew; Hupp, Cliff R.

    1987-01-01

    This study (a) assesses the channel changes and network trends of bed level response after modifications between 1959 and 1972 of alluvial channels in western Tennessee and (b) develops a conceptual model of bank slope development to qualitatively assess bank stability and potential channel widening. A six-step, semiquantitative model of channel evolution in disturbed channels was developed by quantifying bed level trends and recognizing qualitative stages of bank slope development. Development of the bank profile is defined in terms of three dynamic and observable surfaces: (a) vertical face (70 to 90 degrees), (b) upper bank (25 to 50 degrees), and (c) slough line (20 to 25 degrees).

  13. MarkoLAB: A simulator to study ionic channel's stochastic behavior.

    Science.gov (United States)

    da Silva, Robson Rodrigues; Goroso, Daniel Gustavo; Bers, Donald M; Puglisi, José Luis

    2017-08-01

    Mathematical models of the cardiac cell have started to include markovian representations of the ionic channels instead of the traditional Hodgkin & Huxley formulations. There are many reasons for this: Markov models are not restricted to the idea of independent gates defining the channel, they allow more complex description with specific transitions between open, closed or inactivated states, and more importantly those states can be closely related to the underlying channel structure and conformational changes. We used the LabVIEW ® and MATLAB ® programs to implement the simulator MarkoLAB that allow a dynamical 3D representation of the markovian model of the channel. The Monte Carlo simulation was used to implement the stochastic transitions among states. The user can specify the voltage protocol by setting the holding potential, the step-to voltage and the duration of the stimuli. The most studied feature of a channel is the current flowing through it. This happens when the channel stays in the open state, but most of the time, as revealed by the low open probability values, the channel remains on the inactive or closed states. By focusing only when the channel enters or leaves the open state we are missing most of its activity. MarkoLAB proved to be quite useful to visualize the whole behavior of the channel and not only when the channel produces a current. Such dynamic representation provides more complete information about channel kinetics and will be a powerful tool to demonstrate the effect of gene mutations or drugs on the channel function. MarkoLAB provides an original way of visualizing the stochastic behavior of a channel. It clarifies concepts, such as recovery from inactivation, calcium- versus voltage-dependent inactivation, and tail currents. It is not restricted to ionic channels only but it can be extended to other transporters, such as exchangers and pumps. This program is intended as a didactical tool to illustrate the dynamical behavior of a

  14. Gene Therapy in Cardiac Arrhythmias

    Directory of Open Access Journals (Sweden)

    Praveen S.V

    2006-04-01

    Full Text Available Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within the left bundle branch can provide stable heart rates. Genetic modification of the AV node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger.Lastly the ethical concerns need to be addressed.

  15. Modulation of ERG channels by XE991

    DEFF Research Database (Denmark)

    Elmedyb, Pernille; Calloe, Kirstine; Schmitt, Nicole

    2007-01-01

    In neuronal tissue, KCNQ2-5 channels conduct the physiologically important M-current. In some neurones, the M-current may in addition be conducted partly by ERG potassium channels, which have widely overlapping expression with the KCNQ channel subunits. XE991 and linopiridine are known to be stan......In neuronal tissue, KCNQ2-5 channels conduct the physiologically important M-current. In some neurones, the M-current may in addition be conducted partly by ERG potassium channels, which have widely overlapping expression with the KCNQ channel subunits. XE991 and linopiridine are known...... to be standard KCNQ potassium channel blockers. These compounds have been used in many different tissues as specific pharmacological tools to discern native currents conducted by KCNQ channels from other potassium currents. In this article, we demonstrate that ERG1-2 channels are also reversibly inhibited by XE......991 in the micromolar range (EC(50) 107 microM for ERG1). The effect has been characterized in Xenopus laevis oocytes expressing ERG1-2 and in the mammalian HEK293 cell line stably expressing ERG1 channels. The IC(50) values for block of KCNQ channels by XE991 range 1-65 microM. In conclusion, great...

  16. Plasma channels for electron beam transport

    International Nuclear Information System (INIS)

    Schneider, R.F.; Smith, J.R.; Moffatt, M.E.; Nguyen, K.T.; Uhm, H.S.

    1988-01-01

    In recent years, there has been much interest in transport of intense relativistic electron beams using plasma channels. These channels are formed by either: ionization of an organic gas by UV photoionization or electron impact ionization of a low pressure gas utilizing a low energy (typically several hundred volts) electron gun. The second method is discussed here. As their electron gun, the authors used a 12 volt lightbulb filament which is biased to -400 volts with respect to the grounded 15 cm diameter drift tube. The electrons emitted from the filament are confined by an axial magnetic field of --100 Gauss to create a plasma channel which is less than 1 cm in radius. The channel density has been determined with Langmuir probes and the resulting line densities were found to be 10 11 to 10 12 per cm. When a multi-kiloamp electron beam is injected onto this channel, the beam space charge will eject the plasma electrons leaving the ions behind to charge neutralize the electron beam, hence allowing the beam to propagate. In this work, the authors performed experimental studies on the dynamics of the plasma channel. These include Langmuir probe measurements of a steady state (DC) channel, as well as time-resolved Langmuir probe studies of pulsed channels. In addition they performed experimental studies of beam propagation in these plasma channels. Specifically, they observed the behavior of current transport in these channels. Detailed results of beam transport and channel studies are presented

  17. Post-Translational Modifications of TRP Channels

    Directory of Open Access Journals (Sweden)

    Olaf Voolstra

    2014-04-01

    Full Text Available Transient receptor potential (TRP channels constitute an ancient family of cation channels that have been found in many eukaryotic organisms from yeast to human. TRP channels exert a multitude of physiological functions ranging from Ca2+ homeostasis in the kidney to pain reception and vision. These channels are activated by a wide range of stimuli and undergo covalent post-translational modifications that affect and modulate their subcellular targeting, their biophysical properties, or channel gating. These modifications include N-linked glycosylation, protein phosphorylation, and covalent attachment of chemicals that reversibly bind to specific cysteine residues. The latter modification represents an unusual activation mechanism of ligand-gated ion channels that is in contrast to the lock-and-key paradigm of receptor activation by its agonists. In this review, we summarize the post-translational modifications identified on TRP channels and, when available, explain their physiological role.

  18. Quantum capacity of Pauli channels with memory

    International Nuclear Information System (INIS)

    Huang Peng; He Guangqiang; Lu Yuan; Zeng Guihua

    2011-01-01

    The amount of coherent quantum information that can be reliably transmitted down the memory Pauli channels with Markovian correlated noise is investigated. Two methods for evaluating the quantum capacity of the memory Pauli channels are proposed to try to trace the memory effect on the transmissions of quantum information. We show that the evaluation of quantum capacity can be reduced to the calculation of the initial memory state of each successive transmission. Furthermore, we derive quantum capacities of the memory phase flip channel, bit flip channel and bit-phase flip channel. Also, a lower bound of the quantum capacity of the memory depolarizing channel is obtained. An increase of the degree of memory of the channels has a positive effect on the increase of their quantum capacities.

  19. Effects of dislocations on electron channeling

    International Nuclear Information System (INIS)

    George, Juby; Pathak, A P

    2009-01-01

    The phenomenon of electron channeling in a crystal affected by dislocations is considered. Earlier we had considered the quantum aspects of the positron channeling in a crystal bent by dislocations where the effects of longitudinal motion of the particle were also considered along with the transverse motion. In this paper, the effective potential for the electron case is found for the two regions of dislocation-affected channel. There is considerable shift in the potential minima due to dislocations. The frequency and the corresponding spectrum of the channeling radiation due to electrons channeling through the perfect channel and the two regions of dislocation-affected channels are calculated. The spectral distribution of radiation intensity changes with the parameters of dislocation. The continuity of wavefunctions and their derivatives is used at the three boundaries and the reflection and transmission coefficients are found using these boundary conditions in the same way as in the positron case.

  20. Channel selection for automatic seizure detection

    DEFF Research Database (Denmark)

    Duun-Henriksen, Jonas; Kjaer, Troels Wesenberg; Madsen, Rasmus Elsborg

    2012-01-01

    Objective: To investigate the performance of epileptic seizure detection using only a few of the recorded EEG channels and the ability of software to select these channels compared with a neurophysiologist. Methods: Fifty-nine seizures and 1419 h of interictal EEG are used for training and testing...... of an automatic channel selection method. The characteristics of the seizures are extracted by the use of a wavelet analysis and classified by a support vector machine. The best channel selection method is based upon maximum variance during the seizure. Results: Using only three channels, a seizure detection...... sensitivity of 96% and a false detection rate of 0.14/h were obtained. This corresponds to the performance obtained when channels are selected through visual inspection by a clinical neurophysiologist, and constitutes a 4% improvement in sensitivity compared to seizure detection using channels recorded...

  1. On luminescence bleaching of tidal channel sediments

    DEFF Research Database (Denmark)

    Fruergaard, Mikkel; Pejrup, Morten; Murray, Andrew S.

    2015-01-01

    We investigate the processes responsible for bleaching of the quartz OSL signal from tidal channel sediment. Tidal dynamics are expected to play an important role for complete bleaching of tidal sediments. However, no studies have examined the amount of reworking occurring in tidal channels...... and on tidal flats due to the mixing caused by currents and waves. We apply bed level data to evaluate the amount of vertical sediment reworking in modern tidal channels and at a tidal flat. Cycles of deposition and erosion are measured with a bed level sensor, and the results show that gross sedimentation...... was several times higher than net sedimentation. We propose that tidal channel sediment is bleached either on the tidal flat before it is transported to the tidal channels and incorporated in channel-fill successions or, alternatively, on the shallow intertidal part of the channel banks. Based...

  2. Quantum channels with a finite memory

    International Nuclear Information System (INIS)

    Bowen, Garry; Mancini, Stefano

    2004-01-01

    In this paper we study quantum communication channels with correlated noise effects, i.e., quantum channels with memory. We derive a model for correlated noise channels that includes a channel memory state. We examine the case where the memory is finite, and derive bounds on the classical and quantum capacities. For the entanglement-assisted and unassisted classical capacities it is shown that these bounds are attainable for certain classes of channel. Also, we show that the structure of any finite-memory state is unimportant in the asymptotic limit, and specifically, for a perfect finite-memory channel where no information is lost to the environment, achieving the upper bound implies that the channel is asymptotically noiseless

  3. Multicarrier chaotic communications in multipath fading channels without channel estimation

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shilian, E-mail: wangsl@nudt.edu.cn; Zhang, Zhili [College of Electrical Science and Engineering, National University of Defense Technology, Changsha, 410073, P R China (China)

    2015-01-15

    A multi-carrier chaotic shift keying(MC-CSK) communication scheme with low probability of interception(LPI) is proposed in this article. We apply chaotic spreading sequences in the frequency domain, mapping a different chip of a chaotic sequence to an individual orthogonal frequency division multiplexing(OFDM) subcarrier. In each block size of $M$ OFDM symbols, we use one pilot OFDM symbol inserted time-spaced in all-frequency to transmit the reference chaotic signal and use the other M-1 OFDM symbols to transmit the information-bearing signals each spreaded by the reference chaotic signal. At the receiver, we construct a differential detector after DFT and recover the information bits from the correlations between the pilot OFDM symbol and the other M-1 OFDM symbols in each block size of M. Performance analysis and computer simulations show that the MC-CSK outperforms differential chaos shift keying(DCSK) in AWGN channels with high bandwidth efficiency for the block size of M=2 and that the MC-CSK exploits effectively the frequent diversity of the multipath channel.

  4. Multicarrier chaotic communications in multipath fading channels without channel estimation

    Directory of Open Access Journals (Sweden)

    Shilian Wang

    2015-01-01

    Full Text Available A multi-carrier chaotic shift keying(MC-CSK communication scheme with low probability of interception(LPI is proposed in this article. We apply chaotic spreading sequences in the frequency domain, mapping a different chip of a chaotic sequence to an individual orthogonal frequency division multiplexing(OFDM subcarrier. In each block size of $M$ OFDM symbols, we use one pilot OFDM symbol inserted time-spaced in all-frequency to transmit the reference chaotic signal and use the other M-1 OFDM symbols to transmit the information-bearing signals each spreaded by the reference chaotic signal. At the receiver, we construct a differential detector after DFT and recover the information bits from the correlations between the pilot OFDM symbol and the other M-1 OFDM symbols in each block size of M. Performance analysis and computer simulations show that the MC-CSK outperforms differential chaos shift keying(DCSK in AWGN channels with high bandwidth efficiency for the block size of M=2 and that the MC-CSK exploits effectively the frequent diversity of the multipath channel.

  5. Precipitation patterns during channel flow

    Science.gov (United States)

    Jamtveit, B.; Hawkins, C.; Benning, L. G.; Meier, D.; Hammer, O.; Angheluta, L.

    2013-12-01

    Mineral precipitation during channelized fluid flow is widespread in a wide variety of geological systems. It is also a common and costly phenomenon in many industrial processes that involve fluid flow in pipelines. It is often referred to as scale formation and encountered in a large number of industries, including paper production, chemical manufacturing, cement operations, food processing, as well as non-renewable (i.e. oil and gas) and renewable (i.e. geothermal) energy production. We have studied the incipient stages of growth of amorphous silica on steel plates emplaced into the central areas of the ca. 1 meter in diameter sized pipelines used at the hydrothermal power plant at Hellisheidi, Iceland (with a capacity of ca 300 MW electricity and 100 MW hot water). Silica precipitation takes place over a period of ca. 2 months at approximately 120°C and a flow rate around 1 m/s. The growth produces asymmetric ca. 1mm high dendritic structures ';leaning' towards the incoming fluid flow. A novel phase-field model combined with the lattice Boltzmann method is introduced to study how the growth morphologies vary under different hydrodynamic conditions, including non-laminar systems with turbulent mixing. The model accurately predicts the observed morphologies and is directly relevant for understanding the more general problem of precipitation influenced by turbulent mixing during flow in channels with rough walls and even for porous flow. Reference: Hawkins, C., Angheluta, L., Hammer, Ø., and Jamtveit, B., Precipitation dendrites in channel flow. Europhysics Letters, 102, 54001

  6. Multiple channel programmable coincidence counter

    Science.gov (United States)

    Arnone, Gaetano J.

    1990-01-01

    A programmable digital coincidence counter having multiple channels and featuring minimal dead time. Neutron detectors supply electrical pulses to a synchronizing circuit which in turn inputs derandomized pulses to an adding circuit. A random access memory circuit connected as a programmable length shift register receives and shifts the sum of the pulses, and outputs to a serializer. A counter is input by the adding circuit and downcounted by the seralizer, one pulse at a time. The decoded contents of the counter after each decrement is output to scalers.

  7. Mechanosensitive gating of Kv channels.

    Directory of Open Access Journals (Sweden)

    Catherine E Morris

    Full Text Available K-selective voltage-gated channels (Kv are multi-conformation bilayer-embedded proteins whose mechanosensitive (MS Popen(V implies that at least one conformational transition requires the restructuring of the channel-bilayer interface. Unlike Morris and colleagues, who attributed MS-Kv responses to a cooperative V-dependent closed-closed expansion↔compaction transition near the open state, Mackinnon and colleagues invoke expansion during a V-independent closed↔open transition. With increasing membrane tension, they suggest, the closed↔open equilibrium constant, L, can increase >100-fold, thereby taking steady-state Popen from 0→1; "exquisite sensitivity to small…mechanical perturbations", they state, makes a Kv "as much a mechanosensitive…as…a voltage-dependent channel". Devised to explain successive gK(V curves in excised patches where tension spontaneously increased until lysis, their L-based model falters in part because of an overlooked IK feature; with recovery from slow inactivation factored in, their g(V datasets are fully explained by the earlier model (a MS V-dependent closed-closed transition, invariant L≥4. An L-based MS-Kv predicts neither known Kv time courses nor the distinctive MS responses of Kv-ILT. It predicts Kv densities (hence gating charge per V-sensor several-fold different from established values. If opening depended on elevated tension (L-based model, standard gK(V operation would be compromised by animal cells' membrane flaccidity. A MS V-dependent transition is, by contrast, unproblematic on all counts. Since these issues bear directly on recent findings that mechanically-modulated Kv channels subtly tune pain-related excitability in peripheral mechanoreceptor neurons we undertook excitability modeling (evoked action potentials. Kvs with MS V-dependent closed-closed transitions produce nuanced mechanically-modulated excitability whereas an L-based MS-Kv yields extreme, possibly excessive

  8. Sequence genomic organization and expression of two channel catfish Ictalurus punctatus Ghrelin receptors

    Science.gov (United States)

    Two ghrelin receptor (GHS-R) genes were isolated from channel catfish tissue and a bacterial artificial chromosome (BAC) library. The two receptors were characterized by determining tissue distribution, ontogeny of receptor mRNA expression, and effects of exogenous homologous ghrelin administration ...

  9. Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits

    Science.gov (United States)

    Torres, Yolima P.; Granados, Sara T.; Latorre, Ramón

    2014-01-01

    Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca2+-activated K+ channel (BK) is unique among the superfamily of K+ channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K+ channels) and a large C terminus composed of two regulators of K+ conductance domains (RCK domains), where the Ca2+-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca2+ sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above. PMID:25346693

  10. Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits

    Directory of Open Access Journals (Sweden)

    Yolima P. Torres

    2014-10-01

    Full Text Available Coded by a single gene (Slo1, KCM and activated by depolarizing potentials and by a rise in intracellular Ca2+ concentration, the large conductance voltage- and Ca+2-activated K+ channel (BK is unique among the superfamily of K+ channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K+ channels and a large C terminus composed of two regulators of K+ conductance domains (RCK domains, where the Ca2+-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3 & β4 and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca+2 sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

  11. Pharmacological consequences of the coexpression of BK channel α and auxiliary β subunits.

    Science.gov (United States)

    Torres, Yolima P; Granados, Sara T; Latorre, Ramón

    2014-01-01

    Coded by a single gene (Slo1, KCM) and activated by depolarizing potentials and by a rise in intracellular Ca(2+) concentration, the large conductance voltage- and Ca(2+)-activated K(+) channel (BK) is unique among the superfamily of K(+) channels. BK channels are tetramers characterized by a pore-forming α subunit containing seven transmembrane segments (instead of the six found in voltage-dependent K(+) channels) and a large C terminus composed of two regulators of K(+) conductance domains (RCK domains), where the Ca(2+)-binding sites reside. BK channels can be associated with accessory β subunits and, although different BK modulatory mechanisms have been described, greater interest has recently been placed on the role that the β subunits may play in the modulation of BK channel gating due to its physiological importance. Four β subunits have currently been identified (i.e., β1, β2, β3, and β4) and despite the fact that they all share the same topology, it has been shown that every β subunit has a specific tissue distribution and that they modify channel kinetics as well as their pharmacological properties and the apparent Ca(2+) sensitivity of the α subunit in different ways. Additionally, different studies have shown that natural, endogenous, and synthetic compounds can modulate BK channels through β subunits. Considering the importance of these channels in different pathological conditions, such as hypertension and neurological disorders, this review focuses on the mechanisms by which these compounds modulate the biophysical properties of BK channels through the regulation of β subunits, as well as their potential therapeutic uses for diseases such as those mentioned above.

  12. Use of navigation channels by Lake Sturgeon: Does channelization increase vulnerability of fish to ship strikes?

    Directory of Open Access Journals (Sweden)

    Darryl W Hondorp

    Full Text Available Channelization for navigation and flood control has altered the hydrology and bathymetry of many large rivers with unknown consequences for fish species that undergo riverine migrations. In this study, we investigated whether altered flow distributions and bathymetry associated with channelization attracted migrating Lake Sturgeon (Acipenser fulvescens into commercial navigation channels, potentially increasing their exposure to ship strikes. To address this question, we quantified and compared Lake Sturgeon selection for navigation channels vs. alternative pathways in two multi-channel rivers differentially affected by channelization, but free of barriers to sturgeon movement. Acoustic telemetry was used to quantify Lake Sturgeon movements. Under the assumption that Lake Sturgeon navigate by following primary flow paths, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River were expected to choose navigation channels over alternative pathways and to exhibit greater selection for navigation channels than conspecifics in the less-channelized lower St. Clair River. Consistent with these predictions, acoustic-tagged Lake Sturgeon in the more-channelized lower Detroit River selected the higher-flow and deeper navigation channels over alternative migration pathways, whereas in the less-channelized lower St. Clair River, individuals primarily used pathways alternative to navigation channels. Lake Sturgeon selection for navigation channels as migratory pathways also was significantly higher in the more-channelized lower Detroit River than in the less-channelized lower St. Clair River. We speculated that use of navigation channels over alternative pathways would increase the spatial overlap of commercial vessels and migrating Lake Sturgeon, potentially enhancing their vulnerability to ship strikes. Results of our study thus demonstrated an association between channelization and the path use of migrating Lake Sturgeon that could prove

  13. Ageing genes

    DEFF Research Database (Denmark)

    Rattan, Suresh

    2018-01-01

    The idea of gerontogenes is in line with the evolutionary explanation of ageing as being an emergent phenomenon as a result of the imperfect maintenance and repair systems. Although evolutionary processes did not select for any specific ageing genes that restrict and determine the lifespan...... of an individual, the term ‘gerontogenes’ primarily refers to any genes that may seem to influence ageing and longevity, without being specifically selected for that role. Such genes can also be called ‘virtual gerontogenes’ by virtue of their indirect influence on the rate and process of ageing. More than 1000...... virtual gerontogenes have been associated with ageing and longevity in model organisms and humans. The ‘real’ genes, which do influence the essential lifespan of a species, and have been selected for in accordance with the evolutionary life history of the species, are known as the longevity assurance...

  14. ASIC3 channels in multimodal sensory perception.

    Science.gov (United States)

    Li, Wei-Guang; Xu, Tian-Le

    2011-01-19

    Acid-sensing ion channels (ASICs), which are members of the sodium-selective cation channels belonging to the epithelial sodium channel/degenerin (ENaC/DEG) family, act as membrane-bound receptors for extracellular protons as well as nonproton ligands. At least five ASIC subunits have been identified in mammalian neurons, which form both homotrimeric and heterotrimeric channels. The highly proton sensitive ASIC3 channels are predominantly distributed in peripheral sensory neurons, correlating with their roles in multimodal sensory perception, including nociception, mechanosensation, and chemosensation. Different from other ASIC subunit composing ion channels, ASIC3 channels can mediate a sustained window current in response to mild extracellular acidosis (pH 7.3-6.7), which often occurs accompanied by many sensory stimuli. Furthermore, recent evidence indicates that the sustained component of ASIC3 currents can be enhanced by nonproton ligands including the endogenous metabolite agmatine. In this review, we first summarize the growing body of evidence for the involvement of ASIC3 channels in multimodal sensory perception and then discuss the potential mechanisms underlying ASIC3 activation and mediation of sensory perception, with a special emphasis on its role in nociception. We conclude that ASIC3 activation and modulation by diverse sensory stimuli represent a new avenue for understanding the role of ASIC3 channels in sensory perception. Furthermore, the emerging implications of ASIC3 channels in multiple sensory dysfunctions including nociception allow the development of new pharmacotherapy.

  15. A Perspective on the MIMO Wiretap Channel

    KAUST Repository

    Oggier, Frederique; Hassibi, Babak

    2015-01-01

    A wiretap channel is a communication channel between a transmitter Alice and a legitimate receiver Bob, in the presence of an eavesdropper Eve. The goal of communication is to achieve reliability between Alice and Bob, but also confidentiality despite Eve’s presence. Wiretap channels are declined in all kinds of flavors, depending on the underlying channels used by the three players: discrete memoryless channels, additive Gaussian noise channels, or fading channels, to name a few. In this survey, we focus on the case where the three players use multiple-antenna channels with Gaussian noise to communicate. After summarizing known results for multiple-input–multiple-output (MIMO) channels, both in terms of achievable reliable data rate (capacity) and code design, we introduce the MIMO wiretap channel. We then state the MIMO wiretap capacity, summarize the idea of the proof(s) behind this result, and comment on the insights given by the proofs on the physical meaning of the secrecy capacity. We finally discuss design criteria for MIMO wiretap codes.

  16. VKCDB: Voltage-gated potassium channel database

    Directory of Open Access Journals (Sweden)

    Gallin Warren J

    2004-01-01

    Full Text Available Abstract Background The family of voltage-gated potassium channels comprises a functionally diverse group of membrane proteins. They help maintain and regulate the potassium ion-based component of the membrane potential and are thus central to many critical physiological processes. VKCDB (Voltage-gated potassium [K] Channel DataBase is a database of structural and functional data on these channels. It is designed as a resource for research on the molecular basis of voltage-gated potassium channel function. Description Voltage-gated potassium channel sequences were identified by using BLASTP to search GENBANK and SWISSPROT. Annotations for all voltage-gated potassium channels were selectively parsed and integrated into VKCDB. Electrophysiological and pharmacological data for the channels were collected from published journal articles. Transmembrane domain predictions by TMHMM and PHD are included for each VKCDB entry. Multiple sequence alignments of conserved domains of channels of the four Kv families and the KCNQ family are also included. Currently VKCDB contains 346 channel entries. It can be browsed and searched using a set of functionally relevant categories. Protein sequences can also be searched using a local BLAST engine. Conclusions VKCDB is a resource for comparative studies of voltage-gated potassium channels. The methods used to construct VKCDB are general; they can be used to create specialized databases for other protein families. VKCDB is accessible at http://vkcdb.biology.ualberta.ca.

  17. Mechanosensitive Piezo Channels in the Gastrointestinal Tract.

    Science.gov (United States)

    Alcaino, C; Farrugia, G; Beyder, A

    2017-01-01

    Sensation of mechanical forces is critical for normal function of the gastrointestinal (GI) tract and abnormalities in mechanosensation are linked to GI pathologies. In the GI tract there are several mechanosensitive cell types-epithelial enterochromaffin cells, intrinsic and extrinsic enteric neurons, smooth muscle cells and interstitial cells of Cajal. These cells use mechanosensitive ion channels that respond to mechanical forces by altering transmembrane ionic currents in a process called mechanoelectrical coupling. Several mechanosensitive ionic conductances have been identified in the mechanosensory GI cells, ranging from mechanosensitive voltage-gated sodium and calcium channels to the mechanogated ion channels, such as the two-pore domain potassium channels K2P (TREK-1) and nonselective cation channels from the transient receptor potential family. The recently discovered Piezo channels are increasingly recognized as significant contributors to cellular mechanosensitivity. Piezo1 and Piezo2 are nonselective cationic ion channels that are directly activated by mechanical forces and have well-defined biophysical and pharmacologic properties. The role of Piezo channels in the GI epithelium is currently under investigation and their role in the smooth muscle syncytium and enteric neurons is still not known. In this review, we outline the current state of knowledge on mechanosensitive ion channels in the GI tract, with a focus on the known and potential functions of the Piezo channels. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. A Perspective on the MIMO Wiretap Channel

    KAUST Repository

    Oggier, Frederique

    2015-10-01

    A wiretap channel is a communication channel between a transmitter Alice and a legitimate receiver Bob, in the presence of an eavesdropper Eve. The goal of communication is to achieve reliability between Alice and Bob, but also confidentiality despite Eve’s presence. Wiretap channels are declined in all kinds of flavors, depending on the underlying channels used by the three players: discrete memoryless channels, additive Gaussian noise channels, or fading channels, to name a few. In this survey, we focus on the case where the three players use multiple-antenna channels with Gaussian noise to communicate. After summarizing known results for multiple-input–multiple-output (MIMO) channels, both in terms of achievable reliable data rate (capacity) and code design, we introduce the MIMO wiretap channel. We then state the MIMO wiretap capacity, summarize the idea of the proof(s) behind this result, and comment on the insights given by the proofs on the physical meaning of the secrecy capacity. We finally discuss design criteria for MIMO wiretap codes.

  19. The etomidate analog ET-26 HCl retains superior myocardial performance: Comparisons with etomidate in vivo and in vitro.

    Science.gov (United States)

    Liu, Xingxing; Song, Haibo; Yang, Jun; Zhou, Cheng; Kang, Yi; Yang, Linghui; Liu, Jin; Zhang, Wensheng

    2018-01-01

    (R)-2-methoxyethyl1-(1-phenylethyl)-1H-imidazole-5-carboxylate hydrochloride (ET-26 HCl) is a novel etomidate analogue. The purpose of this study was to characterize whether ET-26 HCl could retain the superior myocardial performance of etomidate in vivo and in vitro. In vivo, the influence of ET-26 HCl and etomidate on the cardiac function of dogs was confirmed using echocardiography and electrocardiogram. In vitro, a Langendorff preparation was used to examine direct myocardial performance in isolated rat hearts, and a whole-cell patch-clamp technique was used to study effects on the human ether-a-go-go-related gene (hERG) channel. In vivo, after a single bolus administration of ET-26 HCl or etomidate, no significant difference in echocardiography and electrocardiogram parameters was observed. No arrhythmia occurred and no QT interval prolongation happened during the study period. In the in vitro Langendorff preparation, none of the cardiac parameters were abnormal, and the hERG recordings showed that ET-26 HCl and etomidate inhibited the tail current of the hERG in a concentration-dependent manner with an IC50 of 742.51 μM and 263.60 μM, respectively. In conclusion, through an in vivo experiment and a whole organ preparation, the current study found that ET-26 HCl can maintain a myocardial performance that is similar to that of etomidate. In addition, the electrophysiology study indicated that ET-26 HCl and etomidate inhibited the hERG at a supra-therapeutic concentration.

  20. Sediment sorting at a side channel bifurcation

    Science.gov (United States)

    van Denderen, Pepijn; Schielen, Ralph; Hulscher, Suzanne

    2017-04-01

    Side channels have been constructed to reduce the flood risk and to increase the ecological value of the river. In various Dutch side channels large aggradation in these channels occurred after construction. Measurements show that the grain size of the deposited sediment in the side channel is smaller than the grain size found on the bed of the main channel. This suggest that sorting occurs at the bifurcation of the side channel. The objective is to reproduce with a 2D morphological model the fining of the bed in the side channel and to study the effect of the sediment sorting on morphodynamic development of the side channel. We use a 2D Delft3D model with two sediment fractions. The first fraction corresponds with the grain size that can be found on the bed of the main channel and the second fraction corresponds with the grain size found in the side channel. With the numerical model we compute several side channel configurations in which we vary the length and the width of the side channel, and the curvature of the upstream channel. From these computations we can derive the equilibrium state and the time scale of the morphodynamic development of the side channel. Preliminary results show that even when a simple sediment transport relation is used, like Engelund & Hansen, more fine sediment enters the side channel than coarse sediment. This is as expected, and is probably related to the bed slope effects which are a function of the Shields parameter. It is expected that by adding a sill at the entrance of the side channel the slope effect increases. This might reduce the amount of coarse sediment which enters the side channel even more. It is unclear whether the model used is able to reproduce the effect of such a sill correctly as modelling a sill and reproducing the correct hydrodynamic and morphodynamic behaviour is not straightforward in a 2D model. Acknowledgements: This research is funded by STW, part of the Dutch Organization for Scientific Research under