Intracellular long-chain acyl CoAs activate TRPV1 channels.

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Yi Yu

Full Text Available TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2 is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs, another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes.

Antiproliferative effects of TRPV1 ligands on nonspecific and enteroantigen-specific T cells from wild-type and Trpv1 KO mice

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Belmaáti, Mohammed-Samir; Diemer, Sanne; Hvarness, Tine

2014-01-01

BACKGROUND: Treatment with the TRPV1 agonist, capsaicin, was previously shown to protect against experimental colitis in the severe combined immunodeficiency (SCID) T-cell transfer model. Here, we investigate trpv1 gene expression in lymphoid organs and cells from SCID and BALB/c mice to identify...

Reactive oxygen species mediate TNFR1 increase after TRPV1 activation in mouse DRG neurons

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Westlund Karin N

2009-06-01

Full Text Available Abstract Background Transient receptor potential vanilloid subtype 1 (TRPV1 is activated by low pH/protons and is well known to be involved in hyperalgesia during inflammation. Tumor necrosis factor α (TNF-α, a proinflammatory cytokine, is involved in nociceptive responses causing hyperalgesia through TNF receptor type 1 (TNFR1 activation. Reactive oxygen species (ROS production is also prominently increased in inflamed tissue. The present study investigated TNFR1 receptors in primary cultured mouse dorsal root ganglion (DRG neurons after TRPV1 activation and the involvement of ROS. C57BL/6 mice, both TRPV1 knockout and wild type, were used for immunofluorescent and live cell imaging. The L4 and L5 DRGs were dissected bilaterally and cultured overnight. TRPV1 was stimulated with capsaicin or its potent analog, resiniferatoxin. ROS production was measured with live cell imaging and TNFR1 was detected with immunofluorescence in DRG primary cultures. The TRPV1 knockout mice, TRPV1 antagonist, capsazepine, and ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN, were employed to explore the functional relationship among TRPV1, ROS and TNFR1 in these studies. Results The results demonstrate that TRPV1 activation increases TNFR1 receptors and ROS generation in primary cultures of mouse DRG neurons. Activated increases in TNFR1 receptors and ROS production are absent in TRPV1 deficient mice. The PBN blocks increases in TNFR1 and ROS production induced by capsaicin/resiniferatoxin. Conclusion TRPV1 activation increases TNFR1 in cultured mouse DRG neurons through a ROS signaling pathway, a novel sensitization mechanism in DRG neurons.

TRPV1 and Endocannabinoids: Emerging Molecular Signals that Modulate Mammalian Vision

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Daniel A. Ryskamp

2014-09-01

Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 subunits form a polymodal cation channel responsive to capsaicin, heat, acidity and endogenous metabolites of polyunsaturated fatty acids. While originally reported to serve as a pain and heat detector in the peripheral nervous system, TRPV1 has been implicated in the modulation of blood flow and osmoregulation but also neurotransmission, postsynaptic neuronal excitability and synaptic plasticity within the central nervous system. In addition to its central role in nociception, evidence is accumulating that TRPV1 contributes to stimulus transduction and/or processing in other sensory modalities, including thermosensation, mechanotransduction and vision. For example, TRPV1, in conjunction with intrinsic cannabinoid signaling, might contribute to retinal ganglion cell (RGC axonal transport and excitability, cytokine release from microglial cells and regulation of retinal vasculature. While excessive TRPV1 activity was proposed to induce RGC excitotoxicity, physiological TRPV1 activity might serve a neuroprotective function within the complex context of retinal endocannabinoid signaling. In this review we evaluate the current evidence for localization and function of TRPV1 channels within the mammalian retina and explore the potential interaction of this intriguing nociceptor with endogenous agonists and modulators.

Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea.

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Sulk, Mathias; Seeliger, Stephan; Aubert, Jerome; Schwab, Verena D; Cevikbas, Ferda; Rivier, Michel; Nowak, Pawel; Voegel, Johannes J; Buddenkotte, Jörg; Steinhoff, Martin

2012-04-01

Rosacea is a frequent chronic inflammatory skin disease of unknown etiology. Because early rosacea reveals all characteristics of neurogenic inflammation, a central role of sensory nerves in its pathophysiology has been discussed. Neuroinflammatory mediators and their receptors involved in rosacea are poorly defined. Good candidates may be transient receptor potential (TRP) ion channels of vanilloid type (TRPV), which can be activated by many trigger factors of rosacea. Interestingly, TRPV2, TRPV3, and TRPV4 are expressed by both neuronal and non-neuronal cells. Here, we analyzed the expression and distribution of TRPV receptors in the various subtypes of rosacea on non-neuronal cells using immunohistochemistry, morphometry, double immunoflourescence, and quantitative real-time PCR (qRT-PCR) as compared with healthy skin and lupus erythematosus. Our results show that dermal immunolabeling of TRPV2 and TRPV3 and gene expression of TRPV1 is significantly increased in erythematotelangiectatic rosacea (ETR). Papulopustular rosacea (PPR) displayed an enhanced immunoreactivity for TRPV2, TRPV4, and also of TRPV2 gene expression. In phymatous rosacea (PhR)-affected skin, dermal immunostaining of TRPV3 and TRPV4 and gene expression of TRPV1 and TRPV3 was enhanced, whereas epidermal TRPV2 staining was decreased. Thus, dysregulation of TRPV channels also expressed by non-neuronal cells may be critically involved in the initiation and/or development of rosacea. TRP ion channels may be targets for the treatment of rosacea.

Multisteric TRPV1 nocisensor: a target for analgesics.

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Szolcsányi, János; Sándor, Zoltán

2012-12-01

Cloning of the transient receptor potential vanilloid type 1 (TRPV1), the heat-gated cation channel/capsaicin receptor expressed by sensory neurons, has opened the door for development of new types of analgesics that selectively act on nociceptors. Here we summarize mutagenetic evidence for selective loss of responsiveness to vanilloids, protons, and heat stimuli to provide clues for avoiding on-target side effects of hyperthermia and burn risk. It is suggested that the complex chemoceptive thermosensor function of TRPV1 (which is modulated by depolarizing stimuli) can be attributed to multisteric gating functions. In this way, it forms the prototype of a new class of ion channels different from the canonical voltage-gated and ligand-gated ones. Several endogenous lipid ligands activate and inhibit TRPV1 and its gating initiates sensory transducer and mediator-releasing functions. Second generation TRPV1 antagonists that do not induce hyperthermia are under development, and a dermal capsaicin patch is already on the market for long-term treatment of neuropathic pain. Copyright © 2012 Elsevier Ltd. All rights reserved.

α,β-Unsaturated aldehyde pollutant acrolein suppresses cardiomyocyte contractile function: Role of TRPV1 and oxidative stress.

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Wu, Zhenbiao; He, Emily Y; Scott, Glenda I; Ren, Jun

2015-01-01

Air pollution is associated with an increased prevalence of heart disease and is known to trigger a proinflammatory response via stimulation of transient receptor potential vanilloid cation channels (TRPV1, also known as the capsaicin receptor). This study was designed to examine the effect of acrolein, an essential α,β-unsaturated aldehyde pollutant, on myocardial contractile function and the underlying mechanism involved with a focus on TRPV1 and oxidative stress. Cardiomyocyte mechanical and intracellular Ca(2+) properties were evaluated using an IonOptix MyoCam® system including peak shortening (PS), maximal velocity of shortening/relengthening (± dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR90 ), fura-2 fluorescence intensity (FFI) and intracellular Ca(2+) decay. Changes in apoptosis and TRPV1 were evaluated using Western blot analysis. The degree of oxidative stress was assessed using the ratio between reduced and oxidized glutathione. Results obtained revealed that exposure of cardiomyocytes to acrolein acutely compromised contractile and intracellular Ca(2+) properties including depressed PS, ± dL/dt and ΔFFI, as well as prolonged TR90 and intracellular Ca(2+) decay. In addition, acrolein exposure upregulated TRPV1 associated with an increase in both apoptosis and oxidative stress. However, the acrolein-induced cardiomyocyte contractile and intracellular Ca(2+) anomalies, as well as apoptosis (as evidenced by Bcl-2, Bax, FasL, Caspase-3 and -8), were negated by the reactive oxygen species (ROS) scavenger glutathione or the TRPV1 antagonist capsazepine. Collectively these data suggest that the α,β-unsaturated aldehyde pollutant acrolein may play a role in the pathogenesis and sequelae of air pollution-induced heart disease via a TRPV1- and oxidative stress-dependent mechanism. © 2013 Wiley Periodicals, Inc.

Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

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Yelena Nersesyan

2017-11-01

Full Text Available Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in in vivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.

Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.

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Xiao, Xing; Zhao, Xiao-Tao; Xu, Ling-Chi; Yue, Lu-Peng; Liu, Feng-Yu; Cai, Jie; Liao, Fei-Fei; Kong, Jin-Ge; Xing, Guo-Gang; Yi, Ming; Wan, You

2015-04-01

Transient receptor potential vanilloid 1 (TRPV1) receptors are expressed in nociceptive neurons of rat dorsal root ganglions (DRGs) and mediate inflammatory pain. Nonspecific inhibition of protein-tyrosine phosphatases (PTPs) increases the tyrosine phosphorylation of TRPV1 and sensitizes TRPV1. However, less is known about tyrosine phosphorylation's implication in inflammatory pain, compared with that of serine/threonine phosphorylation. Src homology 2 domain-containing tyrosine phosphatase 1 (Shp-1) is a key phosphatase dephosphorylating TRPV1. In this study, we reported that Shp-1 colocalized with and bound to TRPV1 in nociceptive DRG neurons. Shp-1 inhibitors, including sodium stibogluconate and PTP inhibitor III, sensitized TRPV1 in cultured DRG neurons. In naive rats, intrathecal injection of Shp-1 inhibitors increased both TRPV1 and tyrosine-phosphorylated TRPV1 in DRGs and induced thermal hyperalgesia, which was abolished by pretreatment with TRPV1 antagonists capsazepine, BCTC, or AMG9810. Complete Freund's adjuvant (CFA)-induced inflammatory pain in rats significantly increased the expression of Shp-1, TRPV1, and tyrosine-phosphorylated TRPV1, as well as the colocalization of Shp-1 and TRPV1 in DRGs. Intrathecal injection of sodium stibogluconate aggravated CFA-induced inflammatory pain, whereas Shp-1 overexpression in DRG neurons alleviated it. These results suggested that Shp-1 dephosphorylated and inhibited TRPV1 in DRG neurons, contributing to maintain thermal nociceptive thresholds in normal rats, and as a compensatory mechanism, Shp-1 increased in DRGs of rats with CFA-induced inflammatory pain, which was involved in protecting against excessive thermal hyperalgesia.

Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity

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Pauza Mary E

2008-03-01

Full Text Available Abstract A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN. The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ-induced and transgene-mediated murine models of type 1 diabetes (T1D, we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1 expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL. An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG, and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation

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Wang Juan

2011-05-01

Full Text Available Abstract Background The discovery of heat-sensitive Transient Receptor Potential Vanilloid (TRPV ion channels provided a potential molecular explanation for the perception of innocuous and noxious heat stimuli. TRPV1 has a significant role in acute heat nociception and inflammatory heat hyperalgesia. Yet, substantial innocuous and noxious heat sensitivity remains in TRPV1 knockout animals. Here we investigated the role of two related channels, TRPV3 and TRPV4, in these capacities. We studied TRPV3 knockout animals on both C57BL6 and 129S6 backgrounds, as well as animals deficient in both TRPV3 and TRPV4 on a C57BL6 background. Additionally, we assessed the contributions of TRPV3 and TRPV4 to acute heat nociception and inflammatory heat hyperalgesia during inhibition of TRPV1. Results TRPV3 knockout mice on the C57BL6 background exhibited no obvious alterations in thermal preference behavior. On the 129S6 background, absence of TRPV3 resulted in a more restrictive range of occupancy centered around cooler floor temperatures. TRPV3 knockout mice showed no deficits in acute heat nociception on either background. Mice deficient in both TRPV3 and TRPV4 on a C57BL6 background showed thermal preference behavior similar to wild-type controls on the thermal gradient, and little or no change in acute heat nociception or inflammatory heat hyperalgesia. Masking of TRPV1 by the TRPV1 antagonist JNJ-17203212 did not reveal differences between C57BL6 animals deficient in TRPV3 and TRPV4, compared to their wild-type counterparts. Conclusions Our results support the notion that TRPV3 and TRPV4 likely make limited and strain-dependent contributions to innocuous warm temperature perception or noxious heat sensation, even when TRPV1 is masked. These findings imply the existence of other significant mechanisms for heat perception.

Participation of peripheral TRPV1, TRPV4, TRPA1 and ASIC in a magnesium sulfate-induced local pain model in rat.

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Srebro, Dragana; Vučković, Sonja; Prostran, Milica

2016-12-17

We previously showed that magnesium sulfate (MS) has systemic antinociceptive and local peripheral pronociceptive effects. The role of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in the mechanism of action of MS has not been investigated in detail. The aim of this study was to explore the participation of TRP channels in the pronociceptive action of MS in rats after its intraplantar injection. The paw withdrawal threshold (PWT) to mechanical stimuli was measured by the electronic von Frey test. Drugs that were tested were either co-administered with an isotonic pH-unadjusted or pH-adjusted solution of MS intraplantarily, or to the contralateral paw to exclude systemic effects. We found that the subcutaneous administration of both pH-adjusted (7.4) and pH-unadjusted (about 6.0) isotonic (6.2% w/v in water) solutions of MS induce the pain at the injection site. The pH-unadjusted MS solution-induced mechanical hyperalgesia decreased in a dose-dependent manner as a consequence of co-injection of capsazepine, a selective TRPV1 antagonist (20, 100 and 500pmol/paw), RN-1734, a selective TRPV4 antagonist (1.55, 3.1 and 6.2μmol/paw), HC-030031, a selective TRPA1 antagonist (5.6, 28.1 and 140nmol/paw), and amiloride hydrochloride, a non-selective ASIC inhibitor (0.83, 2.5 and 7.55μmol/paw). In pH-adjusted MS-induced hyperalgesia, the highest doses of TRPV1, TRPV4 and TRPA1 antagonists displayed effects that were, respectively, either similar, less pronounced or delayed in comparison to the effect induced by administration of the pH-unadjusted MS solution; the ASIC antagonist did not have any effect. These results suggest that the MS-induced local peripheral mechanical hyperalgesia is mediated via modulation of the activity of peripheral TRPV1, TRPV4, TRPA1 and ASICs. Specific local inhibition of TRP channels represents a novel approach to treating local injection-related pain. Copyright © 2016 IBRO. Published by Elsevier Ltd. All

CGRPα within the Trpv1-Cre population contributes to visceral nociception.

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Spencer, Nick J; Magnúsdóttir, Elín I; Jakobsson, Jon E T; Kestell, Garreth; Chen, Bao Nan; Morris, David; Brookes, Simon J; Lagerström, Malin C

2018-02-01

The role of calcitonin gene-related peptide (CGRP) in visceral and somatic nociception is incompletely understood. CGRPα is highly expressed in sensory neurons of dorsal root ganglia and particularly in neurons that also express the transient receptor potential cation channel subfamily V member 1 (Trpv1). Therefore, we investigated changes in visceral and somatic nociception following deletion of CGRPα from the Trpv1-Cre population using the Cre/lox system. In control mice, acetic acid injection (0.6%, ip) caused significant immobility (time stationary), an established indicator of visceral pain. In CGRPα-mCherry lx/lx ;Trpv1-Cre mice, the duration of immobility was significantly less than controls, and the distance CGRPα-mCherry lx/lx ;Trpv1-Cre mice traveled over 20 min following acetic acid was significantly greater than controls. However, following acetic acid injection, there was no difference between genotypes in the writhing reflex, number of abdominal licks, or forepaw wipes of the cheek. CGRPα-mCherry lx/lx ;Trpv1-Cre mice developed more pronounced inflammation-induced heat hypersensitivity above baseline values compared with controls. However, analyses of noxious acute heat or cold transmission revealed no difference between genotypes. Also, odor avoidance test, odor preference test, and buried food test for olfaction revealed no differences between genotypes. Our findings suggest that CGRPα-mediated transmission within the Trpv1-Cre population plays a significant role in visceral nociceptive pathways underlying voluntary movement. Monitoring changes in movement over time is a sensitive parameter to identify differences in visceral nociception, compared with writhing reflexes, abdominal licks, or forepaw wipes of the cheek that were unaffected by deletion of CGRPα- from Trpv1-Cre population and likely utilize different mechanisms. NEW & NOTEWORTHY The neuropeptide calcitonin gene-related peptide (CGRP) is highly colocalized with transient receptor

Trpv4 Mediates Hypotonic Inhibition of Central Osmosensory Neurons via Taurine Gliotransmission

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Sorana Ciura

2018-05-01

Full Text Available Summary: The maintenance of hydromineral homeostasis requires bidirectional detection of changes in extracellular fluid osmolality by primary osmosensory neurons (ONs in the organum vasculosum laminae terminalis (OVLT. Hypertonicity excites ONs in part through the mechanical activation of a variant transient receptor potential vanilloid-1 channel (dn-Trpv1. However, the mechanism by which local hypotonicity inhibits ONs in the OVLT remains unknown. Here, we show that hypotonicity can reduce the basal activity of dn-Trpv1 channels and hyperpolarize acutely isolated ONs. Surprisingly, we found that mice lacking dn-Trpv1 maintain normal inhibitory responses to hypotonicity when tested in situ. In the intact setting, hypotonicity inhibits ONs through a non-cell-autonomous mechanism that involves glial release of the glycine receptor agonist taurine through hypotonicity activated anion channels (HAAC that are activated subsequent to Ca2+ influx through Trpv4 channels. Our study clarifies how Trpv4 channels contribute to the inhibition of OVLT ONs during hypotonicity in situ. : Ciura et al. show that osmosensory neurons in organum vasculosum lamina terminalis are inhibited by hypotonicity. This effect is triggered by activation of Trpv4 channels and Ca2+ accumulation in astrocytes, causing these cells to release taurine through anion channels. Taurine inhibits firing by activating glycine receptors on the osmosensory neurons. Keywords: hyptonicity, taurine, TRPV, osmosensitive, gliotransmission, swelling

TRPV1 channels and the progesterone receptor Sig-1R interact to regulate pain.

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Ortíz-Rentería, Miguel; Juárez-Contreras, Rebeca; González-Ramírez, Ricardo; Islas, León D; Sierra-Ramírez, Félix; Llorente, Itzel; Simon, Sidney A; Hiriart, Marcia; Rosenbaum, Tamara; Morales-Lázaro, Sara L

2018-02-13

The Transient Receptor Potential Vanilloid 1 (TRPV1) ion channel is expressed in nociceptors where, when activated by chemical or thermal stimuli, it functions as an important transducer of painful and itch-related stimuli. Although the interaction of TRPV1 with proteins that regulate its function has been previously explored, their modulation by chaperones has not been elucidated, as is the case for other mammalian TRP channels. Here we show that TRPV1 physically interacts with the Sigma 1 Receptor (Sig-1R), a chaperone that binds progesterone, an antagonist of Sig-1R and an important neurosteroid associated to the modulation of pain. Antagonism of Sig-1R by progesterone results in the down-regulation of TRPV1 expression in the plasma membrane of sensory neurons and, consequently, a decrease in capsaicin-induced nociceptive responses. This is observed both in males treated with a synthetic antagonist of Sig-1R and in pregnant females where progesterone levels are elevated. This constitutes a previously undescribed mechanism by which TRPV1-dependent nociception and pain can be regulated.

Role of TRPV1 channels in ischemia/reperfusion-induced acute kidney injury.

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Lan Chen

Full Text Available OBJECTIVES: Transient receptor potential vanilloid 1 (TRPV1 -positive sensory nerves are widely distributed in the kidney, suggesting that TRPV1-mediated action may participate in the regulation of renal function under pathophysiological conditions. Stimulation of TRPV1 channels protects against ischemia/reperfusion (I/R-induced acute kidney injury (AKI. However, it is unknown whether inhibition of these channels is detrimental in AKI or not. We tested the role of TRPV1 channels in I/R-induced AKI by modulating these channels with capsaicin (TRPV1 agonist, capsazepine (TRPV1 antagonist and using Trpv1-/- mice. METHODS AND RESULTS: Anesthetized C57BL/6 mice were subjected to 25 min of renal ischemia and 24 hrs of reperfusion. Mice were pretreated with capsaicin (0.3 mg/kg body weight or capsazepine (50 mg/kg body weight. Capsaicin ameliorated the outcome of AKI, as measured by serum creatinine levels, tubular damage,neutrophil gelatinase-associated lipocalin (NGAL abundance and Ly-6B.2 positive polymorphonuclear inflammatory cells in injured kidneys. Neither capsazepine nor deficiency of TRPV1 did deteriorate renal function or histology after AKI. Measurements of endovanilloids in kidney tissue indicate that 20-hydroxyeicosatetraeonic acid (20-HETE or epoxyeicosatrienoic acids (EETs are unlikely involved in the beneficial effects of capsaicin on I/R-induced AKI. CONCLUSIONS: Activation of TRPV1 channels ameliorates I/R-induced AKI, but inhibition of these channels does not affect the outcome of AKI. Our results may have clinical implications for long-term safety of renal denervation to treat resistant hypertension in man, with respect to the function of primary sensory nerves in the response of the kidney to ischemic stimuli.

Activation of the Chemosensory Ion Channels TRPA1 and TRPV1 by Hydroalcohol Extract of Kalopanax pictus Leaves.

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Son, Hee Jin; Kim, Yiseul; Misaka, Takumi; Noh, Bong Soo; Rhyu, Mee-Ra

2012-11-01

TRPA1 and TRPV1 are members of the TRP superfamily of structurally related, nonselective cation channels. TRPA1 and TRPV1 are often co-expressed in sensory neurons and play an important role in somatosense such as cold, pain, and irritants. The first leaves of Kalopanax pictus Nakai (Araliaceae) have long been used as a culinary ingredient in Korea because of their unique chemesthetic flavor. In this study, we observed the intracellular Ca(2+) response to cultured cells expressing human TRPA1 (hTRPA1) and human TRPV1 (hTRPV1) by Ca(2+) imaging analysis to investigate the ability of the first leaves of K. pictus to activate the hTRPA1 and hTRPV1. An 80% ethanol extract of K. pictus (KPEx) increased intracellular Ca(2+) influx in a response time- and concentration-dependent manner via either hTRPA1 or hTRPV1. KPEx-induced response to hTRPA1 was markedly attenuated by ruthenium red, a general blocker of TRP channels, and HC-030031, a specific antagonist of TRPA1. In addition, the intracellular Ca(2+) influx attained with KPEx to hTRPV1 was mostly blocked by ruthenium red, and capsazepine, a specific antagonist of TRPV1. These results indicate that KPEx selectively activates both hTRPA1 and hTRPV1, which may provide evidence that the first leaves of K. pictus primarily activate TRPA1 and TRPV1 to induce their unique chemesthetic sense.

Integrating TRPV1 Receptor Function with Capsaicin Psychophysics

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Gregory Smutzer

2016-01-01

Full Text Available Capsaicin is a naturally occurring vanilloid that causes a hot, pungent sensation in the human oral cavity. This trigeminal stimulus activates TRPV1 receptors and stimulates an influx of cations into sensory cells. TRPV1 receptors function as homotetramers that also respond to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Kinase-mediated phosphorylation of TRPV1 leads to increased sensitivity to both chemical and thermal stimuli. In contrast, desensitization occurs via a calcium-dependent mechanism that results in receptor dephosphorylation. Human psychophysical studies have shown that capsaicin is detected at nanomole amounts and causes desensitization in the oral cavity. Psychophysical studies further indicate that desensitization can be temporarily reversed in the oral cavity if stimulation with capsaicin is resumed at short interstimulus intervals. Pretreatment of lingual epithelium with capsaicin modulates the perception of several primary taste qualities. Also, sweet taste stimuli may decrease the intensity of capsaicin perception in the oral cavity. In addition, capsaicin perception and hedonic responses may be modified by diet. Psychophysical studies with capsaicin are consistent with recent findings that have identified TRPV1 channel modulation by phosphorylation and interactions with membrane inositol phospholipids. Future studies will further clarify the importance of capsaicin and its receptor in human health and nutrition.

Increased transient receptor potential vanilloid type 1 (TRPV1) channel expression in hypertrophic heart

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Thilo, Florian; Liu, Ying; Schulz, Nico

2010-01-01

The aim of this study was to compare the expression of transient receptor potential vanilloid type 1 (TRPV1) channels in hypertrophic hearts from transgenic mice showing overexpression of the catalytic subunit alpha of protein phosphatase 2A alpha (PP2Ac alpha) with wild-type mice and with TRPV1-...... alpha transgenic mice compared to wild-type mice and TRPV1-/- mice (8.6±1.3mg/g; 5.4±0.3mg/g; and 5.4±0.4mg/g; respectively; p...

Acidification of rat TRPV1 alters the kinetics of capsaicin responses

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Faltynek Connie R

2005-09-01

Full Text Available Abstract TRPV1 (vanilloid receptor 1 receptors are activated by a variety of ligands such as capsaicin, as well as by acidic conditions and temperatures above 42°C. These activators can enhance the potency of one another, shifting the activation curve for TRPV1 to the left. In this study, for example, we observed an approximately 10-fold shift in the capsaicin EC50 (640 nM to 45 nM for rat TRPV1 receptors expressed in HEK-293 cells when the pH was lowered from 7.4 to 5.5. To investigate potential causes for this shift in capsaicin potency, the rates of current activation and deactivation of whole-cell currents were measured in individual cells exposed to treatments of pH 5.5, 1 μM capsaicin or in combination. Acidic pH was found to both increase the activation rate and decrease the deactivation rate of capsaicin-activated currents providing a possible mechanism for the enhanced potency of capsaicin under acidic conditions. Utilizing a paired-pulse protocol, acidic pH slowed the capsaicin deactivation rate and was readily reversible. Moreover, the effect could occur under modestly acidic conditions (pH 6.5 that did not directly activate TRPV1. When TRPV1 was maximally activated by capsaicin and acidic pH, the apparent affinity of the novel and selective capsaicin-site competitive TRPV1 antagonist, A-425619, was reduced ~35 fold. This shift was overcome by reducing the capsaicin concentration co-applied with acidic pH. Since inflammation is associated with tissue acidosis, these findings enhance understanding of TRPV1 receptor responses in inflammatory pain where tissue acidosis is prevalent.

TRPV6 channels.

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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

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses.

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Kang, So Min; Han, Sangbum; Oh, Jang-Hee; Lee, Young Mee; Park, Chi-Hyun; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

2017-10-01

Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr 705 , and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging. Copyright © 2017 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.

Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis

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Ma, Liqun; Zhong, Jian; Zhao, Zhigang

2011-01-01

Activation of transient receptor potential vanilloid type-1 (TRPV1) channels may affect lipid storage and the cellular inflammatory response. Now, we tested the hypothesis that activation of TRPV1 channels attenuates atherosclerosis in apolipoprotein E knockout mice (ApoE(-/-)) but not Apo...

Structural insights into transient receptor potential vanilloid type 1 (TRPV1) from homology modeling, flexible docking, and mutational studies.

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Lee, Jin Hee; Lee, Yoonji; Ryu, HyungChul; Kang, Dong Wook; Lee, Jeewoo; Lazar, Jozsef; Pearce, Larry V; Pavlyukovets, Vladimir A; Blumberg, Peter M; Choi, Sun

2011-04-01

The transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel composed of four monomers with six transmembrane helices (TM1-TM6). TRPV1 is found in the central and peripheral nervous system, and it is an important therapeutic target for pain relief. We describe here the construction of a tetrameric homology model of rat TRPV1 (rTRPV1). We experimentally evaluated by mutational analysis the contribution of residues of rTRPV1 contributing to ligand binding by the prototypical TRPV1 agonists, capsaicin and resiniferatoxin (RTX). We then performed docking analysis using our homology model. The docking results with capsaicin and RTX showed that our homology model was reliable, affording good agreement with our mutation data. Additionally, the binding mode of a simplified RTX (sRTX) ligand as predicted by the modeling agreed well with those of capsaicin and RTX, accounting for the high binding affinity of the sRTX ligand for TRPV1. Through the homology modeling, docking and mutational studies, we obtained important insights into the ligand-receptor interactions at the molecular level which should prove of value in the design of novel TRPV1 ligands.

TRPV1 Channels and Gastric Vagal Afferent Signalling in Lean and High Fat Diet Induced Obese Mice.

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Stephen J Kentish

Full Text Available Within the gastrointestinal tract vagal afferents play a role in control of food intake and satiety signalling. Activation of mechanosensitive gastric vagal afferents induces satiety. However, gastric vagal afferent responses to mechanical stretch are reduced in high fat diet mice. Transient receptor potential vanilloid 1 channels (TRPV1 are expressed in vagal afferents and knockout of TRPV1 reduces gastro-oesophageal vagal afferent responses to stretch. We aimed to determine the role of TRPV1 on gastric vagal afferent mechanosensitivity and food intake in lean and HFD-induced obese mice.TRPV1+/+ and -/- mice were fed either a standard laboratory diet or high fat diet for 20wks. Gastric emptying of a solid meal and gastric vagal afferent mechanosensitivity was determined.Gastric emptying was delayed in high fat diet mice but there was no difference between TRPV1+/+ and -/- mice on either diet. TRPV1 mRNA expression in whole nodose ganglia of TRPV1+/+ mice was similar in both dietary groups. The TRPV1 agonist N-oleoyldopamine potentiated the response of tension receptors in standard laboratory diet but not high fat diet mice. Food intake was greater in the standard laboratory diet TRPV1-/- compared to TRPV1+/+ mice. This was associated with reduced response of tension receptors to stretch in standard laboratory diet TRPV1-/- mice. Tension receptor responses to stretch were decreased in high fat diet compared to standard laboratory diet TRPV1+/+ mice; an effect not observed in TRPV1-/- mice. Disruption of TRPV1 had no effect on the response of mucosal receptors to mucosal stroking in mice on either diet.TRPV1 channels selectively modulate gastric vagal afferent tension receptor mechanosensitivity and may mediate the reduction in gastric vagal afferent mechanosensitivity in high fat diet-induced obesity.

Protease-activated receptor-2 activation exaggerates TRPV1-mediated cough in guinea pigs.

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Gatti, Raffaele; Andre, Eunice; Amadesi, Silvia; Dinh, Thai Q; Fischer, Axel; Bunnett, Nigel W; Harrison, Selena; Geppetti, Pierangelo; Trevisani, Marcello

2006-08-01

A lowered threshold to the cough response frequently accompanies chronic airway inflammatory conditions. However, the mechanism(s) that from chronic inflammation results in a lowered cough threshold is poorly understood. Irritant agents, including capsaicin, resiniferatoxin, and citric acid, elicit cough in humans and in experimental animals through the activation of the transient receptor potential vanilloid 1 (TRPV1). Protease-activated receptor-2 (PAR2) activation plays a role in inflammation and sensitizes TRPV1 in cultured sensory neurons by a PKC-dependent pathway. Here, we have investigated whether PAR2 activation exaggerates TRPV1-dependent cough in guinea pigs and whether protein kinases are involved in the PAR2-induced cough modulation. Aerosolized PAR2 agonists (PAR2-activating peptide and trypsin) did not produce any cough per se. However, they potentiated citric acid- and resiniferatoxin-induced cough, an effect that was completely prevented by the TRPV1 receptor antagonist capsazepine. In contrast, cough induced by hypertonic saline, a stimulus that provokes cough in a TRPV1-independent manner, was not modified by aerosolized PAR2 agonists. The PKC inhibitor GF-109203X, the PKA inhibitor H-89, and the cyclooxygenase inhibitor indomethacin did not affect cough induced by TRPV1 agonists, but abated the exaggeration of this response produced by PAR2 agonists. In conclusion, PAR2 stimulation exaggerates TRPV1-dependent cough by activation of diverse mechanism(s), including PKC, PKA, and prostanoid release. PAR2 activation, by sensitizing TRPV1 in primary sensory neurons, may play a role in the exaggerated cough observed in certain airways inflammatory diseases such as asthma and chronic obstructive pulmonary disease.

Event-Triggered Asynchronous Guaranteed Cost Control for Markov Jump Discrete-Time Neural Networks With Distributed Delay and Channel Fading.

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Yan, Huaicheng; Zhang, Hao; Yang, Fuwen; Zhan, Xisheng; Peng, Chen

2017-08-18

This paper is concerned with the guaranteed cost control problem for a class of Markov jump discrete-time neural networks (NNs) with event-triggered mechanism, asynchronous jumping, and fading channels. The Markov jump NNs are introduced to be close to reality, where the modes of the NNs and guaranteed cost controller are determined by two mutually independent Markov chains. The asynchronous phenomenon is considered, which increases the difficulty of designing required mode-dependent controller. The event-triggered mechanism is designed by comparing the relative measurement error with the last triggered state at the process of data transmission, which is used to eliminate dispensable transmission and reduce the networked energy consumption. In addition, the signal fading is considered for the effect of signal reflection and shadow in wireless networks, which is modeled by the novel Rice fading models. Some novel sufficient conditions are obtained to guarantee that the closed-loop system reaches a specified cost value under the designed jumping state feedback control law in terms of linear matrix inequalities. Finally, some simulation results are provided to illustrate the effectiveness of the proposed method.

Involvement of TRPV1 channels in the periaqueductal grey on the modulation of innate fear responses.

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Aguiar, Daniele C; Almeida-Santos, Ana F; Moreira, Fabricio A; Guimarães, Francisco S

2015-04-01

The transient receptor potential vanilloid type-1 channel (TRPV1) is expressed in the midbrain periaqueductal grey (PAG), a region of the brain related to aversive responses. TRPV1 antagonism in the dorsolateral PAG (dlPAG) induces anxiolytic-like effects in models based on conflict situations. No study, however, has investigated whether these receptors could contribute to fear responses to proximal threat. Thus, we tested the hypothesis that TRPV1 in the PAG could mediate fear response in rats exposed to a predator. We verified whether exposure to a live cat (a natural predator) would activate TRPV1-expressing neurons in the PAG. Double-staining immunohistochemistry was used as a technique to detect c-Fos, a marker of neuronal activation, and TRPV1 expression. We also investigated whether intra-dlPAG injections of the TRPV1 antagonist, capsazepine (CPZ), would attenuate the behavioural consequences of predator exposure. Exposure to a cat increased c-Fos expression in TRPV1-positive neurons, mainly in the dorsal columns of the PAG, suggesting that TRPV1-expressing neurons are activated by threatening stimuli. Accordingly, local injection of CPZ inhibited the fear responses. These data support the hypothesis that TRPV1 channels mediate fear reactions in the dlPAG. This may have an implication for the development of TRPV1-antagonists as potential drugs for the treatment of certain psychiatric disorders.

A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

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Miyanohara, Jun [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Shirakawa, Hisashi, E-mail: shirakaw@pharm.kyoto-u.ac.jp [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Sanpei, Kazuaki [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Nakagawa, Takayuki [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital (Japan); Kaneko, Shuji [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan)

2015-11-20

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.

A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

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Miyanohara, Jun; Shirakawa, Hisashi; Sanpei, Kazuaki; Nakagawa, Takayuki; Kaneko, Shuji

2015-01-01

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca"2"+ permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.

TRPV1 expression on peritoneal endometriosis foci is associated with chronic pelvic pain.

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Rocha, Marcelo Gondim; e Silva, Júlio César Rosa; Ribeiro da Silva, Alfredo; Candido Dos Reis, Francisco José; Nogueira, Antonio Alberto; Poli-Neto, Omero Benedicto

2011-06-01

To investigate the expression of capsaicin receptor (transient receptor potential vanilloid type 1 [TRPV1]) in the peritoneal endometriosis foci of women with and without chronic pelvic pain (CPP). A case-control study was conducted on 49 women with endometriosis who underwent laparoscopy, 28 of whom had CPP and 21 without CPP. Samples from peritoneum of the rectouterine excavation (2 cm2) were obtained by laparoscopy, fixed in 4% formaldehyde, and underwent immunohistochemistry analysis using rabbit anti-TRPV1 (1:400) polyclonal antibody. Image analysis revealed that the immunoreactivity for TRPV1 was more frequent in specimens (endometriosis foci) from women with CPP (n = 15 of 28, 53.6%), compared to samples from the endometriosis foci of women without CPP (n = 6 of 21, 28.6%; P = .04). There was no correlation with duration, intensity of pain, or stage of the disease (endometriosis). The present study shows that TRPV1 expression in peritoneal endometriosis foci is related to CPP in women. However, this association is not related to the endometriosis stage. In view of the immunoreactivity for TRPV1 observed here, we believe that some endometriotic lesions may provide a scenario for TRPV1 to be tonically active and this activity may contribute to the underlying pathology of CPP.

TRPV1 inhibition attenuates IL-13 mediated asthma features in mice by reducing airway epithelial injury.

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Rehman, Rakhshinda; Bhat, Younus Ahmad; Panda, Lipsa; Mabalirajan, Ulaganathan

2013-03-01

Even though neurogenic axis is well known in asthma pathogenesis much attention had not been given on this aspect. Recent studies have reported the importance of TRP channels, calcium-permeable ion channels and key molecules in neurogenic axis, in asthma therapeutics. The role of TRPV1 channels has been underestimated in chronic respiratory diseases as TRPV1 knockout mice of C57BL/6 strains did not attenuate the features of these diseases. However, this could be due to strain differences in the distribution of airway capsaicin receptors. Here, we show that TRPV1 inhibition attenuates IL-13 induced asthma features by reducing airway epithelial injury in BALB/c mice. We found that IL-13 increased not only the lung TRPV1 levels but also TRPV1 expression in bronchial epithelia in BALB/c rather than in C57BL/6 mice. TRPV1 knockdown attenuated airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and subepithelial fibrosis induced by IL-13 in BALB/c mice. Further, TRPV1 siRNA treatment reduced not only the cytosolic calpain and mitochondrial calpain 10 activities in the lung but also bronchial epithelial apoptosis indicating that TRPV1 siRNA might have corrected the intracellular and intramitochondrial calcium overload and its consequent apoptosis. Knockdown of IL-13 in allergen induced asthmatic mice reduced TRPV1, cytochrome c, and activities of calpain and caspase 3 in lung cytosol. Thus, these findings suggest that induction of TRPV1 with IL-13 in bronchial epithelia could lead to epithelial injury in in vivo condition. Since TRPV1 expression is correlated with human asthma severity, TRPV1 inhibition could be beneficial in attenuating airway epithelial injury and asthma features. Copyright © 2013 Elsevier B.V. All rights reserved.

Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake.

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Jae Hoon Jeong

2018-04-01

Full Text Available Proopiomelanocortin (POMC neurons in the arcuate nucleus of the hypothalamus (ARC respond to numerous hormonal and neural signals, resulting in changes in food intake. Here, we demonstrate that ARC POMC neurons express capsaicin-sensitive transient receptor potential vanilloid 1 receptor (TRPV1-like receptors. To show expression of TRPV1-like receptors in ARC POMC neurons, we use single-cell reverse transcription-polymerase chain reaction (RT-PCR, immunohistochemistry, electrophysiology, TRPV1 knock-out (KO, and TRPV1-Cre knock-in mice. A small elevation of temperature in the physiological range is enough to depolarize ARC POMC neurons. This depolarization is blocked by the TRPV1 receptor antagonist and by Trpv1 gene knockdown. Capsaicin-induced activation reduces food intake that is abolished by a melanocortin receptor antagonist. To selectively stimulate TRPV1-like receptor-expressing ARC POMC neurons in the ARC, we generate an adeno-associated virus serotype 5 (AAV5 carrying a Cre-dependent channelrhodopsin-2 (ChR2-enhanced yellow fluorescent protein (eYFP expression cassette under the control of the two neuronal POMC enhancers (nPEs. Optogenetic stimulation of TRPV1-like receptor-expressing POMC neurons decreases food intake. Hypothalamic temperature is rapidly elevated and reaches to approximately 39 °C during treadmill running. This elevation is associated with a reduction in food intake. Knockdown of the Trpv1 gene exclusively in ARC POMC neurons blocks the feeding inhibition produced by increased hypothalamic temperature. Taken together, our findings identify a melanocortinergic circuit that links acute elevations in hypothalamic temperature with acute reductions in food intake.

Molecular Docking Analysis of Ginger Active Compound on Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1

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Fifteen Aprila Fajrin

2018-02-01

Full Text Available Ginger had been reported to ameliorate painful diabetic neuropathy (PDN in an animal model. Gingerol and shogaol were active compounds of ginger that potentially act on transient receptor potential cation channel subfamily V member 1 (TRPV1, a key receptor in PDN. This study aims to predict the binding of gingerol and shogaol to TRPV1 using an in silico model. The ligands of the docking study were 3 chemical compounds of each gingerol and shogaol, i.e. 6-shogaol, 8-shogaol, 10-shogaol, 6-gingerol, 8 gingerol and 10-gingerol. Capsaicin, a TRPV1 agonist, was used as a native ligand. The TRPV1 structure was taken from Protein Data Bank (ID 3J9J. The docking analysis was performed using Autodock Vina. The result showed that among the ginger active compounds, 6-shogaol had the strongest binding energy (-7.10 kcal/mol to TRPV1. The 6-shogaol lacked the potential hydrogen bond to Ile265 of TRPV1 protein, which capsacin had. However, it's binding energy towards TRPV1 was not significantly different compared to capsaicin. Therefore, 6-shogaol had potential to be developed as a treatment for PDN.

Tris-hydroxymethyl-aminomethane enhances capsaicin-induced intracellular Ca2+ influx through transient receptor potential V1 (TRPV1 channels

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Satoshi Murakami

2016-02-01

Full Text Available Non-selective transient receptor potential vanilloid (TRPV cation channels are activated by various insults, including exposure to heat, acidity, and the compound capsaicin, resulting in sensations of pain in the skin, visceral organs, and oral cavity. Recently, TRPV1 activation was also demonstrated in response to basic pH elicited by ammonia and intracellular alkalization. Tris-hydroxymethyl aminomethane (THAM is widely used as an alkalizing agent; however, the effects of THAM on TRPV1 channels have not been defined. In this study, we characterized the effects of THAM-induced TRPV1 channel activation in baby hamster kidney cells expressing human TRPV1 (hTRPV1 and the Ca2+-sensitive fluorescent sensor GCaMP2 by real-time confocal microscopy. Notably, both capsaicin (1 μM and pH 6.5 buffer elicited steep increases in the intracellular Ca2+ concentration ([Ca2+]i, while treatment with THAM (pH 8.5 alone had no effect. However, treatment with THAM (pH 8.5 following capsaicin application elicited a profound, long-lasting increase in [Ca2+]i that was completely inhibited by the TRPV1 antagonist capsazepine. Taken together, these results suggest that hTRPV1 pre-activation is required to provoke enhanced, THAM-induced [Ca2+]i increases, which could be a mechanism underlying pain induced by basic pH.

TRPV1 channels in human skeletal muscle feed arteries: implications for vascular function.

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Ives, Stephen J; Park, Song Young; Kwon, Oh Sung; Gifford, Jayson R; Andtbacka, Robert H I; Hyngstrom, John R; Richardson, Russell S

2017-09-01

What is the central question of this study? We sought to determine whether human skeletal muscle feed arteries (SFMAs) express TRPV 1 channels and what role they play in modulating vascular function. What is the main finding and its importance? Human SMFAs do express functional TRPV 1 channels that modulate vascular function, specifically opposing α-adrenergic receptor-mediated vasocontraction and potentiating vasorelaxation, in an endothelium-dependent manner, as evidenced by the α 1 -receptor-mediated responses. Thus, the vasodilatory role of TRPV 1 channels, and their ligand capsaicin, could be a potential therapeutic target for improving vascular function. Additionally, given the 'sympatholytic' effect of TRPV 1 activation and known endogenous activators (anandamide, reactive oxygen species, H + , etc.), TRPV 1 channels might contribute to functional sympatholysis during exercise. To examine the role of the transient receptor potential vanilloid type 1 (TRPV 1 ) ion channel in the vascular function of human skeletal muscle feed arteries (SMFAs) and whether activation of this heat-sensitive receptor could be involved in modulating vascular function, SMFAs from 16 humans (63 ± 5 years old, range 41-89 years) were studied using wire myography with capsaicin (TRPV 1 agonist) and without (control). Specifically, phenylephrine (α 1 -adrenergic receptor agonist), dexmedetomidine (α 2 -adrenergic receptor agonist), ACh and sodium nitroprusside concentration-response curves were established to assess the role of TRPV 1 channels in α-receptor-mediated vasocontraction as well as endothelium-dependent and -independent vasorelaxation, respectively. Compared with control conditions, capsaicin significantly attenuated maximal vasocontraction in response to phenylephrine [control, 52 ± 8% length-tension max (LT max ) and capsaicin, 21 ± 5%LT max ] and dexmedetomidine (control, 29 ± 12%LT max and capsaicin, 2 ± 3%LT max ), while robustly enhancing maximal

Topographical organization of TRPV1-immunoreactive epithelium and CGRP-immunoreactive nerve terminals in rodent tongue

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M. Kawashima

2012-05-01

Full Text Available Transient receptor potential vanilloid subfamily member 1 (TRPV1 is activated by capsaicin, acid, and heat and mediates pain through peripheral nerves. In the tongue, TRPV1 expression has been reported also in the epithelium. This indicates a possibility that sensation is first received by the epithelium. However, how nerves receive sensations from the epithelium remains unclear. To clarify the anatomical basis of this interaction, we performed immunohistochemical studies in the rodent tongue to detect TRPV1 and calcitonin gene-related peptide (CGRP, a neural marker. Strong expression of TRPV1 in the epithelium was observed and was restricted to the apex of the tongue. Double immunohistochemical staining revealed that CGRP-expressing nerve terminals were in close apposition to the strongly TRPV1-expressing epithelium of fungiform papilla in the apex of rodent tongues. These results suggest that the TRPV1-expressing epithelium monitors the oral environment and acquired information may then be conducted to the adjacent CGRPexpressing terminals.

Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

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Lebovitz Evan E

2012-09-01

Full Text Available Abstract Background The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. Results Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing

TRPV1 deletion exacerbates hyperthermic seizures in an age-dependent manner in mice.

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Barrett, Karlene T; Wilson, Richard J A; Scantlebury, Morris H

2016-12-01

Febrile seizures (FS) are the most common seizure disorder to affect children. Although there is mounting evidence to support that FS occur when children have fever-induced hyperventilation leading to respiratory alkalosis, the underlying mechanisms of hyperthermia-induced hyperventilation and links to FS remain poorly understood. As transient receptor potential vanilloid-1 (TRPV1) receptors are heat-sensitive, play an important role in adult thermoregulation and modulate respiratory chemoreceptors, we hypothesize that TRPV1 activation is important for hyperthermia-induced hyperventilation leading to respiratory alkalosis and decreased FS thresholds, and consequently, TRPV1 KO mice will be relatively protected from hyperthermic seizures. To test our hypothesis we subjected postnatal (P) day 8-20 TRPV1 KO and C57BL/6 control mice to heated dry air. Seizure threshold temperature, latency and the rate of rise of body temperature during hyperthermia were assessed. At ages where differences in seizure thresholds were identified, head-out plethysmography was used to assess breathing and the rate of expired CO 2 in response to hyperthermia, to determine if the changes in seizure thresholds were related to respiratory alkalosis. Paradoxically, we observed a pro-convulsant effect of TRPV1 deletion (∼4min decrease in seizure latency), and increased ventilation in response to hyperthermia in TRPV1 KO compared to control mice at P20. This pro-convulsant effect of TRPV1 absence was not associated with an increased rate of expired CO 2 , however, these mice had a more rapid rise in body temperature following exposure to hyperthermia than controls, and the expected linear relationship between body weight and seizure latency was absent. Based on these findings, we conclude that deletion of the TRPV1 receptor prevents reduction in hyperthermic seizure susceptibility in older mouse pups, via a mechanism that is independent of hyperthermia-induced respiratory alkalosis, but

Differential regulation of TRPV1 channels by H2O2: implications for diabetic microvascular dysfunction

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DelloStritto, Daniel J.; Connell, Patrick J.; Dick, Gregory M.; Fancher, Ibra S.; Klarich, Brittany; Fahmy, Joseph N.; Kang, Patrick T.; Chen, Yeong-Renn; Damron, Derek S.; Thodeti, Charles K.

2016-01-01

We demonstrated previously that TRPV1-dependent coupling of coronary blood flow (CBF) to metabolism is disrupted in diabetes. A critical amount of H2O2 contributes to CBF regulation; however, excessive H2O2 impairs responses. We sought to determine the extent to which differential regulation of TRPV1 by H2O2 modulates CBF and vascular reactivity in diabetes. We used contrast echocardiography to study TRPV1 knockout (V1KO), db/db diabetic, and wild type C57BKS/J (WT) mice. H2O2 dose-dependently increased CBF in WT mice, a response blocked by the TRPV1 antagonist SB366791. H2O2-induced vasodilation was significantly inhibited in db/db and V1KO mice. H2O2 caused robust SB366791-sensitive dilation in WT coronary microvessels; however, this response was attenuated in vessels from db/db and V1KO mice, suggesting H2O2-induced vasodilation occurs, in part, via TRPV1. Acute H2O2 exposure potentiated capsaicin-induced CBF responses and capsaicin-mediated vasodilation in WT mice, whereas prolonged luminal H2O2 exposure blunted capsaicin-induced vasodilation. Electrophysiology studies re-confirms acute H2O2 exposure activated TRPV1 in HEK293A and bovine aortic endothelial cells while establishing that H2O2 potentiate capsaicin-activated TRPV1 currents, whereas prolonged H2O2 exposure attenuated TRPV1 currents. Verification of H2O2-mediated activation of intrinsic TRPV1 specific currents were found in isolated mouse coronary endothelial cells from WT mice and decreased in endothelial cells from V1KO mice. These data suggest prolonged H2O2 exposure impairs TRPV1-dependent coronary vascular signaling. This may contribute to microvascular dysfunction and tissue perfusion deficits characteristic of diabetes. PMID:26907473

Distinctive changes in plasma membrane phosphoinositides underlie differential regulation of TRPV1 in nociceptive neurons.

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Lukacs, Viktor; Yudin, Yevgen; Hammond, Gerald R; Sharma, Esseim; Fukami, Kiyoko; Rohacs, Tibor

2013-07-10

Transient Receptor Potential Vanilloid 1 (TRPV1) is a polymodal, Ca(2+)-permeable cation channel crucial to regulation of nociceptor responsiveness. Sensitization of TRPV1 by G-protein coupled receptor (GPCR) agonists to its endogenous activators, such as low pH and noxious heat, is a key factor in hyperalgesia during tissue injury as well as pathological pain syndromes. Conversely, chronic pharmacological activation of TRPV1 by capsaicin leads to calcium influx-induced adaptation of the channel. Paradoxically, both conditions entail activation of phospholipase C (PLC) enzymes, which hydrolyze phosphoinositides. We found that in sensory neurons PLCβ activation by bradykinin led to a moderate decrease in phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), but no sustained change in the levels of its precursor PI(4)P. Preventing this selective decrease in PI(4,5)P2 inhibited TRPV1 sensitization, while selectively decreasing PI(4,5)P2 independently of PLC potentiated the sensitizing effect of protein kinase C (PKC) on the channel, thereby inducing increased TRPV1 responsiveness. Maximal pharmacological TRPV1 stimulation led to a robust decrease of both PI(4,5)P2 and its precursor PI(4)P in sensory neurons. Attenuating the decrease of either lipid significantly reduced desensitization, and simultaneous reduction of PI(4,5)P2 and PI(4)P independently of PLC inhibited TRPV1. We found that, on the mRNA level, the dominant highly Ca(2+)-sensitive PLC isoform in dorsal root ganglia is PLCδ4. Capsaicin-induced desensitization of TRPV1 currents was significantly reduced, whereas capsaicin-induced nerve impulses in the skin-nerve preparation increased in mice lacking this isoform. We propose a comprehensive model in which differential changes in phosphoinositide levels mediated by distinct PLC isoforms result in opposing changes in TRPV1 activity.

Differential effects of temperature on acid-activated currents mediated by TRPV1 and ASIC channels in rat dorsal root ganglion neurons.

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Neelands, Torben R; Zhang, Xu-Feng; McDonald, Heath; Puttfarcken, Pamela

2010-05-06

Elevated temperature and decreased extracellular pH are hallmarks of inflammatory pain states. Dorsal root ganglia (DRG) neurons are integral in transferring painful stimuli from the periphery to central sites. This study investigated the effect of elevated temperatures on the response of DRG neurons to acute application of acidic solutions. At room temperature (22 degrees C), in response to pH 5.5, there were a variety of kinetic responses consistent with differential expression of TRPV1 and ASIC channels. Increasing the temperature resulted in a significant increase in the peak and total current mediated by TRPV1 in response to an acidic solution. In contrast, the amplitude of a fast activating, rapidly inactivating ASIC1-like current was not affected by increasing the temperature but did result in an increased rate of desensitization that reduced the total current level. This effect on the rate of desensitization was temperature-dependent and could be reversed by returning to 22 degrees C. Likewise, cells exhibiting slowly inactivating ASIC2-like responses also had temperature-dependent increase in the rate of desensitization. The ASIC2-like responses and the TRPV1 responses tended to decrease in amplitude with repetitive application of pH 5.5 even at 22 degrees C. The rate of desensitization of ASIC-like currents activated by less acidic solutions (pH 6.8) was also increased in a temperature-dependent manner. Finally, acidic pH reduced threshold to trigger action potentials, however, the pattern of action potential firing was shaped by the distribution of ASIC and TRPV1 channels. These results indicate that the ambient temperature at which acidosis occurs has a profound effect on the contribution of ASIC and TRPV1 channels, therefore, altering the neuronal excitability. Copyright 2010 Elsevier B.V. All rights reserved.

Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain.

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Urano, Hiroko; Ara, Toshiaki; Fujinami, Yoshiaki; Hiraoka, B Yukihiro

2012-01-01

Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model.

Prostanoid-dependent bladder pain caused by proteinase-activated receptor-2 activation in mice: Involvement of TRPV1 and T-type Ca2+ channels

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Maho Tsubota

2018-01-01

Full Text Available We studied the pronociceptive role of proteinase-activated receptor-2 (PAR2 in mouse bladder. In female mice, intravesical infusion of the PAR2-activating peptide, SLIGRL-amide (SL, caused delayed mechanical hypersensitivity in the lower abdomen, namely ‘referred hyperalgesia’, 6–24 h after the administration. The PAR2-triggered referred hyperalgesia was prevented by indomethacin or a selective TRPV1 blocker, and restored by a T-type Ca2+ channel blocker. In human urothelial T24 cells, SL caused delayed prostaglandin E2 production and COX-2 upregulation. Our data suggest that luminal PAR2 stimulation in the bladder causes prostanoid-dependent referred hyperalgesia in mice, which involves the activation of TRPV1 and T-type Ca2+ channels.

TRPV1 and the MCP-1/CCR2 Axis Modulate Post-UTI Chronic Pain.

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Rosen, John M; Yaggie, Ryan E; Woida, Patrick J; Miller, Richard J; Schaeffer, Anthony J; Klumpp, David J

2018-05-08

The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.

TRPV3 in Drug Development

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Lisa M. Broad

2016-09-01

Full Text Available Transient receptor potential vanilloid 3 (TRPV3 is a member of the TRP (Transient Receptor Potential super-family. It is a relatively underexplored member of the thermo-TRP sub-family (Figure 1, however, genetic mutations and use of gene knock-outs and selective pharmacological tools are helping to provide insights into its role and therapeutic potential. TRPV3 is highly expressed in skin, where it is implicated in skin physiology and pathophysiology, thermo-sensing and nociception. Gain of function TRPV3 mutations in rodent and man have enabled the role of TRPV3 in skin health and disease to be particularly well defined. Pre-clinical studies provide some rationale to support development of TRPV3 antagonists for therapeutic application for the treatment of inflammatory skin conditions, itch and pain. However, to date, only one compound directed towards block of the TRPV3 receptor (GRC15300 has progressed into clinical trials. Currently, there are no known clinical trials in progress employing a TRPV3 antagonist.

Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension

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Yang, Dachun; Luo, Zhidan; Ma, Shuangtao

2010-01-01

Some plant-based diets lower the cardiometabolic risks and prevalence of hypertension. New evidence implies a role for the transient receptor potential vanilloid 1 (TRPV1) cation channel in the pathogenesis of cardiometabolic diseases. Little is known about impact of chronic TRPV1 activation...

Role of TRPV1 in acupuncture modulation of reflex excitatory cardiovascular responses.

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Guo, Zhi-Ling; Fu, Liang-Wu; Su, Hou-Fen; Tjen-A-Looi, Stephanie C; Longhurst, John C

2018-05-01

We have shown that acupuncture, including manual and electroacupuncture (MA and EA), at the P5-6 acupoints stimulates afferent fibers in the median nerve (MN) to modulate sympathoexcitatory cardiovascular reflexes through central regulation of autonomic function. However, the mechanisms underlying acupuncture activation of these sensory afferent nerves and their cell bodies in the dorsal root ganglia (DRG) are unclear. Transient receptor potential vanilloid type 1 (TRPV1) is present in sensory nerve fibers distributed in the general region of acupoints like ST36 and BL 40 located in the hindlimb. However, the contribution of TRPV1 to activation of sensory nerves by acupuncture, leading to modulation of pressor responses, has not been studied. We hypothesized that TRPV1 participates in acupuncture's activation of sensory afferents and their associated cell bodies in the DRG to modulate pressor reflexes. Local injection of iodoresiniferatoxin (Iodo-RTX; a selective TRPV1 antagonist), but not 5% DMSO (vehicle), into the P6 acupoint on the forelimb reversed the MA's inhibition of pressor reflexes induced by gastric distension (GD). Conversely, inhibition of GD-induced sympathoexcitatory responses by EA at P5-6 was unchanged after administration of Iodo-RTX into P5-6. Single-unit activity of Group III or IV bimodal afferents sensitive to both mechanical and capsaicin stimuli responded to MA stimulation at P6. MA-evoked activity was attenuated significantly ( P < 0.05) by local administration of Iodo-RTX ( n = 12) but not by 5% DMSO ( n = 12) into the region of the P6 acupoint in rats. Administration of Iodo-RTX into P5-6 did not reduce bimodal afferent activity evoked by EA stimulation ( n = 8). Finally, MA at P6 and EA at P5-6 induced phosphorylation of extracellular signal-regulated kinases (ERK; an intracellular signaling messenger involved in cellular excitation) in DRG neurons located at C 7-8 spinal levels receiving MN inputs. After TRPV1 was knocked down in the

Deletion of vanilloid receptor (TRPV1) in mice alters behavioral effects of ethanol

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Blednov, Y.A.; Harris, R.A.

2009-01-01

The vanilloid receptor TRPV1 is activated by ethanol and this may be important for some of the central and peripheral actions of ethanol. To determine if this receptor has a role in ethanol-mediated behaviors, we studied null mutant mice in which the Trpv1 gene was deleted. Mice lacking this gene showed significantly higher preference for ethanol and consumed more ethanol in a two-bottle choice test as compared with wild type littermates. Null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol (2 g/kg). However, there were no differences between null mutant and wild type mice in severity of ethanol-induced acute withdrawal (4 g/kg) or conditioned taste aversion to ethanol (2.5 g/kg). Two behavioral phenotypes (decreased sensitivity to ethanol-induced sedation and faster recovery from ethanol-induced motor incoordination) seen in null mutant mice were reproduced in wild type mice by injection of a TRPV1 antagonist, capsazepine (10 mg/kg). These two ethanol behaviors were changed in the opposite direction after injection of capsaicin, a selective TRPV1 agonist, in wild type mice. The studies provide the first evidence that TRPV1 is important for specific behavioral actions of ethanol. PMID:19705551

Pellitorine, an extract of Tetradium daniellii, is an antagonist of the ion channel TRPV1.

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Oláh, Zoltán; Rédei, Dóra; Pecze, László; Vizler, Csaba; Jósvay, Katalin; Forgó, Péter; Winter, Zoltán; Dombi, György; Szakonyi, Gerda; Hohmann, Judit

2017-10-15

Transient Receptor Potential Vanilloid 1 (TRPV1) confers noxious heat and inflammatory pain signals in the peripheral nervous system. Clinical trial of resiniferatoxin from Euphorbia species is successfully aimed at TRPV1 in cancer pain management and heading toward new selective painkiller status that further validates this target for drug discovery efforts. Evodia species, used in traditional medicine for hundreds of years, are a recognised source of different TRPV1 agonists, but no antagonist has yet been reported. In a search for painkiller leads, we noted for the first time a TRPV1 antagonist activity in the fresh fruits of Tetradium daniellii (Benn.) T.G. Hartley (syn. Evodia hupehensis Dode). Through a combination of extraction and purification methods with functional TRPV1-specific Ca 2+ uptake assays (bioactivity-guided fractionation/isolation/purification); we isolated a new painkiller candidate that is a distant structural homologue of capsiate exovanilloids and endovanilloids such as anandamide, but a putative competitive inhibitor of the TRPV1. Four additional inactive compounds (N-isobutyl-4,5-epoxy-2E-decadienamide, geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol) were also co-purified with pellitorine. Their structures were established by extensive 1D- and 2D-NMR spectroscopic analysis. 1 H- and 13 C NMR determination of the chemical structure revealed it to be pellitorine, (2E,4E)-N-(2-methylpropyl)deca-2,4-dienamide, which can compete structurally with algesics released in inflammation. In contrast to previous isolates from Evodia species, pellitorine blocked capsaicin-evoked Ca 2+ uptake with an IC 50 of 154 µg/ml (0.69 mM/l). N-Isobutyl-4,5-epoxy-2E-decadienamide and geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol did not affect the TRPV1. This is the first evidence that pellitorine, an aliphatic alkylamide analogue of capsaicin, can serve as an antagonist of the TRPV1 and may inhibit exovanilloid

Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.

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Zoltán Oláh

2007-06-01

Full Text Available Ca(2+-loaded calmodulin normally inhibits multiple Ca(2+-channels upon dangerous elevation of intracellular Ca(2+ and protects cells from Ca(2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca(2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca(2+-uptake via the vanilloid inducible Ca(2+-channel/inflamatory pain receptor 1 (TRPV1, which suggests that calmodulin inhibitors may block pore formation and Ca(2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced (45Ca(2+-uptake at microM concentrations: calmidazolium (broad range > or = trifluoperazine (narrow range chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially. Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca(2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca(2+-uptake in intact TRPV1(+ cells, and suggests an extracellular site of inhibition. TRPV1(+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca(2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca(2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca(2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca(2

Identification of a tetrameric assembly domain in the C terminus of heat-activated TRPV1 channels.

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Zhang, Feng; Liu, Shuang; Yang, Fan; Zheng, Jie; Wang, KeWei

2011-04-29

Transient receptor potential (TRP) channels as cellular sensors are thought to function as tetramers. Yet, the molecular determinants governing channel multimerization remain largely elusive. Here we report the identification of a segment comprising 21 amino acids (residues 752-772 of mouse TRPV1) after the known TRP-like domain in the channel C terminus that functions as a tetrameric assembly domain (TAD). Purified recombinant C-terminal proteins of TRPV1-4, but not the N terminus, mediated the protein-protein interaction in an in vitro pulldown assay. Western blot analysis combined with electrophysiology and calcium imaging demonstrated that TAD exerted a robust dominant-negative effect on wild-type TRPV1. When fused with the membrane-tethered peptide Gap43, the TAD blocked the formation of stable homomultimers. Calcium imaging and current recordings showed that deletion of the TAD in a poreless TRPV1 mutant subunit suppressed its dominant-negative phenotype, confirming the involvement of the TAD in assembly of functional channels. Our findings suggest that the C-terminal TAD in TRPV1 channels functions as a domain that is conserved among TRPV1-4 and mediates a direct subunit-subunit interaction for tetrameric assembly.

Expression of TRPV1 channels after nerve injury provides an essential delivery tool for neuropathic pain attenuation.

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Hossain Md Zakir

Full Text Available Increased expression of the transient receptor potential vanilloid 1 (TRPV1 channels, following nerve injury, may facilitate the entry of QX-314 into nociceptive neurons in order to achieve effective and selective pain relief. In this study we hypothesized that the level of QX-314/capsaicin (QX-CAP--induced blockade of nocifensive behavior could be used as an indirect in-vivo measurement of functional expression of TRPV1 channels. We used the QX-CAP combination to monitor the functional expression of TRPV1 in regenerated neurons after inferior alveolar nerve (IAN transection in rats. We evaluated the effect of this combination on pain threshold at different time points after IAN transection by analyzing the escape thresholds to mechanical stimulation of lateral mental skin. At 2 weeks after IAN transection, there was no QX-CAP mediated block of mechanical hyperalgesia, implying that there was no functional expression of TRPV1 channels. These results were confirmed immunohistochemically by staining of regenerated trigeminal ganglion (TG neurons. This suggests that TRPV1 channel expression is an essential necessity for the QX-CAP mediated blockade. Furthermore, we show that 3 and 4 weeks after IAN transection, application of QX-CAP produced a gradual increase in escape threshold, which paralleled the increased levels of TRPV1 channels that were detected in regenerated TG neurons. Immunohistochemical analysis also revealed that non-myelinated neurons regenerated slowly compared to myelinated neurons following IAN transection. We also show that TRPV1 expression shifted towards myelinated neurons. Our findings suggest that nerve injury modulates the TRPV1 expression pattern in regenerated neurons and that the effectiveness of QX-CAP induced blockade depends on the availability of functional TRPV1 receptors in regenerated neurons. The results of this study also suggest that the QX-CAP based approach can be used as a new behavioral tool to detect

TRPV5 and TRPV6 in transcellular Ca(2+) transport: regulation, gene duplication, and polymorphisms in African populations.

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Peng, Ji-Bin

2011-01-01

TRPV5 and TRPV6 are unique members of the TRP super family. They are highly selective for Ca(2+) ions with multiple layers of Ca(2+)-dependent inactivation mechanisms, expressed at the apical membrane of Ca(2+) transporting epithelia, and robustly responsive to 1,25-dihydroxivitamin D(3). These features are well suited for their roles as Ca(2+) entry channels in the first step of transcellular Ca(2+) transport pathways, which are involved in intestinal absorption, renal reabsorption of Ca(2+), placental transfer of Ca(2+) to fetus, and many other processes. While TRPV6 is more broadly expressed in a variety of tissues such as esophagus, stomach, small intestine, colon, kidney, placenta, pancreas, prostate, uterus, salivary gland, and sweat gland, TRPV5 expression is relatively restricted to the distal convoluted tubule and connecting tubule of the kidney. There is only one TRPV6-like gene in fish and birds in comparison to both TRPV5 and TRPV6 genes in mammals, indicating TRPV5 gene was likely generated from duplication of TRPV6 gene during the evolution of mammals to meet the needs of complex renal function. TRPV5 and TRPV6 are subjected to vigorous regulations under physiological, pathological, and therapeutic conditions. The elevated TRPV6 level in malignant tumors such as prostate and breast cancers makes it a potential therapeutic target. TRPV6, and to a lesser extent TRPV5, exhibit unusually high levels of single nucleotide polymorphisms (SNPs) in African populations as compared to other populations, indicating TRPV6 gene was under selective pressure during or after humans migrated out of Africa. The SNPs of TRPV6 and TRPV5 likely contribute to the Ca(2+) conservation mechanisms in African populations.

Involvement of TRPV1 and AQP2 in hypertonic stress by xylitol in odontoblast cells.

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Tokuda, M; Fujisawa, M; Miyashita, K; Kawakami, Y; Morimoto-Yamashita, Y; Torii, M

2015-02-01

To examine the responses of mouse odontoblast-lineage cell line (OLC) cultures to xylitol-induced hypertonic stress. OLCs were treated with xylitol, sucrose, sorbitol, mannitol, arabinose and lyxose. Cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay. The expression of transient receptor potential vanilloids (TRPV) 1, 3 and 4 was detected using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. The expression of aquaporin (AQP) 2 was detected using immunofluorescence and Western blotting analysis. The expression of interleukin-6 (IL-6) under xylitol-induced hypertonic stress was assessed using an enzyme-linked immunosorbent assay (ELISA). Small interfering ribonucleic acid (siRNA) for AQP-2 was used to inhibition assay. Xylitol-induced hypertonic stress did not decrease OLC viability, unlike the other sugars tested. OLCs expressed TRPV1, 3 and 4 as well as AQP2. Xylitol inhibited lipopolysaccharide (LPS)-induced IL-6 expression after 3 h of hypertonic stress. TRPV1 mRNA expression was upregulated by xylitol. Costimulation with HgCl2 (AQP inhibitor) and Ruthenium red (TRPV1 inhibitor) decreased cell viability with xylitol stimulation. OLCs treated with siRNA against TRPV1 exhibited decreased cell viability with xylitol stimulation. OLCs have high-cell viability under xylitol-induced hypertonic stress, which may be associated with TRPV1 and AQP2 expressions.

The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1.

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Bertin, Samuel; Aoki-Nonaka, Yukari; Lee, Jihyung; de Jong, Petrus R; Kim, Peter; Han, Tiffany; Yu, Timothy; To, Keith; Takahashi, Naoki; Boland, Brigid S; Chang, John T; Ho, Samuel B; Herdman, Scott; Corr, Maripat; Franco, Alessandra; Sharma, Sonia; Dong, Hui; Akopian, Armen N; Raz, Eyal

2017-09-01

Transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-1 (TRPV1) are calcium (Ca 2+ )-permeable ion channels mostly known as pain receptors in sensory neurons. However, growing evidence suggests their crucial involvement in the pathogenesis of IBD. We explored the possible contribution of TRPA1 and TRPV1 to T-cell-mediated colitis. We evaluated the role of Trpa1 gene deletion in two models of experimental colitis (ie, interleukin-10 knockout and T-cell-adoptive transfer models). We performed electrophysiological and Ca 2+ imaging studies to analyse TRPA1 and TRPV1 functions in CD4+ T cells. We used genetic and pharmacological approaches to evaluate TRPV1 contribution to the phenotype of Trpa1 -/- CD4+ T cells. We also analysed TRPA1 and TRPV1 gene expression and TRPA1 + TRPV1 + T cell infiltration in colonic biopsies from patients with IBD. We identified a protective role for TRPA1 in T-cell-mediated colitis. We demonstrated the functional expression of TRPA1 on the plasma membrane of CD4+ T cells and identified that Trpa1 -/- CD4+ T cells have increased T-cell receptor-induced Ca 2+ influx, activation profile and differentiation into Th1-effector cells. This phenotype was abrogated upon genetic deletion or pharmacological inhibition of the TRPV1 channel in mouse and human CD4+ T cells. Finally, we found differential regulation of TRPA1 and TRPV1 gene expression as well as increased infiltration of TRPA1 + TRPV1 + T cells in the colon of patients with IBD. Our study indicates that TRPA1 inhibits TRPV1 channel activity in CD4+ T cells, and consequently restrains CD4+ T-cell activation and colitogenic responses. These findings may therefore have therapeutic implications for human IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Cold stress-induced brain injury regulates TRPV1 channels and the PI3K/AKT signaling pathway.

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Liu, Ying; Liu, Yunen; Jin, Hongxu; Cong, Peifang; Zhang, Yubiao; Tong, Changci; Shi, Xiuyun; Liu, Xuelei; Tong, Zhou; Shi, Lin; Hou, Mingxiao

2017-09-01

Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that interacts with several intracellular proteins in vivo, including calmodulin and Phosphatidylinositol-3-Kinase/Protein Kinase B (PI3K/Akt). TRPV1 activation has been reported to exert neuroprotective effects. The aim of this study was to examine the impact of cold stress on the mouse brain and the underlying mechanisms of TRPV1 involvement. Adult male C57BL/6 mice were subjected to cold stress (4°C for 8h per day for 2weeks). The behavioral deficits of the mice were then measured using the Morris water maze. Expression levels of brain injury-related proteins and mRNA were measured by western blot, immunofluorescence or RT-PCR analysis. The mice displayed behavioral deficits, inflammation and changes in brain injury markers following cold stress. As expected, upregulated TRPV1 expression levels and changes in PI3K/Akt expression were found. The TRPV1 inhibitor reduced the levels of brain injury-related proteins and inflammation. These data suggest that cold stress can induce brain injury, possibly through TRPV1 activation and the PI3K/Akt signaling pathway. Suppression of inflammation by inhibition of TRPV1 and the PI3K/Akt pathway may be helpful to prevent cold stress-induced brain injury. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol.

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Venkatesh L Hegde

2011-04-01

Full Text Available Myeloid-derived suppressor cells (MDSCs are getting increased attention as one of the main regulatory cells of the immune system. They are induced at sites of inflammation and can potently suppress T cell functions. In the current study, we demonstrate how activation of TRPV1 vanilloid receptors can trigger MDSCs, which in turn, can inhibit inflammation and hepatitis.Polyclonal activation of T cells, following injection of concanavalin A (ConA, in C57BL/6 mice caused acute hepatitis, characterized by significant increase in aspartate transaminase (AST, induction of inflammatory cytokines, and infiltration of mononuclear cells in the liver, leading to severe liver injury. Administration of cannabidiol (CBD, a natural non-psychoactive cannabinoid, after ConA challenge, inhibited hepatitis in a dose-dependent manner, along with all of the associated inflammation markers. Phenotypic analysis of liver infiltrating cells showed that CBD-mediated suppression of hepatitis was associated with increased induction of arginase-expressing CD11b(+Gr-1(+ MDSCs. Purified CBD-induced MDSCs could effectively suppress T cell proliferation in vitro in arginase-dependent manner. Furthermore, adoptive transfer of purified MDSCs into naïve mice conferred significant protection from ConA-induced hepatitis. CBD failed to induce MDSCs and suppress hepatitis in the livers of vanilloid receptor-deficient mice (TRPV1(-/- thereby suggesting that CBD primarily acted via this receptor to induce MDSCs and suppress hepatitis. While MDSCs induced by CBD in liver consisted of granulocytic and monocytic subsets at a ratio of ∼2∶1, the monocytic MDSCs were more immunosuppressive compared to granulocytic MDSCs. The ability of CBD to induce MDSCs and suppress hepatitis was also demonstrable in Staphylococcal enterotoxin B-induced liver injury.This study demonstrates for the first time that MDSCs play a critical role in attenuating acute inflammation in the liver, and that agents

High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors

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Messlinger Karl

2009-04-01

Full Text Available Abstract Background Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 – 10 mM, two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. Results Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. Conclusion Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.

Noxious heat threshold temperature and pronociceptive effects of allyl isothiocyanate (mustard oil) in TRPV1 or TRPA1 gene-deleted mice.

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Tékus, Valéria; Horváth, Ádám; Hajna, Zsófia; Borbély, Éva; Bölcskei, Kata; Boros, Melinda; Pintér, Erika; Helyes, Zsuzsanna; Pethő, Gábor; Szolcsányi, János

2016-06-01

To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate (AITC)-evoked nociceptive responses by comparing wild-type and gene-deficient mice. In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold. It was revealed that the heat threshold of the tail measured by an increasing-temperature water bath is significantly higher in TRPV1(-/-), but not TRPA1(-/-), mice compared to respective wild-types. There was no difference between the noxious heat thresholds of the hind paw as measured by an increasing-temperature hot plate in TRPV1(-/-), TRPA1(-/-) and the corresponding wild-type mice. The withdrawal latency of the tail from 0°C water was prolonged in TRPA1(-/-), but not TRPV1(-/-), mice compared to respective wild-types. In wild-type animals, dipping the tail or paw into 1% AITC induced an 8-14°C drop of the noxious heat threshold (heat allodynia) of both the tail and paw, and 40-50% drop of the mechanonociceptive threshold (mechanical allodynia) of the paw measured by dynamic plantar esthesiometry. These AITC-evoked responses were diminished in TRPV1(-/-), but not TRPA1(-/-), mice. Tail withdrawal latency to 1% AITC was significantly prolonged in both gene-deleted strains. Different heat sensors determine the noxious heat threshold in distinct areas: a pivotal role for TRPV1 on the tail is contrasted with no involvement of either TRPV1 or TRPA1 on the hind paw. Noxious heat threshold measurement appears appropriate for preclinical screening of TRP channel ligands as novel analgesics. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of TRPV1 and ASIC3 channels in experimental occlusal interference-induced hyperalgesia in rat masseter muscle.

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Xu, X X; Cao, Y; Ding, T T; Fu, K Y; Li, Y; Xie, Q F

2016-04-01

Masticatory muscle pain may occur following immediate occlusal alteration by dental treatment. The underlying mechanisms are poorly understood. Transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channel-3 (ASIC3) mediate muscle hyperalgesia under various pathologic conditions. We have developed a rat model of experimental occlusal interference (EOI) that consistently induces mechanical hyperalgesia in jaw muscles. Whether TRPV1 and ASIC3 mediate this EOI-induced hyperalgesia is unknown. Rat model of EOI-induced masseter hyperalgesia was established. Real-time polymerase chain reaction, Western blot and retrograde labelling combined with immunofluorescence were performed to evaluate the modulation of TRPV1 and ASIC3 expression in trigeminal ganglia (TGs) and masseter afferents of rats after EOI. The effects of intramuscular administration of TRPV1 and ASIC3 antagonists on the EOI-induced hyperalgesia in masseter muscle were examined. After EOI, gene expressions and protein levels of TRPV1 and ASIC3 in bilateral TGs were up-regulated. The percentage of ASIC3- (but not TRPV1-) positive neurons in masseter afferents increased after EOI. More small-sized and small to medium-sized masseter afferents expressed TRPV1 and ASIC3 separately following EOI. These changes peaked at day 7 and then returned to original status within 10 days after EOI. Intramuscular administration of the TRPV1 antagonist AMG-9810 partially reversed this mechanical hyperalgesia in masseter muscle. No improvement was exhibited after administration of the ASIC3 antagonist APETx2. Co-injection of AMG-9810 and APETx2 enhanced the effect of AMG-9810 administration alone. Peripheral TRPV1 and ASIC3 contribute to the development of the EOI-induced mechanical hyperalgesia in masseter muscle. © 2015 European Pain Federation - EFIC®

TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch.

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Jian, Tunyu; Yang, Niuniu; Yang, Yan; Zhu, Chan; Yuan, Xiaolin; Yu, Guang; Wang, Changming; Wang, Zhongli; Shi, Hao; Tang, Min; He, Qian; Lan, Lei; Wu, Guanyi; Tang, Zongxiang

2016-01-01

Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG) neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip)-a histamine H4 receptor special agonist under cutaneous injection-obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3-50 μM) could also induce a dose-dependent increase in intracellular Ca(2+) ([Ca(2+)]i) of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca(2+) responses. In addition, immepip-induced [Ca(2+)]i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons' responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

TRPV1 and PLC Participate in Histamine H4 Receptor-Induced Itch

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Tunyu Jian

2016-01-01

Full Text Available Histamine H4 receptor has been confirmed to play a role in evoking peripheral pruritus. However, the ionic and intracellular signaling mechanism of activation of H4 receptor on the dorsal root ganglion (DRG neurons is still unknown. By using cell culture and calcium imaging, we studied the underlying mechanism of activation of H4 receptor on the DRG neuron. Immepip dihydrobromide (immepip—a histamine H4 receptor special agonist under cutaneous injection—obviously induced itch behavior of mice. Immepip-induced scratching behavior could be blocked by TRPV1 antagonist AMG9810 and PLC pathway inhibitor U73122. Application of immepip (8.3–50 μM could also induce a dose-dependent increase in intracellular Ca2+ (Ca2+i of DRG neurons. We found that 77.8% of the immepip-sensitized DRG neurons respond to the TRPV1 selective agonist capsaicin. U73122 could inhibit immepip-induced Ca2+ responses. In addition, immepip-induced Ca2+i increase could be blocked by ruthenium red, capsazepine, and AMG9810; however it could not be blocked by TRPA1 antagonist HC-030031. These results indicate that TRPV1 but not TRPA1 is the important ion channel to induce the DRG neurons’ responses in the downstream signaling pathway of histamine H4 receptor and suggest that TRPV1 may be involved in the mechanism of histamine-induced itch response by H4 receptor activation.

Effects of Moxibustion Temperature on Blood Cholesterol Level in a Mice Model of Acute Hyperlipidemia: Role of TRPV1

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Gui-Ying Wang

2013-01-01

Full Text Available Objectives. To compare the effects of moxibustion at two different temperatures (38°C and 46°C on the blood cholesterol level in a mice model of acute hyperlipidemia, to detect the different expression levels of transient receptor potential vanilloid subfamily 1 (TRPV1 in the dorsal root ganglions of the wild mice, and to explore the correlation between TRPV1 and moxibustion’s cholesterol-lowering effects. Method. Two different mice models were used: C57BL/6J wild type (WT and TRPV1 gene knockout (TRPV1−/−. Each model was randomly divided into control group and model group with three subgroups after acute hyperlipidemia was established: model control group, 38°C moxibustion group, and 46°C moxibustion group. The mice in 38°C group and 46°C group were subject to moxibustion. After the therapy, the cholesterol concentration in serum was measured, and the expression of TRPV1 was quantified. Results. In WT mice, moxibustion caused a decrease in blood cholesterol level and upregulation of TRPV1 at the mRNA level, which was significantly greater in the 46°C group. In contrast, in TRPV1−/− mice, the differences of cholesterol-lowering effects of moxibustion were lost. Conclusions. Temperature is one of the important factors affecting the effects of moxibustion, and the cholesterol -lowering effect of moxibustion is related to the activation of TRPV1.

Correlation between Urothelial Differentiation and Sensory Proteins P2X3, P2X5, TRPV1, and TRPV4 in Normal Urothelium and Papillary Carcinoma of Human Bladder

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Igor Sterle

2014-01-01

Full Text Available Terminal differentiation of urothelium is a prerequisite for blood-urine barrier formation and enables normal sensory function of the urinary bladder. In this study, urothelial differentiation of normal human urothelium and of low and high grade papillary urothelial carcinomas was correlated with the expression and localization of purinergic receptors (P2X3, and P2X5 and transient receptor potential vanilloid channels (TRPV1, and TRPV4. Western blotting and immunofluorescence of uroplakins together with scanning electron microscopy of urothelial apical surface demonstrated terminal differentiation of normal urothelium, partial differentiation of low grade carcinoma, and poor differentiation of high grade carcinoma. P2X3 was expressed in normal urothelium as well as in low grade carcinoma and in both cases immunolabeling was stronger in the superficial cells. P2X3 expression decreased in high grade carcinoma. P2X5 expression was detected in normal urothelium and in high grade carcinoma, while in low grade carcinoma its expression was diminished. The expression of TRPV1 decreased in low grade and even more in high grade carcinoma when compared with normal urothelium, while TRPV4 expression was unchanged in all samples. Our results suggest that sensory proteins P2X3 and TRPV1 are in correlation with urothelial differentiation, while P2X5 and TRPV4 have unique expression patterns.

Subgroup-Elimination Transcriptomics Identifies Signaling Proteins that Define Subclasses of TRPV1-Positive Neurons and a Novel Paracrine Circuit

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Isensee, Jörg; Wenzel, Carsten; Buschow, Rene; Weissmann, Robert; Kuss, Andreas W.; Hucho, Tim

2014-01-01

Normal and painful stimuli are detected by specialized subgroups of peripheral sensory neurons. The understanding of the functional differences of each neuronal subgroup would be strongly enhanced by knowledge of the respective subgroup transcriptome. The separation of the subgroup of interest, however, has proven challenging as they can hardly be enriched. Instead of enriching, we now rapidly eliminated the subgroup of neurons expressing the heat-gated cation channel TRPV1 from dissociated rat sensory ganglia. Elimination was accomplished by brief treatment with TRPV1 agonists followed by the removal of compromised TRPV1(+) neurons using density centrifugation. By differential microarray and sequencing (RNA-Seq) based expression profiling we compared the transcriptome of all cells within sensory ganglia versus the same cells lacking TRPV1 expressing neurons, which revealed 240 differentially expressed genes (adj. p1.5). Corroborating the specificity of the approach, many of these genes have been reported to be involved in noxious heat or pain sensitization. Beyond the expected enrichment of ion channels, we found the TRPV1 transcriptome to be enriched for GPCRs and other signaling proteins involved in adenosine, calcium, and phosphatidylinositol signaling. Quantitative population analysis using a recent High Content Screening (HCS) microscopy approach identified substantial heterogeneity of expressed target proteins even within TRPV1-positive neurons. Signaling components defined distinct further subgroups within the population of TRPV1-positive neurons. Analysis of one such signaling system showed that the pain sensitizing prostaglandin PGD2 activates DP1 receptors expressed predominantly on TRPV1(+) neurons. In contrast, we found the PGD2 producing prostaglandin D synthase to be expressed exclusively in myelinated large-diameter neurons lacking TRPV1, which suggests a novel paracrine neuron-neuron communication. Thus, subgroup analysis based on the elimination

Activation of TRPV1-dependent calcium oscillation exacerbates seawater inhalation-induced acute lung injury.

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Li, Congcong; Bo, Liyan; Liu, Qingqing; Liu, Wei; Chen, Xiangjun; Xu, Dunquan; Jin, Faguang

2016-03-01

Calcium is an important second messenger and it is widely recognized that acute lung injury (ALI) is often caused by oscillations of cytosolic free Ca2+. Previous studies have indicated that the activation of transient receptor potential‑vanilloid (TRPV) channels and subsequent Ca2+ entry initiates an acute calcium‑dependent permeability increase during ALI. However, whether seawater exposure induces such an effect through the activation of TRPV channels remains unknown. In the current study, the effect of calcium, a component of seawater, on the inflammatory reactions that occur during seawater drowning‑induced ALI, was examined. The results demonstrated that a high concentration of calcium ions in seawater increased lung tissue myeloperoxidase activity and the secretion of inflammatory mediators, such as tumor necrosis factor‑α (TNF‑α) and interleukin (IL)‑1β and IL‑6. Further study demonstrated that the seawater challenge elevated cytosolic Ca2+ concentration, indicated by [Ca2+]c, by inducing calcium influx from the extracellular medium via TRPV1 channels. The elevated [Ca2+c] may have resulted in the increased release of TNF‑α and IL‑1β via increased phosphorylation of nuclear factor‑κB (NF‑κB). It was concluded that a high concentration of calcium in seawater exacerbated lung injury, and TRPV1 channels were notable mediators of the calcium increase initiated by the seawater challenge. Calcium influx through TRPV1 may have led to greater phosphorylation of NF‑κB and increased release of TNF‑α and IL‑1β.

Structure of the TRPV1 ion channel determined by electron cryo-microscopy.

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Liao, Maofu; Cao, Erhu; Julius, David; Cheng, Yifan

2013-12-05

Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4 Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane segments 5-6 (S5-S6) and the intervening pore loop, which is flanked by S1-S4 voltage-sensor-like domains. TRPV1 has a wide extracellular 'mouth' with a short selectivity filter. The conserved 'TRP domain' interacts with the S4-S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including amino-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.

Differential Effects of TRPA and TRPV Channels on Behaviors of

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Jennifer Thies

2016-01-01

Full Text Available TRPA and TRPV ion channels are members of the transient receptor potential (TRP cation channel superfamily, which mediates various sensory transductions. In Caenorhabditis elegans , the TRPV channels are known to affect chemosensation, while the TRPA-1 channel is associated with thermosensation and mechanosensation. We examined thermosensation, chemosensation, and osmosensation in strains lacking TRPA-1 or TRPV channels. We found that TRPV channel knockout worms exhibited similar behavioral deficits associated with thermotaxis as the TRPA-1 channel knockout, suggesting a dual role for TRPV channels. In contrast, chemosensation responses, assessed by both avoidance reversal behavior and NaCl osmosensation, were dependent on TRPV channels but seemed independent of TRPA-1 channel. Our findings suggest that, in addition to TRPA-1 channel, TRPV channels are necessary for thermotaxis and may activate, or modulate, the function of TRPA-1 channels. In contrast, TRPA-1 channels do not have a dual responsibility, as they have no functional role in odorant avoidance or osmosensation.

Structural analyses of the Ankyrin Repeat Domain of TRPV6 and related TRPV ion channels†‡

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Phelps, Christopher B.; Huang, Robert J.; Lishko, Polina V.; Wang, Ruiqi R.; Gaudet, Rachelle

2008-01-01

Transient Receptor Potential (TRP) proteins are cation channels composed of a transmembrane domain flanked by large N- and C-terminal cytoplasmic domains. All members of the vanilloid family of TRP channels (TRPV) possess an N-terminal ankyrin repeat domain (ARD). The ARD of mammalian TRPV6, an important regulator of calcium uptake and homeostasis, is essential for channel assembly and regulation. The 1.7 Å crystal structure of the TRPV6-ARD reveals conserved structural elements unique to the...

Effect of a temperature increase in the non-noxious range on proton-evoked ASIC and TRPV1 activity.

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Blanchard, Maxime G; Kellenberger, Stephan

2011-01-01

Acid-sensing ion channels (ASICs) are neuronal H(+)-gated cation channels, and the transient receptor potential vanilloid 1 channel (TRPV1) is a multimodal cation channel activated by low pH, noxious heat, capsaicin, and voltage. ASICs and TRPV1 are present in sensory neurons. It has been shown that raising the temperature increases TRPV1 and decreases ASIC H(+)-gated current amplitudes. To understand the underlying mechanisms, we have analyzed ASIC and TRPV1 function in a recombinant expression system and in dorsal root ganglion (DRG) neurons at room and physiological temperature. We show that temperature in the range studied does not affect the pH dependence of ASIC and TRPV1 activation. A temperature increase induces, however, a small alkaline shift of the pH dependence of steady-state inactivation of ASIC1a, ASIC1b, and ASIC2a. The decrease in ASIC peak current amplitudes at higher temperatures is likely in part due to the observed accelerated open channel inactivation kinetics and for some ASIC types to the changed pH dependence of steady-state inactivation. The increase in H(+)-activated TRPV1 current at the higher temperature is at least in part due to a hyperpolarizing shift in its voltage dependence. The contribution of TRPV1 relative to ASICs to H(+)-gated currents in DRG neurons increases with higher temperature and acidity. Still, ASICs remain the principal pH sensors of DRG neurons at 35°C in the pH range ≥6.

The μ opioid agonist morphine modulates potentiation of capsaicin-evoked TRPV1 responses through a cyclic AMP-dependent protein kinase A pathway

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Roberts-Thomson Sarah J

2006-07-01

Full Text Available Abstract Background The vanilloid receptor 1 (TRPV1 is critical in the development of inflammatory hyperalgesia. Several receptors including G-protein coupled prostaglandin receptors have been reported to functionally interact with the TRPV1 through a cAMP-dependent protein kinase A (PKA pathway to potentiate TRPV1-mediated capsaicin responses. Such regulation may have significance in inflammatory pain. However, few functional receptor interactions that inhibit PKA-mediated potentiation of TRPV1 responses have been described. Results In the present studies we investigated the hypothesis that the μ opioid receptor (MOP agonist morphine can modulate forskolin-potentiated capsaicin responses through a cAMP-dependent PKA pathway. HEK293 cells were stably transfected with TRPV1 and MOP, and calcium (Ca2+ responses to injection of the TRPV1 agonist capsaicin were monitored in Fluo-3-loaded cells. Pre-treatment with morphine did not inhibit unpotentiated capsaicin-induced Ca2+ responses but significantly altered capsaicin responses potentiated by forskolin. TRPV1-mediated Ca2+ responses potentiated by the direct PKA activator 8-Br-cAMP and the PKC activator Phorbol-12-myristate-13-acetatewere not modulated by morphine. Immunohistochemical studies confirmed that the TRPV1 and MOP are co-expressed on cultured Dorsal Root Ganglion neurones, pointing towards the existence of a functional relationship between the G-protein coupled MOP and nociceptive TRPV1. Conclusion The results presented here indicate that the opioid receptor agonist morphine acts via inhibition of adenylate cyclase to inhibit PKA-potentiated TRPV1 responses. Targeting of peripheral opioid receptors may therefore have therapeutic potential as an intervention to prevent potentiation of TRPV1 responses through the PKA pathway in inflammation.

On the mechanism of TBA block of the TRPV1 channel.

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Oseguera, Andrés Jara; Islas, León D; García-Villegas, Refugio; Rosenbaum, Tamara

2007-06-01

The transient receptor potential vanilloid 1 (TRPV1) channel is a nonselective cation channel activated by capsaicin and responsible for thermosensation. To date, little is known about the gating characteristics of these channels. Here we used tetrabutylammonium (TBA) to determine whether this molecule behaves as an ion conduction blocker in TRPV1 channels and to gain insight into the nature of the activation gate of this protein. TBA belongs to a family of classic potassium channel blockers that have been widely used as tools for determining the localization of the activation gate and the properties of the pore of several ion channels. We found TBA to be a voltage-dependent pore blocker and that the properties of block are consistent with an open-state blocker, with the TBA molecule binding to multiple open states, each with different blocker affinities. Kinetics of channel closure and burst-length analysis in the presence of blocker are consistent with a state-dependent blocking mechanism, with TBA interfering with closing of an activation gate. This activation gate may be located cytoplasmically with respect to the binding site of TBA ions, similar to what has been observed in potassium channels. We propose an allosteric model for TRPV1 activation and block by TBA, which explains our experimental data.

Differential regulation of proton-sensitive ion channels by phospholipids: a comparative study between ASICs and TRPV1.

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Hae-Jin Kweon

Full Text Available Protons are released in pain-generating pathological conditions such as inflammation, ischemic stroke, infection, and cancer. During normal synaptic activities, protons are thought to play a role in neurotransmission processes. Acid-sensing ion channels (ASICs are typical proton sensors in the central nervous system (CNS and the peripheral nervous system (PNS. In addition to ASICs, capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1 channels can also mediate proton-mediated pain signaling. In spite of their importance in perception of pH fluctuations, the regulatory mechanisms of these proton-sensitive ion channels still need to be further investigated. Here, we compared regulation of ASICs and TRPV1 by membrane phosphoinositides, which are general cofactors of many receptors and ion channels. We observed that ASICs do not require membrane phosphatidylinositol 4-phosphate (PI(4P or phosphatidylinositol 4,5-bisphosphate (PI(4,5P2 for their function. However, TRPV1 currents were inhibited by simultaneous breakdown of PI(4P and PI(4,5P2. By using a novel chimeric protein, CF-PTEN, that can specifically dephosphorylate at the D3 position of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5P3, we also observed that neither ASICs nor TRPV1 activities were altered by depletion of PI(3,4,5P3 in intact cells. Finally, we compared the effects of arachidonic acid (AA on two proton-sensitive ion channels. We observed that AA potentiates the currents of both ASICs and TRPV1, but that they have different recovery aspects. In conclusion, ASICs and TRPV1 have different sensitivities toward membrane phospholipids, such as PI(4P, PI(4,5P2, and AA, although they have common roles as proton sensors. Further investigation about the complementary roles and respective contributions of ASICs and TRPV1 in proton-mediated signaling is necessary.

Involvement of MrgprC in Electroacupuncture Analgesia for Attenuating CFA-Induced Thermal Hyperalgesia by Suppressing the TRPV1 Pathway

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Ying-jun Liu

2018-01-01

Full Text Available Mas-related G-protein-coupled receptor C (MrgprC plays an important role in modulating chronic inflammatory pain. Electroacupuncture (EA has a satisfactory analgesic effect on chronic pain. This study aimed to investigate the involvement of MrgprC and its transient receptor potential vanilloid 1 (TRPV1 pathway in EA analgesia in chronic inflammatory pain. Chronic inflammatory pain was induced by subcutaneously injecting complete Freund’s adjuvant (CFA into the left hind paw. EA (2/100 Hz stimulation was administered. MrgprC siRNAs were intrathecally administered to inhibit MrgprC expression, and bovine adrenal medulla 8-22 (BAM8-22 was used to activate MrgprC. The mechanical allodynia was decreased by EA significantly since day 3. The piled analgesic effect of EA was partially blocked by 6 intrathecal administrations of MrgprC siRNA. Both EA and BAM8-22 could downregulate the expression of TRPV1 and PKC in both the DRG and the SCDH. Both EA and BAM8-22 could also decrease the TRPV1 translocation and p-TRPV1 level in both the DRG and the SCDH. The effects of EA on PKCε, TRPV1 translocation, and p-TRPV1 in both the DRG and the SCDH were reversed by MrgprC siRNA. The results indicated that MrgprC played crucial roles in chronic pain modulation and was involved in EA analgesia partially through the regulation of TRPV1 function at the DRG and SCDH levels.

Involvement of MrgprC in Electroacupuncture Analgesia for Attenuating CFA-Induced Thermal Hyperalgesia by Suppressing the TRPV1 Pathway.

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Liu, Ying-Jun; Lin, Xiao-Xi; Fang, Jian-Qiao; Fang, Fang

2018-01-01

Mas-related G-protein-coupled receptor C (MrgprC) plays an important role in modulating chronic inflammatory pain. Electroacupuncture (EA) has a satisfactory analgesic effect on chronic pain. This study aimed to investigate the involvement of MrgprC and its transient receptor potential vanilloid 1 (TRPV1) pathway in EA analgesia in chronic inflammatory pain. Chronic inflammatory pain was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the left hind paw. EA (2/100 Hz) stimulation was administered. MrgprC siRNAs were intrathecally administered to inhibit MrgprC expression, and bovine adrenal medulla 8-22 (BAM8-22) was used to activate MrgprC. The mechanical allodynia was decreased by EA significantly since day 3. The piled analgesic effect of EA was partially blocked by 6 intrathecal administrations of MrgprC siRNA. Both EA and BAM8-22 could downregulate the expression of TRPV1 and PKC in both the DRG and the SCDH. Both EA and BAM8-22 could also decrease the TRPV1 translocation and p-TRPV1 level in both the DRG and the SCDH. The effects of EA on PKC ε , TRPV1 translocation, and p-TRPV1 in both the DRG and the SCDH were reversed by MrgprC siRNA. The results indicated that MrgprC played crucial roles in chronic pain modulation and was involved in EA analgesia partially through the regulation of TRPV1 function at the DRG and SCDH levels.

Melatonin synthesis in the human ciliary body triggered by TRPV4 activation: Involvement of AANAT phosphorylation.

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Alkozi, Hanan Awad; Perez de Lara, María J; Pintor, Jesús

2017-09-01

Melatonin is a substance synthesized in the pineal gland as well as in other organs. This substance is involved in many ocular functions, giving its synthesis in numerous eye structures. Melatonin is synthesized from serotonin through two enzymes, the first limiting step into the synthesis of melatonin being aralkylamine N-acetyltransferase (AANAT). In this current study, AANAT phosphorylation after the activation of TRPV4 was studied using human non-pigmented epithelial ciliary body cells. Firstly, it was necessary to determine the adequate time and dose of the TRPV4 agonist GSK1016790A to reach the maximal phosphorylation of AANAT. An increase of 72% was observed after 5 min incubation with 10 nM GSK (**p melatonin synthesis. The involvement of a TRPV4 channel in melatonin synthesis was verified by antagonist and siRNA studies as a previous step to studying intracellular signalling. Studies performed on the second messengers involved in GSK induced AANAT phosphorylation were carried out by inhibiting several pathways. In conclusion, the activation of calmodulin and calmodulin-dependent protein kinase II was confirmed, as shown by the cascade seen in AANAT phosphorylation (***p melatonin levels. In conclusion, the activation of a TRPV4 present in human ciliary body epithelial cells produced an increase in AANAT phosphorylation and a further melatonin increase by a mechanism in which Ca-calmodulin and the calmodulin-dependent protein kinase II are involved. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cutaneous C-polymodal fibers lacking TRPV1 are sensitized to heat following inflammation, but fail to drive heat hyperalgesia in the absence of TPV1 containing C-heat fibers

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Koerber H Richard

2010-09-01

Full Text Available Abstract Background Previous studies have shown that the TRPV1 ion channel plays a critical role in the development of heat hyperalgesia after inflammation, as inflamed TRPV1-/- mice develop mechanical allodynia but fail to develop thermal hyperalgesia. In order to further investigate the role of TRPV1, we have used an ex vivo skin/nerve/DRG preparation to examine the effects of CFA-induced-inflammation on the response properties of TRPV1-positive and TRPV1-negative cutaneous nociceptors. Results In wildtype mice we found that polymodal C-fibers (CPMs lacking TRPV1 were sensitized to heat within a day after CFA injection. This sensitization included both a drop in average heat threshold and an increase in firing rate to a heat ramp applied to the skin. No changes were observed in the mechanical response properties of these cells. Conversely, TRPV1-positive mechanically insensitive, heat sensitive fibers (CHs were not sensitized following inflammation. However, results suggested that some of these fibers may have gained mechanical sensitivity and that some previous silent fibers gained heat sensitivity. In mice lacking TRPV1, inflammation only decreased heat threshold of CPMs but did not sensitize their responses to the heat ramp. No CH-fibers could be identified in naïve nor inflamed TRPV1-/- mice. Conclusions Results obtained here suggest that increased heat sensitivity in TRPV1-negative CPM fibers alone following inflammation is insufficient for the induction of heat hyperalgesia. On the other hand, TRPV1-positive CH fibers appear to play an essential role in this process that may include both afferent and efferent functions.

A prospective study on symptom generation according to spicy food intake and TRPV1 genotypes in functional dyspepsia patients.

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Lee, S-Y; Masaoka, T; Han, H S; Matsuzaki, J; Hong, M J; Fukuhara, S; Choi, H S; Suzuki, H

2016-09-01

Capsaicin is an ingredient of red peppers that binds to transient receptor potential vanilloid subtype 1 (TRPV1), and Koreans eat more capsaicin-rich food than do Japanese. This study aimed to compare symptom generation according to TRPV1 genotypes and the intake of spicy foods. Consecutive functional dyspepsia (FD) patients who were evaluated at Konkuk University Medical Centre (Korea) and Keio University Hospital (Japan) were included. Questionnaires on spicy food intake, patient assessment of gastrointestinal symptoms (PAGI-SYM), patient assessment of quality of life, and hospital anxiety and depression scale were provided. Blood was sampled for the detection of TRPV1 polymorphisms, and upper gastrointestinal endoscopy was performed with biopsies. Of 121 included subjects, 35 and 28 carried the TRPV1 CC and GG genotypes, respectively, with the prevalence rates not differing between Japan and Korea. The prevalence of FD subtypes did not differ with the spicy food intake, TRPV1 genotypes, or Helicobacter pylori infection. Neither TRPV1 polymorphisms nor H. pylori infections were related to scores on the PAGI-SYM questionnaires, but spicy food intake was positively correlated with the scores for stomach fullness (p = 0.001) and retching (p = 0.001). Using the linear regression analysis, stomach fullness was associated with spicy food intake (p = 0.007), whereas retching was related to younger age (p foods, younger age and female gender, regardless of TRPV1 genotypes and the H. pylori infection status. Capsaicin-rich foods may induce stomach fullness. © 2016 John Wiley & Sons Ltd.

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

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Kiyatkin, Michael E.; Feng, Bin; Schwartz, Erica S.; Gebhart, G. F.

2013-01-01

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined chann...

Adrenergic receptors inhibit TRPV1 activity in the dorsal root ganglion neurons of rats.

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Matsushita, Yumi; Manabe, Miki; Kitamura, Naoki; Shibuya, Izumi

2018-01-01

Transient receptor potential vanilloid type 1 (TRPV1) is a polymodal receptor channel that responds to multiple types of stimuli, such as heat, acid, mechanical pressure and some vanilloids. Capsaicin is the most commonly used vanilloid to stimulate TRPV1. TRPV1 channels are expressed in dorsal root ganglion neurons that extend to Aδ- and C-fibers and have a role in the transduction of noxious inputs to the skin into the electrical signals of the sensory nerve. Although noradrenergic nervous systems, including the descending antinociceptive system and the sympathetic nervous system, are known to modulate pain sensation, the functional association between TRPV1 and noradrenaline in primary sensory neurons has rarely been examined. In the present study, we examined the effects of noradrenaline on capsaicin-evoked currents in cultured dorsal root ganglion neurons of the rat by the whole-cell voltage clamp method. Noradrenaline at concentrations higher than 0.1 pM significantly reduced the amplitudes of the inward capsaicin currents recorded at -60 mV holding potential. This inhibitory action was reversed by either yohimbine (an α2 antagonist, 10 nM) or propranolol (a β antagonist, 10 nM). The α2 agonists, clonidine (1 pM) and dexmedetomidine (1 pM) inhibited capsaicin currents, and yohimbine (1 nM) reversed the effects of clonidine. The inhibitory action of noradrenaline was not seen in the neurons pretreated with pertussis toxin (100 μg/ml for 24 h) and the neurons dialyzed intracellularly with guanosine 5'- [β-thio] diphosphate (GDPβS, 200 μM), the catalytic subunit of protein kinase A (250 U/ml) or okadaic acid (1 μM). These results suggest that noradrenaline directly acts on dorsal root ganglion neurons to inhibit the activity of TRPV1 depending on the activation of α2-adrenoceptors followed by the inhibition of the adenylate cyclase/cAMP/protein kinase A pathway.

Polymodal Transient Receptor Potential Vanilloid (TRPV Ion Channels in Chondrogenic Cells

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Csilla Szűcs Somogyi

2015-08-01

Full Text Available Mature and developing chondrocytes exist in a microenvironment where mechanical load, changes of temperature, osmolarity and acidic pH may influence cellular metabolism. Polymodal Transient Receptor Potential Vanilloid (TRPV receptors are environmental sensors mediating responses through activation of linked intracellular signalling pathways. In chondrogenic high density cultures established from limb buds of chicken and mouse embryos, we identified TRPV1, TRPV2, TRPV3, TRPV4 and TRPV6 mRNA expression with RT-PCR. In both cultures, a switch in the expression pattern of TRPVs was observed during cartilage formation. The inhibition of TRPVs with the non-selective calcium channel blocker ruthenium red diminished chondrogenesis and caused significant inhibition of proliferation. Incubating cell cultures at 41 °C elevated the expression of TRPV1, and increased cartilage matrix production. When chondrogenic cells were exposed to mechanical load at the time of their differentiation into matrix producing chondrocytes, we detected increased mRNA levels of TRPV3. Our results demonstrate that developing chondrocytes express a full palette of TRPV channels and the switch in the expression pattern suggests differentiation stage-dependent roles of TRPVs during cartilage formation. As TRPV1 and TRPV3 expression was altered by thermal and mechanical stimuli, respectively, these are candidate channels that contribute to the transduction of environmental stimuli in chondrogenic cells.

Membrane-tethered peptides patterned after the TRP domain (TRPducins) selectively inhibit TRPV1 channel activity.

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Valente, Pierluigi; Fernández-Carvajal, Asia; Camprubí-Robles, María; Gomis, Ana; Quirce, Susana; Viana, Félix; Fernández-Ballester, Gregorio; González-Ros, José M; Belmonte, Carlos; Planells-Cases, Rosa; Ferrer-Montiel, Antonio

2011-05-01

The transient receptor potential vanilloid 1 (TRPV1) channel is a thermosensory receptor implicated in diverse physiological and pathological processes. The TRP domain, a highly conserved region in the C terminus adjacent to the internal channel gate, is critical for subunit tetramerization and channel gating. Here, we show that cell-penetrating, membrane-anchored peptides patterned after this protein domain are moderate and selective TRPV1 antagonists both in vitro and in vivo, blocking receptor activity in intact rat primary sensory neurons and their peripheral axons with mean decline time of 30 min. The most potent lipopeptide, TRP-p5, blocked all modes of TRPV1 gating with micromolar efficacy (IC(50)100 μM). TRP-p5 did not affect the capsaicin sensitivity of the vanilloid receptor. Our data suggest that TRP-p5 interferes with protein-protein interactions at the level of the TRP domain that are essential for the "conformational" change that leads to gate opening. Therefore, these palmitoylated peptides, which we termed TRPducins, are noncompetitive, voltage-independent, sequence-specific TRPV1 blockers. Our findings indicate that TRPducin-like peptides may embody a novel molecular strategy that can be exploited to generate a selective pharmacological arsenal for the TRP superfamily of ion channels.

Characterization of Transient Receptor Potential Vanilloid-1 (TRPV1) Variant Activation by Coal Fly Ash Particles and Associations with Altered Transient Receptor Potential Ankyrin-1 (TRPA1) Expression and Asthma.

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Deering-Rice, Cassandra E; Stockmann, Chris; Romero, Erin G; Lu, Zhenyu; Shapiro, Darien; Stone, Bryan L; Fassl, Bernhard; Nkoy, Flory; Uchida, Derek A; Ward, Robert M; Veranth, John M; Reilly, Christopher A

2016-11-25

Transient receptor potential (TRP) channels are activated by environmental particulate materials. We hypothesized that polymorphic variants of transient receptor potential vanilloid-1 (TRPV1) would be uniquely responsive to insoluble coal fly ash compared with the prototypical soluble agonist capsaicin. Furthermore, these changes would manifest as differences in lung cell responses to these agonists and perhaps correlate with changes in asthma symptom control. The TRPV1-I315M and -T469I variants were more responsive to capsaicin and coal fly ash. The I585V variant was less responsive to coal fly ash particles due to reduced translation of protein and an apparent role for Ile-585 in activation by particles. In HEK-293 cells, I585V had an inhibitory effect on wild-type TRPV1 expression, activation, and internalization/agonist-induced desensitization. In normal human bronchial epithelial cells, IL-8 secretion in response to coal fly ash treatment was reduced for cells heterozygous for TRPV1-I585V. Finally, both the I315M and I585V variants were associated with worse asthma symptom control with the effects of I315M manifesting in mild asthma and those of the I585V variant manifesting in severe, steroid-insensitive individuals. This effect may be due in part to increased transient receptor potential ankyrin-1 (TRPA1) expression by lung epithelial cells expressing the TRPV1-I585V variant. These findings suggest that specific molecular interactions control TRPV1 activation by particles, differential activation, and desensitization of TRPV1 by particles and/or other agonists, and cellular changes in the expression of TRPA1 as a result of I585V expression could contribute to variations in asthma symptom control. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular Understanding of the Activation of CB1 and Blockade of TRPV1 Receptors: Implications for Novel Treatment Strategies in Osteoarthritis

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Jakub Mlost

2018-01-01

Full Text Available Osteoarthritis (OA is a joint disease in which cartilage degenerates as a result of mechanical and biochemical changes. The main OA symptom is chronic pain involving both peripheral and central mechanisms of nociceptive processing. Our previous studies have implicated the benefits of dual- over single-acting compounds interacting with the endocannabinoid system (ECS in OA treatment. In the present study, we focused on the specific molecular alterations associated with pharmacological treatment. OA was induced in Wistar rats by intra-articular injection of 3 mg of monoiodoacetate (MIA. Single target compounds (URB597, an FAAH inhibitor, and SB366791, a TRPV1 antagonist and a dual-acting compound OMDM198 (FAAH inhibitor/TRPV1 antagonist were used in the present study. At day 21 post-MIA injection, rats were sacrificed 1 h after i.p. treatment, and changes in mRNA expression were evaluated in the lumbar spinal cord by RT-qPCR. Following MIA administration, we observed 2-4-fold increase in mRNA expression of targeted receptors (Cnr1, Cnr2, and Trpv1, endocannabinoid degradation enzymes (Faah, Ptgs2, and Alox12, and TRPV1 sensitizing kinases (Mapk3, Mapk14, Prkcg, and Prkaca. OMDM198 treatment reversed some of the MIA effects on the spinal cord towards intact levels (Alox12, Mapk14, and Prkcg. Apparent regulation of ECS and TRPV1 in response to pharmacological intervention is a strong justification for novel ECS-based multi-target drug treatment in OA.

Contribution of TRPV1 to microglia-derived IL-6 and NFkappaB translocation with elevated hydrostatic pressure.

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Sappington, Rebecca M; Calkins, David J

2008-07-01

The authors investigated the contributions of the transient receptor potential vanilloid-1 receptor (TRPV1) and Ca(2+) to microglial IL-6 and nuclear factor kappa B (NFkappaB) translocation with elevated hydrostatic pressure. The authors first examined IL-6 colocalization with the microglia marker Iba-1 in the DBA/2 mouse model of glaucoma to establish relevance. They isolated microglia from rat retina and maintained them at ambient or elevated (+70 mm Hg) hydrostatic pressure in vitro and used ELISA and immunocytochemistry to measure changes in the IL-6 concentration and NFkappaB translocation induced by the Ca(2+) chelator EGTA, the broad-spectrum Ca(2+) channel inhibitor ruthenium red, and the TRPV1 antagonist iodo-resiniferatoxin (I-RTX). They applied the Ca(2+) dye Fluo-4 AM to measure changes in intracellular Ca(2+) at elevated pressure induced by I-RTX and confirmed TRPV1 expression in microglia using PCR and immunocytochemistry. In DBA/2 retina, elevated intraocular pressure increased microglial IL-6 in the ganglion cell layer. Elevated hydrostatic pressure (24 hours) increased microglial IL-6 release, cytosolic NFkappaB, and NFkappaB translocation in vitro. These effects were reduced substantially by EGTA and ruthenium red. Antagonism of TRPV1 in microglia partially inhibited pressure-induced increases in IL-6 release and NFkappaB translocation. Brief elevated pressure (1 hour) induced a significant increase in microglial intracellular Ca(2+) that was partially attenuated by TRPV1 antagonism. Elevated pressure induces an influx of extracellular Ca(2+) in retinal microglia that precedes the activation of NFkappaB and the subsequent production and release of IL-6 and is at least partially dependent on the activation of TRPV1 and other ruthenium red-sensitive channels.

PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells.

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Wu, Liping; Oshima, Tadayuki; Shan, Jing; Sei, Hiroo; Tomita, Toshihiko; Ohda, Yoshio; Fukui, Hirokazu; Watari, Jiro; Miwa, Hiroto

2015-10-15

Esophageal visceral hypersensitivity has been proposed to be the pathogenesis of heartburn sensation in nonerosive reflux disease. Protease-activated receptor-2 (PAR-2) is expressed in human esophageal epithelial cells and is believed to play a role in inflammation and sensation. PAR-2 activation may modulate these responses through adenosine triphosphate (ATP) release, which is involved in transduction of sensation and pain. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) are both acid-sensitive nociceptors. However, the interaction among these molecules and the mechanisms of heartburn sensation are still not clear. We therefore examined whether ATP release in human esophageal epithelial cells in response to acid is modulated by TRPV1 and ASICs and whether PAR-2 activation influences the sensitivity of TRPV1 and ASICs. Weak acid (pH 5) stimulated the release of ATP from primary human esophageal epithelial cells (HEECs). This effect was significantly reduced after pretreatment with 5-iodoresiniferatoxin (IRTX), a TRPV1-specific antagonist, or with amiloride, a nonselective ASIC blocker. TRPV1 and ASIC3 small interfering RNA (siRNA) transfection also decreased weak acid-induced ATP release. Pretreatment of HEECs with trypsin, tryptase, or a PAR-2 agonist enhanced weak acid-induced ATP release. Trypsin treatment led to the phosphorylation of TRPV1. Acid-induced ATP release enhancement by trypsin was partially blocked by IRTX, amiloride, or a PAR-2 antagonist. Conversely, acid-induced ATP release was augmented by PAR-2 activation through TRPV1 and ASICs. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and ASICs. Copyright © 2015 the American Physiological Society.

4,5-Di-O-Caffeoylquinic Acid from Ligularia fischeri Suppresses Inflammatory Responses Through TRPV1 Activation.

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Kim, Yiseul; Kim, Jung Tae; Park, Joonwoo; Son, Hee Jin; Kim, Eun-Young; Lee, Young Joo; Rhyu, Mee-Ra

2017-10-01

Ligularia fischeri (Ledeb.) Turcz., a perennial plant native to northeastern Asia, has long been used as folk remedies for the alleviation of inflammatory symptoms. We investigated whether the extract of L. fischeri (LFEx) and caffeoylquinic acid (CQA) derivatives, the pharmacologically active ingredients identified from L. fischeri, regulate inflammation via a transient receptor potential vanilloid 1 (TRPV1)-mediated pathway. Changes in intracellular Ca 2+ levels to the LFEx and trans-5-O-CQA, 3,4-di-O-CQA, 3,5-di-O-CQA, and 4,5-di-O-CQA were monitored in TRPV1-expressing human embryonic kidney cell HEK 293T. LFEx and 4,5-di-O-CQA (EC 50  = 69.34 ± 1.12 μM) activated TRPV1, and these activations were significantly inhibited by ruthenium red, a general blocker of TRP channels, and capsazepine, a specific antagonist of TRPV1. 4,5-Di-O-CQA has been determined having antiinflammatory effect under hypoxic conditions by detecting the expression of cyclooxygenase-2 (COX-2), a representative inflammatory marker, and cellular migration in human pulmonary epithelial A549 cells. 4,5-Di-O-CQA suppressed COX-2 expression and cell migration, and this inhibition was countered by co-treatment with capsazepine. This study provides evidence that L. fischeri is selective to inflammatory responses via a TRPV1-mediated pathway, and 4,5-di-O-CQA might play a key role to create these effects. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

A Combined Water Extract of Frankincense and Myrrh Alleviates Neuropathic Pain in Mice via Modulation of TRPV1

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Danyou Hu

2017-01-01

Full Text Available Frankincense and myrrh are widely used in clinics as a pair of herbs to obtain a synergistic effect for relieving pain. To illuminate the analgesia mechanism of frankincense and myrrh, we assessed its effect in a neuropathic pain mouse model. Transient receptor potential vanilloid 1 (TRPV1 plays a crucial role in neuropathic pain and influences the plasticity of neuronal connectivity. We hypothesized that the water extraction of frankincense and myrrh (WFM exerted its analgesia effect by modulating the neuronal function of TRPV1. In our study, WFM was verified by UHPLC-TQ/MS assay. In vivo study showed that nociceptive response in mouse by heat and capsaicin induced were relieved by WFM treatment. Furthermore, thermal hypersensitivity and mechanical allodynia were also alleviated by WFM treatment in a chronic constriction injury (CCI mouse model. CCI resulted in increased TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons. However, after WFM treatment, TRPV1 expression was reverted in real-time PCR, Western blot, and immunofluorescence experiments. Calcium response to capsaicin was also decreased in cultured DRG neurons from CCI model mouse after WFM treatment. In conclusion, WFM alleviated CCI-induced mechanical allodynia and thermal hypersensitivity via modulating TRPV1.

Activation of TRPV1 by capsaicin induces functional Kinin B1 receptor in rat spinal cord microglia

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Talbot Sébastien

2012-01-01

Full Text Available Abstract Background The kinin B1 receptor (B1R is upregulated by pro-inflammatory cytokines and oxydative stress, which are enhanced by transient receptor potential vanilloid subtype 1 (TRPV1 activation. To examine the link between TRPV1 and B1R in inflammatory pain, this study aimed to determine the ability of TRPV1 to regulate microglial B1R expression in the spinal cord dorsal horn, and the underlying mechanism. Methods B1R expression (mRNA, protein and binding sites was measured in cervical, thoracic and lumbar spinal cord in response to TRPV1 activation by systemic capsaicin (1-50 mg/kg, s.c in rats pre-treated with TRPV1 antagonists (capsazepine or SB-366791, the antioxidant N-acetyl-L-cysteine (NAC, or vehicle. B1R function was assessed using a tail-flick test after intrathecal (i.t. injection of a selective B1R agonist (des-Arg9-BK, and its microglial localization was investigated by confocal microscopy with the selective fluorescent B1R agonist, [Nα-bodipy]-des-Arg9-BK. The effect of i.t. capsaicin (1 μg/site was also investigated. Results Capsaicin (10 to 50 mg/kg, s.c. enhanced time-dependently (0-24h B1R mRNA levels in the lumbar spinal cord; this effect was prevented by capsazepine (10 mg/kg, i.p.; 10 μg/site, i.t. and SB-366791 (1 mg/kg, i.p.; 30 μg/site, i.t.. Increases of B1R mRNA were correlated with IL-1β mRNA levels, and they were significantly less in cervical and thoracic spinal cord. Intrathecal capsaicin (1 μg/site also enhanced B1R mRNA in lumbar spinal cord. NAC (1 g/kg/d × 7 days prevented B1R up-regulation, superoxide anion production and NF-kB activation induced by capsaicin (15 mg/kg. Des-Arg9-BK (9.6 nmol/site, i.t. decreased by 25-30% the nociceptive threshold at 1 min post-injection in capsaicin-treated rats (10-50 mg/kg while it was without effect in control rats. Des-Arg9-BK-induced thermal hyperalgesia was blocked by capsazepine, SB-366791 and by antagonists/inhibitors of B1R (SSR240612, 10 mg/kg, p

Canonical Transient Receptor Potential (TRPC) 1 Acts as a Negative Regulator for Vanilloid TRPV6-mediated Ca2+ Influx*

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Schindl, Rainer; Fritsch, Reinhard; Jardin, Isaac; Frischauf, Irene; Kahr, Heike; Muik, Martin; Riedl, Maria Christine; Groschner, Klaus; Romanin, Christoph

2012-01-01

TRP proteins mostly assemble to homomeric channels but can also heteromerize, preferentially within their subfamilies. The TRPC1 protein is the most versatile member and forms various TRPC channel combinations but also unique channels with the distantly related TRPP2 and TRPV4. We show here a novel cross-family interaction between TRPC1 and TRPV6, a Ca2+ selective member of the vanilloid TRP subfamily. TRPV6 exhibited substantial co-localization and in vivo interaction with TRPC1 in HEK293 ce...

TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization

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Olivier Gouin

2017-03-01

Full Text Available ABSTRACT Cutaneous neurogenic inflammation (CNI is inflammation that is induced (or enhanced in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.

Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.

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Bhaskaran, Muthu D; Smith, Bret N

2010-06-01

Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system. Copyright (c) 2009 Elsevier Inc. All rights reserved.

Low Frequency Electroacupuncture Alleviated Spinal Nerve Ligation Induced Mechanical Allodynia by Inhibiting TRPV1 Upregulation in Ipsilateral Undamaged Dorsal Root Ganglia in Rats

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Yong-Liang Jiang

2013-01-01

Full Text Available Neuropathic pain is an intractable problem in clinical practice. Accumulating evidence shows that electroacupuncture (EA with low frequency can effectively relieve neuropathic pain. Transient receptor potential vanilloid type 1 (TRPV1 plays a key role in neuropathic pain. The study aimed to investigate whether neuropathic pain relieved by EA administration correlates with TRPV1 inhibition. Neuropathic pain was induced by right L5 spinal nerve ligation (SNL in rats. 2 Hz EA stimulation was administered. SNL induced mechanical allodynia in ipsilateral hind paw. SNL caused a significant reduction of TRPV1 expression in ipsilateral L5 dorsal root ganglia (DRG, but a significant up-regulation in ipsilateral L4 and L6 DRGs. Calcitonin gene-related peptide (CGRP change was consistent with that of TRPV1. EA alleviated mechanical allodynia, and inhibited TRPV1 and CGRP overexpressions in ipsilateral L4 and L6 DRGs. SNL did not decrease pain threshold of contralateral hind paw, and TRPV1 expression was not changed in contralateral L5 DRG. 0.001, 0.01 mg/kg TRPV1 agonist 6′-IRTX fully blocked EA analgesia in ipsilateral hind paw. 0.01 mg/kg 6′-IRTX also significantly decreased pain threshold of contralateral paw. These results indicated that inhibition of TRPV1 up-regulation in ipsilateral adjacent undamaged DRGs contributed to low frequency EA analgesia for mechanical allodynia induced by spinal nerve ligation.

Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation.

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Canetta, Sarah E; Luca, Edlira; Pertot, Elyse; Role, Lorna W; Talmage, David A

2011-01-01

Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs). Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling) can acutely activate phosphatidylinositol-3-kinase (PtdIns3K) signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1) is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Type III Nrg1 back signaling enhances functional TRPV1 along sensory axons contributing to basal and inflammatory thermal pain sensation.

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Sarah E Canetta

Full Text Available Type III Nrg1, a member of the Nrg1 family of signaling proteins, is expressed in sensory neurons, where it can signal in a bi-directional manner via interactions with the ErbB family of receptor tyrosine kinases (ErbB RTKs. Type III Nrg1 signaling as a receptor (Type III Nrg1 back signaling can acutely activate phosphatidylinositol-3-kinase (PtdIns3K signaling, as well as regulate levels of α7* nicotinic acetylcholine receptors, along sensory axons. Transient receptor potential vanilloid 1 (TRPV1 is a cation-permeable ion channel found in primary sensory neurons that is necessary for the detection of thermal pain and for the development of thermal hypersensitivity to pain under inflammatory conditions. Cell surface expression of TRPV1 can be enhanced by activation of PtdIns3K, making it a potential target for regulation by Type III Nrg1. We now show that Type III Nrg1 signaling in sensory neurons affects functional axonal TRPV1 in a PtdIns3K-dependent manner. Furthermore, mice heterozygous for Type III Nrg1 have specific deficits in their ability to respond to noxious thermal stimuli and to develop capsaicin-induced thermal hypersensitivity to pain. Cumulatively, these results implicate Type III Nrg1 as a novel regulator of TRPV1 and a molecular mediator of nociceptive function.

Maresin 1 Inhibits TRPV1 in Temporomandibular Joint-Related Trigeminal Nociceptive Neurons and TMJ Inflammation-Induced Synaptic Plasticity in the Trigeminal Nucleus

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Chul-Kyu Park

2015-01-01

Full Text Available In the trigeminal system, disruption of acute resolution processing may lead to uncontrolled inflammation and chronic pain associated with the temporomandibular joint (TMJ. Currently, there are no effective treatments for TMJ pain. Recently, it has been recognized that maresin 1, a newly identified macrophage-derived mediator of inflammation resolution, is a potent analgesic for somatic inflammatory pain without noticeable side effects in mice and a potent endogenous inhibitor of transient receptor potential vanilloid 1 (TRPV1 in the somatic system. However, the molecular mechanisms underlying the analgesic actions of maresin 1 on TMJ pain are unclear in the trigeminal system. Here, by performing TMJ injection of a retrograde labeling tracer DiI (a fluorescent dye, I showed that maresin 1 potently inhibits capsaicin-induced TRPV1 currents and neuronal activity via Gαi-coupled G-protein coupled receptors in DiI-labeled trigeminal nociceptive neurons. Further, maresin 1 blocked TRPV1 agonist-evoked increases in spontaneous excitatory postsynaptic current frequency and abolished TMJ inflammation-induced synaptic plasticity in the trigeminal nucleus. These results demonstrate the potent actions of maresin 1 in regulating TRPV1 in the trigeminal system. Thus, maresin 1 may serve as a novel endogenous inhibitor for treating TMJ-inflammatory pain in the orofacial region.

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

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

Tumor necrosis factor α sensitizes spinal cord TRPV1 receptors to the endogenous agonist N-oleoyldopamine

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Spicarova Diana

2010-08-01

Full Text Available Abstract Modulation of synaptic transmission in the spinal cord dorsal horn is thought to be involved in the development and maintenance of different pathological pain states. The proinflamatory cytokine, tumor necrosis factor α (TNFα, is an established pain modulator in both the peripheral and the central nervous system. Up-regulation of TNFα and its receptors (TNFR in dorsal root ganglion (DRG cells and in the spinal cord has been shown to play an important role in neuropathic and inflammatory pain conditions. Transient receptor potential vanilloid 1 (TRPV1 receptors are known as molecular integrators of nociceptive stimuli in the periphery, but their role on the spinal endings of nociceptive DRG neurons is unclear. The endogenous TRPV1 receptor agonist N-oleoyldopamine (OLDA was shown previously to activate spinal TRPV1 receptors. In our experiments the possible influence of TNFα on presynaptic spinal cord TRPV1 receptor function was investigated. Using the patch-clamp technique, miniature excitatory postsynaptic currents (mEPSCs were recorded in superficial dorsal horn neurons in acute slices after incubation with 60 nM TNFα. A population of dorsal horn neurons with capsaicin sensitive primary afferent input recorded after the TNFα pretreatment had a basal mEPSC frequency of 1.35 ± 0.20 Hz (n = 13, which was significantly higher when compared to a similar population of neurons in control slices (0.76 ± 0.08 Hz; n = 53; P

The stress protein heat shock cognate 70 (Hsc70) inhibits the Transient Receptor Potential Vanilloid type 1 (TRPV1) channel.

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Iftinca, Mircea; Flynn, Robyn; Basso, Lilian; Melo, Helvira; Aboushousha, Reem; Taylor, Lauren; Altier, Christophe

2016-01-01

Specialized cellular defense mechanisms prevent damage from chemical, biological, and physical hazards. The heat shock proteins have been recognized as key chaperones that maintain cell survival against a variety of exogenous and endogenous stress signals including noxious temperature. However, the role of heat shock proteins in nociception remains poorly understood. We carried out an expression analysis of the constitutively expressed 70 kDa heat-shock cognate protein, a member of the stress-induced HSP70 family in lumbar dorsal root ganglia from a mouse model of Complete Freund's Adjuvant-induced chronic inflammatory pain. We used immunolabeling of dorsal root ganglion neurons, behavioral analysis and patch clamp electrophysiology in both dorsal root ganglion neurons and HEK cells transfected with Hsc70 and Transient Receptor Potential Channels to examine their functional interaction in heat shock stress condition. We report an increase in protein levels of Hsc70 in mouse dorsal root ganglia, 3 days post Complete Freund's Adjuvant injection in the hind paw. Immunostaining of Hsc70 was observed in most of the dorsal root ganglion neurons, including the small size nociceptors immunoreactive to the TRPV1 channel. Standard whole-cell patch-clamp technique was used to record Transient Receptor Potential Vanilloid type 1 current after exposure to heat shock. We found that capsaicin-evoked currents are inhibited by heat shock in dorsal root ganglion neurons and transfected HEK cells expressing Hsc70 and TRPV1. Blocking Hsc70 with matrine or spergualin compounds prevented heat shock-induced inhibition of the channel. We also found that, in contrast to TRPV1, both the cold sensor channels TRPA1 and TRPM8 were unresponsive to heat shock stress. Finally, we show that inhibition of TRPV1 depends on the ATPase activity of Hsc70 and involves the rho-associated protein kinase. Our work identified Hsc70 and its ATPase activity as a central cofactor of TRPV1 channel function

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

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Hakimizadeh, Elham; Shamsizadeh, Ali; Roohbakhsh, Ali; Arababadi, Mohammad Kazemi; Hajizadeh, Mohammad Reza; Shariati, Mehdi; Fatemi, Iman; Moghadam-ahmadi, Amir; Bazmandegan, Gholamreza; Rezazadeh, Hossein; Allahtavakoli, Mohammad

2017-01-01

Objective(s): Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1) channels and toll-like receptors (TLRs) are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist) -treated and capsaicin (TRPV1 agonist) -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke. PMID:29085577

Long-term activation of group I metabotropic glutamate receptors increases functional TRPV1-expressing neurons in mouse dorsal root ganglia

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Takayoshi eMasuoka

2016-03-01

Full Text Available Damaged tissues release glutamate and other chemical mediators for several hours. These chemical mediators contribute to modulation of pruritus and pain. Herein, we investigated the effects of long-term activation of excitatory glutamate receptors on functional expression of transient receptor potential vaniloid type 1 (TRPV1 in dorsal root ganglion (DRG neurons and then on thermal pain behavior. In order to detect the TRPV1-mediated responses in cultured DRG neurons, we monitored intracellular calcium responses to capsaicin, a TRPV1 agonist, with Fura-2. Long-term (4 h treatment with glutamate receptor agonists (glutamate, quisqualate or DHPG increased the proportion of neurons responding to capsaicin through activation of metabotropic glutamate receptor mGluR1, and only partially through the activation of mGluR5; engagement of these receptors was evident in neurons responding to allylisothiocyanate (AITC, a transient receptor potential ankyrin type 1 (TRPA1 agonist. Increase in the proportion was suppressed by phospholipase C, protein kinase C, mitogen/extracellular signal-regulated kinase, p38 mitogen-activated protein kinase or transcription inhibitors. Whole-cell recording was performed to record TRPV1-mediated membrane current; TRPV1 current density significantly increased in the AITC-sensitive neurons after the quisqualate treatment. To elucidate the physiological significance of this phenomenon, a hot plate test was performed. Intraplantar injection of quisqualate or DHPG induced heat hyperalgesia that lasted for 4 h post injection. This chronic hyperalgesia was attenuated by treatment with either mGluR1 or mGluR5 antagonists. These results suggest that long-term activation of mGluR1/5 by peripherally released glutamate may increase the number of neurons expressing functional TRPV1 in DRG, which may be strongly associated with chronic hyperalgesia.

TRPV1 Gene Polymorphisms Are Associated with Type 2 Diabetes by Their Interaction with Fat Consumption in the Korean Genome Epidemiology Study.

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Park, Sunmin; Zhang, Xin; Lee, Na Ra; Jin, Hyun-Seok

2016-01-01

Different transient receptor potential vanilloid 1 (TRPV1) variants may be differently activated by noxious stimuli. We investigated how TRPV1 variants modulated the prevalence of type 2 diabetes and specific gene-nutrient interactions. Among 8,842 adults aged 40-69 years in the Korean Genome Epidemiology Study, the associations between TRPV1 genotypes and the prevalence of type 2 diabetes as well as their gene-nutrient interactions were investigated after adjusting for the covariates of age, gender, residence area, body mass index, daily energy intake, and total activity. The TRPV1 rs161364 and rs8065080 minor alleles lowered HOMA-IR and the risk of type 2 diabetes after adjusting for covariates. There were gene-nutrient interactions between TRPV1 variants rs161364 and rs8065080 and preference for oily taste, intake of oily foods, and fat intake after adjusting for covariates. Among subjects with the minor alleles of TRPV1 rs161364 and rs8065080, the group with a high preference for oily foods had a lower odds ratio for type 2 diabetes. Consistent with the preference for taste, among subjects with the minor alleles, the group with high fat intake from oily foods also exhibited a lower risk of type 2 diabetes than subjects with the major alleles. People with the minor alleles of the TRPV1 single nucleotide polymorphisms rs161364 and rs8065080 have a lower risk of diabetes with a high-fat diet, but people with the major alleles are at a higher risk of type 2 diabetes when consuming high-fat diets. The majority of people should be careful about a high fat intake. © 2016 S. Karger AG, Basel.

Wu-Tou Decoction Inhibits Chronic Inflammatory Pain in Mice: Participation of TRPV1 and TRPA1 Ion Channels

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Chao Wang

2015-01-01

Full Text Available Wu-tou decoction (WTD is a classic traditional Chinese medicine formula and has been used effectively to treat joint diseases clinically. Previous reports indicated that WTD possesses anti-inflammatory activity; however, its actions on pain have not been clarified. Here, we investigated the antinociceptive activity of WTD in CFA-induced mice, and its possible mechanism of the action associated with transient receptor potential (TRP ion channels was also explored. Our results showed that 1.58, 3.15, and 6.30 g/kg WTD significantly attenuated mechanical, cold, and heat hypersensitivities. Moreover, WTD effectively inhibited spontaneous nociceptive responses to intraplantar injections of capsaicin and cinnamaldehyde, respectively. WTD also effectively suppressed jumping and wet-dog-shake behaviors to intraperitoneal injection of icilin. Additionally, WTD significantly reduced protein expression of TRPV1 and TRPA1 in dorsal root ganglia and skins of injured paw. Collectively, our data demonstrate firstly that WTD exerts antinociceptive activity in inflammatory conditions by attenuating mechanical, cold, and heat hypersensitivities. This antinociceptive effect may result in part from inhibiting the activities of TRPV1, TRPA1, and TRPM8, and the suppression of TRPV1 and TRPA1 protein by WTD was also highly effective. These findings suggest that WTD might be an attractive and suitable therapeutic agent for the management of chronic inflammatory pain.

The TRPV1 channel in rodents is a major target for antinociceptive effect of the probiotic Lactobacillus reuteri DSM 17938

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Perez-Burgos, Azucena; Wang, Lu; McVey Neufeld, Karen-Anne; Mao, Yu-Kang; Ahmadzai, Mustafa; Janssen, Luke J; Stanisz, Andrew M; Bienenstock, John; Kunze, Wolfgang A

2015-01-01

Abstract Certain bacteria exert visceral antinociceptive activity, but the mechanisms involved are not determined. Lactobacillus reuteri DSM 17938 was examined since it may be antinociceptive in children. Since transient receptor potential vanilloid 1 (TRPV1) channel activity may mediate nociceptive signals, we hypothesized that TRPV1 current is inhibited by DSM. We tested this by examining the effect of DSM on the firing frequency of spinal nerve fibres in murine jejunal mesenteric nerve bundles following serosal application of capsaicin. We also measured the effects of DSM on capsaicin-evoked increase in intracellular Ca2+ or ionic current in dorsal root ganglion (DRG) neurons. Furthermore, we tested the in vivo antinociceptive effects of oral DSM on gastric distension in rats. Live DSM reduced the response of capsaicin- and distension-evoked firing of spinal nerve action potentials (238 ± 27.5% vs. 129 ± 17%). DSM also reduced the capsaicin-evoked TRPV1 ionic current in DRG neuronal primary culture from 83 ± 11% to 41 ± 8% of the initial response to capsaicin only. Another lactobacillus (Lactobacillus rhamnosus JB-1) with known visceral anti-nociceptive activity did not have these effects. DSM also inhibited capsaicin-evoked Ca2+ increase in DRG neurons; an increase in Ca2+ fluorescence intensity ratio of 2.36 ± 0.31 evoked by capsaicin was reduced to 1.25 ± 0.04. DSM releasable products (conditioned medium) mimicked DSM inhibition of capsaicin-evoked excitability. The TRPV1 antagonist 6-iodonordihydrocapsaicin or the use of TRPV1 knock-out mice revealed that TRPV1 channels mediate about 80% of the inhibitory effect of DSM on mesenteric nerve response to high intensity gut distension. Finally, feeding with DSM inhibited perception in rats of painful gastric distension. Our results identify a specific target channel for a probiotic with potential therapeutic properties. Key points Certain probiotic bacteria have been shown to reduce distension

Comparison of the transport of QX-314 through TRPA1, TRPM8, and TRPV1 channels

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Nakagawa H

2013-03-01

Full Text Available Hiroshi Nakagawa,1 Akio Hiura2 1Dentistry for Persons with Disability, Tokushima University Hospital, Tokushima, Japan; 2Department of Oral Histology, School of Dentistry, University of Tokushima, Tokushima, Japan Background: It has been demonstrated that N-ethyl-lidocaine (QX-314 can target the transient receptor protein vanilloid 1 (TRPV1 nociceptors when coadministered with capsaicin, resulting in a selective block of the nociceptors. Capsaicin is problematic in therapeutic use because it induces firing of nociceptors. The present study aimed to search for substitutes for capsaicin. We also examined the transportability of QX-314 into nociceptive neurons, through the pores of transient receptor potential ankyrin 1 (TRPA1, transient receptor potential melastatin-8 (TRPM8, and TRPV1. Methods: To investigate the effect on TRPA1, injections of a vehicle, allyl isothiocyanate (AITC, QX-314, or AITC/QX-314 were made into the hind paws of rats. The effects of menthol and capsaicin on the opening of TRPM8 and TRPV1 were also examined and compared with the potency of QX-314. To examine inhibition of the antinociceptive effect by capsaicin/QX-314, capsazepine (50 µg/mL; 10 µL was injected 30 minutes prior to capsaicin/QX-314 (10 µL injection. Thermal sensitivity was investigated by the Hargreaves method. 5(6-carboxyfluorescein (FAM-conjugated QX-314 was used as a tracer to examine how many and which kind of dorsal root ganglia accumulate this molecule. QX-314-FAM, capsaicin/QX-314-FAM, AITC/QX-314-FAM, and menthol/QX-314-FAM were injected into the paw. Two weeks after injections, dorsal root ganglia were removed and sectioned with a cryostat. Results: The capsaicin/QX-314 group induced longer withdrawal-response latency at 60 to 300 minutes after injection than the control. Both menthol only and menthol/QX-314 injections showed analgesia 10 to 60 minutes after injection. No significant difference was seen between the capsazepine/capsaicin/QX-314

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

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Elham Hakimizadeh

2017-08-01

Full Text Available Objective(s: Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1 channels and toll-like receptors (TLRs are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist -treated and capsaicin (TRPV1 agonist -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke.

TRPV6 alleles do not influence prostate cancer progression

International Nuclear Information System (INIS)

Kessler, Thorsten; Wissenbach, Ulrich; Grobholz, Rainer; Flockerzi, Veit

2009-01-01

The transient receptor potential, subfamily V, member 6 (TRPV6) is a Ca 2+ selective cation channel. Several studies have shown that TRPV6 transcripts are expressed in locally advanced prostatic adenocarcinoma, metastatic and androgen-insensitive prostatic lesions but are undetectable in healthy prostate tissue and benign prostatic hyperplasia. Two allelic variants of the human trpv6 gene have been identified which are transcribed into two independent mRNAs, TRPV6a and TRPV6b. We now asked, whether the trpv6a allele is correlated with the onset of prostate cancer, with the Gleason score and the tumour stage. Genomic DNA of prostate cancer patients and control individuals was isolated from resections of prostatic adenocarcinomas and salivary fluid respectively. Genotyping of SNPs of the TRPV6 gene was performed by restriction length polymorphism or by sequencing analysis. RNA used for RT-PCR was isolated from prostate tissue. Data sets were analyzed by Chi-Square test. We first characterized in detail the five polymorphisms present in the protein coding exons of the trpv6 gene and show that these polymorphisms are coupled and are underlying the TRPV6a and the TRPV6b variants. Next we analysed the frequencies of the two TRPV6 alleles using genomic DNA from saliva samples of 169 healthy individuals. The homozygous TRPV6b genotype predominated with 86%, whereas no homozygous TRPV6a carriers could be identified. The International HapMap Project identified a similar frequency for an Utah based population whereas in an African population the a-genotype prevailed. The incidence of prostate cancer is several times higher in African populations than in non-African and we then investigated the TRPV6a/b frequencies in 141 samples of prostatic adenocarcinoma. The TRPV6b allele was found in 87% of the samples without correlation with Gleason score and tumour stage. Our results show that the frequencies of trpv6 alleles in healthy control individuals and prostate cancer patients

TRPV6 alleles do not influence prostate cancer progression.

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Kessler, Thorsten; Wissenbach, Ulrich; Grobholz, Rainer; Flockerzi, Veit

2009-10-26

The transient receptor potential, subfamily V, member 6 (TRPV6) is a Ca(2+) selective cation channel. Several studies have shown that TRPV6 transcripts are expressed in locally advanced prostatic adenocarcinoma, metastatic and androgen-insensitive prostatic lesions but are undetectable in healthy prostate tissue and benign prostatic hyperplasia. Two allelic variants of the human trpv6 gene have been identified which are transcribed into two independent mRNAs, TRPV6a and TRPV6b. We now asked, whether the trpv6a allele is correlated with the onset of prostate cancer, with the Gleason score and the tumour stage. Genomic DNA of prostate cancer patients and control individuals was isolated from resections of prostatic adenocarcinomas and salivary fluid respectively. Genotyping of SNPs of the TRPV6 gene was performed by restriction length polymorphism or by sequencing analysis. RNA used for RT-PCR was isolated from prostate tissue. Data sets were analyzed by Chi-Square test. We first characterized in detail the five polymorphisms present in the protein coding exons of the trpv6 gene and show that these polymorphisms are coupled and are underlying the TRPV6a and the TRPV6b variants. Next we analysed the frequencies of the two TRPV6 alleles using genomic DNA from saliva samples of 169 healthy individuals. The homozygous TRPV6b genotype predominated with 86%, whereas no homozygous TRPV6a carriers could be identified. The International HapMap Project identified a similar frequency for an Utah based population whereas in an African population the a-genotype prevailed. The incidence of prostate cancer is several times higher in African populations than in non-African and we then investigated the TRPV6a/b frequencies in 141 samples of prostatic adenocarcinoma. The TRPV6b allele was found in 87% of the samples without correlation with Gleason score and tumour stage. Our results show that the frequencies of trpv6 alleles in healthy control individuals and prostate cancer patients

TRPV6 alleles do not influence prostate cancer progression

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Flockerzi Veit

2009-10-01

Full Text Available Abstract Background The transient receptor potential, subfamily V, member 6 (TRPV6 is a Ca2+ selective cation channel. Several studies have shown that TRPV6 transcripts are expressed in locally advanced prostatic adenocarcinoma, metastatic and androgen-insensitive prostatic lesions but are undetectable in healthy prostate tissue and benign prostatic hyperplasia. Two allelic variants of the human trpv6 gene have been identified which are transcribed into two independent mRNAs, TRPV6a and TRPV6b. We now asked, whether the trpv6a allele is correlated with the onset of prostate cancer, with the Gleason score and the tumour stage. Methods Genomic DNA of prostate cancer patients and control individuals was isolated from resections of prostatic adenocarcinomas and salivary fluid respectively. Genotyping of SNPs of the TRPV6 gene was performed by restriction length polymorphism or by sequencing analysis. RNA used for RT-PCR was isolated from prostate tissue. Data sets were analyzed by Chi-Square test. Results We first characterized in detail the five polymorphisms present in the protein coding exons of the trpv6 gene and show that these polymorphisms are coupled and are underlying the TRPV6a and the TRPV6b variants. Next we analysed the frequencies of the two TRPV6 alleles using genomic DNA from saliva samples of 169 healthy individuals. The homozygous TRPV6b genotype predominated with 86%, whereas no homozygous TRPV6a carriers could be identified. The International HapMap Project identified a similar frequency for an Utah based population whereas in an African population the a-genotype prevailed. The incidence of prostate cancer is several times higher in African populations than in non-African and we then investigated the TRPV6a/b frequencies in 141 samples of prostatic adenocarcinoma. The TRPV6b allele was found in 87% of the samples without correlation with Gleason score and tumour stage. Conclusion Our results show that the frequencies of trpv6

TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia

Czech Academy of Sciences Publication Activity Database

Špicarová, Diana; Adámek, Pavel; Kalynovska, Nataliia; Mrózková, Petra; Paleček, Jiří

2014-01-01

Roč. 81, JUN (2014), s. 75-84 ISSN 0028-3908 R&D Projects: GA ČR(CZ) GA305/09/1228; GA ČR(CZ) GPP303/12/P510; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) LH12058 Grant - others:Univerzita Karlova(CZ) 253154 Institutional support: RVO:67985823 Keywords : pain * spinal cord * synaptic transmission * CCL2 * TRPV1 * EPSC Subject RIV: FH - Neurology Impact factor: 5.106, year: 2014

Polymorphisms in TRPV1 and TAS2Rs associate with sensations from sampled ethanol.

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Allen, Alissa L; McGeary, John E; Hayes, John E

2014-10-01

Genetic variation in chemosensory genes can explain variability in individual's perception of and preference for many foods and beverages. To gain insight into variable preference and intake of alcoholic beverages, we explored individual variability in the responses to sampled ethanol (EtOH). In humans, EtOH elicits sweet, bitter, and burning sensations. Here, we explore the relationship between variation in EtOH sensations and polymorphisms in genes encoding bitter taste receptors (TAS2Rs) and a polymodal nociceptor (TRPV1). Caucasian participants (n = 93) were genotyped for 16 single nucleotide polymorphisms (SNPs) in TRPV1, 3 SNPs in TAS2R38, and 1 SNP in TAS2R13. Participants rated sampled EtOH on a generalized Labeled Magnitude Scale. Two stimuli were presented: a 16% EtOH whole-mouth sip-and-spit solution with a single time-point rating of overall intensity and a cotton swab saturated with 50% EtOH on the circumvallate papillae (CV) with ratings of multiple qualities over 3 minutes. Area-under-the-curve (AUC) was calculated for the time-intensity data. The EtOH whole-mouth solution had overall intensity ratings near "very strong." Burning/stinging had the highest mean AUC values, followed by bitterness and sweetness. Whole-mouth intensity ratings were significantly associated with burning/stinging and bitterness AUC values on the CV. Three TRPV1 SNPs (rs224547, rs4780521, rs161364) were associated with EtOH sensations on the CV, with 2 (rs224547 and rs4780521) exhibiting strong linkage disequilibrium. Additionally, the TAS2R38 SNPs rs713598, rs1726866, and rs10246939 formed a haplotype, and were associated with bitterness on the CV. Last, overall intensity for whole-mouth EtOH associated with the TAS2R13 SNP rs1015443. These data suggest genetic variation in TRPV1 and TAS2Rs influence sensations from sampled EtOH and may potentially influence how individuals initially respond to alcoholic beverages. Copyright © 2014 by the Research Society on Alcoholism.

Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.

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Sonja M Mueller-Tribbensee

Full Text Available Various transient receptor potential (TRP channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin8 was suggested to be involved in murine colonic mechano-nociception.To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT were used. Visceromotor responses (VMR to colorectal distension (CRD in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA.Distension-induced colonic CGRP release was markedly reduced in TRPA1-/- and TRPV4-/- mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 μM; RN1734, 10 μM; AMTB, 10 μM showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM and stretch-activated channels (gadolinium, 50 μM. VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg in TRPA1-/- and TRPV4-/- but not TRPM8-/- mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene.TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.

Investigation of the transient receptor potential vanilloid 1 (TRPV1) ion channel

OpenAIRE

Winter Zoltán

2013-01-01

The aims of this research were to determine sensory modalities that may be lost after the RTX treatment of newborn or adult mice, to dissect potential side-effect(s) of molecular neurosurgery, to gather information about the structure and function of the channel by investigating the effects of M2+ on the TRPV1 and by collecting the literature data on the functionally important point mutations of the channel for prospective in silico modeling. The findings of the research work can be summa...

TRPV6 alleles do not influence prostate cancer progression

OpenAIRE

Kessler, Thorsten; Wissenbach, Ulrich; Grobholz, Rainer; Flockerzi, Veit

2009-01-01

Abstract Background The transient receptor potential, subfamily V, member 6 (TRPV6) is a Ca2+ selective cation channel. Several studies have shown that TRPV6 transcripts are expressed in locally advanced prostatic adenocarcinoma, metastatic and androgen-insensitive prostatic lesions but are undetectable in healthy prostate tissue and benign prostatic hyperplasia. Two allelic variants of the human trpv6 gene have been identified which are transcribed into two independent mRNAs, TRPV6a and TRPV...

Combined genetic and pharmacological inhibition of TRPV1 and P2X3 attenuates colorectal hypersensitivity and afferent sensitization

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Kiyatkin, Michael E.; Feng, Bin; Schwartz, Erica S.

2013-01-01

The ligand-gated channels transient receptor potential vanilloid 1 (TRPV1) and P2X3 have been reported to facilitate colorectal afferent neuron sensitization, thus contributing to organ hypersensitivity and pain. In the present study, we hypothesized that TRPV1 and P2X3 cooperate to modulate colorectal nociception and afferent sensitivity. To test this hypothesis, we employed TRPV1-P2X3 double knockout (TPDKO) mice and channel-selective pharmacological antagonists and evaluated combined channel contributions to behavioral responses to colorectal distension (CRD) and afferent fiber responses to colorectal stretch. Baseline responses to CRD were unexpectedly greater in TPDKO compared with control mice, but zymosan-produced CRD hypersensitivity was absent in TPDKO mice. Relative to control mice, proportions of mechanosensitive and -insensitive pelvic nerve afferent classes were not different in TPDKO mice. Responses of mucosal and serosal class afferents to mechanical probing were unaffected, whereas responses of muscular (but not muscular/mucosal) afferents to stretch were significantly attenuated in TPDKO mice; sensitization of both muscular and muscular/mucosal afferents by inflammatory soup was also significantly attenuated. In pharmacological studies, the TRPV1 antagonist A889425 and P2X3 antagonist TNP-ATP, alone and in combination, applied onto stretch-sensitive afferent endings attenuated responses to stretch; combined antagonism produced greater attenuation. In the aggregate, these observations suggest that 1) genetic manipulation of TRPV1 and P2X3 leads to reduction in colorectal mechanosensation peripherally and compensatory changes and/or disinhibition of other channels centrally, 2) combined pharmacological antagonism produces more robust attenuation of mechanosensation peripherally than does antagonism of either channel alone, and 3) the relative importance of these channels appears to be enhanced in colorectal hypersensitivity. PMID:23989007

[Effects of ingredients from Chinese herbs with nature of cold or hot on expression of TRPV1 and TRPM8].

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Sui, Feng; Yang, Na; Zhang, Changbin; Du, Xinliang; Li, Lanfang; Weng, Xiaogang; Guo, Shuying; Huo, Hairu; Jiang, Tingliang

2010-06-01

To study the effects of the ingredients from Chinese herbs with the nature of cold or hot on the expression of TRPV1 and TRPM8. The effects of ingredients from herbs on primary culture DRG neurons are observed in vitro. The expression quantity of gene is detected by the method of real time PCR. the 2 (-deltadeltaCT) method is applied to analyze the data. Ingredients from herbs with the nature of cold up-regulate the expression level of TRPV1 and down-regulate that of TRPM8, especially under the temperature condition of 39 degrees C; while ingredients from herbs with the nature of hot up-regulate the expression level of TRPM8 and down-regulated that of TRPV1, which is more significant under the temperature condition of 19 degrees C. The regulatory changes of TRPV1 and TRPM8 mRNA expression induced by the chemical ingredients might be related to the cold and hot natures of the herbs from which the ingredients are extracted. And this could be one of the therapeutic mechanisms for the treatment of Chinese herbal medicines to cold- and heat-related diseases.

(Patho)physiological implications of the novel epithelial Ca2+ channels TRPV5 and TRPV6.

NARCIS (Netherlands)

Nijenhuis, T.; Hoenderop, J.G.J.; Nilius, B.; Bindels, R.J.M.

2003-01-01

The epithelial Ca(2+) channels TRPV5 and TRPV6 constitute the apical Ca(2+) entry mechanism in active Ca(2+) (re)absorption. These two members of the superfamily of transient receptor potential (TRP) channels were cloned from the vitamin-D-responsive epithelia of kidney and small intestine and

Reducing and oxidizing agents sensitize heat-activated vanilloid receptor (TRPV1) current

Czech Academy of Sciences Publication Activity Database

Sušánková, Klára; Toušová, Karolina; Vyklický st., Ladislav; Teisinger, Jan; Vlachová, Viktorie

2006-01-01

Roč. 70, č. 1 (2006), s. 383-394 ISSN 0026-895X R&D Projects: GA MŠk(CZ) 1M0517; GA MŠk(CZ) LC554; GA ČR(CZ) GA309/04/0496; GA ČR(CZ) GA305/06/0319 Institutional research plan: CEZ:AV0Z5011922 Keywords : capsaicin * TRPV1 * receptor Subject RIV: ED - Physiology Impact factor: 4.469, year: 2006

RAGE-dependent potentiation of TRPV1 currents in sensory neurons exposed to high glucose.

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Lam, Doris; Momeni, Zeinab; Theaker, Michael; Jagadeeshan, Santosh; Yamamoto, Yasuhiko; Ianowski, Juan P; Campanucci, Verónica A

2018-01-01

Diabetes mellitus is associated with sensory abnormalities, including exacerbated responses to painful (hyperalgesia) or non-painful (allodynia) stimuli. These abnormalities are symptoms of diabetic peripheral neuropathy (DPN), which is the most common complication that affects approximately 50% of diabetic patients. Yet, the underlying mechanisms linking hyperglycemia and symptoms of DPN remain poorly understood. The transient receptor potential vanilloid 1 (TRPV1) channel plays a central role in such sensory abnormalities and shows elevated expression levels in animal models of diabetes. Here, we investigated the function of TRPV1 channels in sensory neurons cultured from the dorsal root ganglion (DRG) of neonatal mice, under control (5mM) and high glucose (25mM) conditions. After maintaining DRG neurons in high glucose for 1 week, we observed a significant increase in capsaicin (CAP)-evoked currents and CAP-evoked depolarizations, independent of TRPV1 channel expression. These functional changes were largely dependent on the expression of the receptor for Advanced Glycation End-products (RAGE), calcium influx, cytoplasmic ROS accumulation, PKC, and Src kinase activity. Like cultured neurons from neonates, mature neurons from adult mice also displayed a similar potentiation of CAP-evoked currents in the high glucose condition. Taken together, our data demonstrate that under the diabetic condition, DRG neurons are directly affected by elevated levels of glucose, independent of vascular or glial signals, and dependent on RAGE expression. These early cellular and molecular changes to sensory neurons in vitro are potential mechanisms that might contribute to sensory abnormalities that can occur in the very early stages of diabetes.

TRPV1 antagonist attenuates postoperative hypersensitivity by central and peripheral mechanisms

Czech Academy of Sciences Publication Activity Database

Uchytilová, Eva; Špicarová, Diana; Paleček, Jiří

2014-01-01

Roč. 10, č. 2014 (2014), s. 67 ISSN 1744-8069 R&D Projects: GA MŠk(CZ) EE2.3.30.0025; GA MŠk(CZ) ED1.1.00/02.0109; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) LH12058; GA ČR(CZ) GPP303/12/P510 Institutional support: RVO:67985823 Keywords : SB366791 * TRPV1 * allodynia * hyperalgesia * surgical pain * spinal cord Subject RIV: FH - Neurology Impact factor: 3.654, year: 2014

Dissecting the role of TRPV1 in detecting multiple trigeminal irritants in three behavioral assays for sensory irritation [v1; ref status: indexed, http://f1000r.es/p8

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CJ Saunders

2013-03-01

Full Text Available Polymodal neurons of the trigeminal nerve innervate the nasal cavity, nasopharynx, oral cavity and cornea. Trigeminal nociceptive fibers express a diverse collection of receptors and are stimulated by a wide variety of chemicals. However, the mechanism of stimulation is known only for relatively few of these compounds. Capsaicin, for example, activates transient receptor potential vanilloid 1 (TRPV1 channels. In the present study, wildtype (C57Bl/6J and TRPV1 knockout mice were tested in three behavioral assays for irritation to determine if TRPV1 is necessary to detect trigeminal irritants in addition to capsaicin. In one assay mice were presented with a chemical via a cotton swab and their response scored on a 5 level scale. In another assay, a modified two bottle preference test, which avoids the confound of mixing irritants with the animal’s drinking water, was used to assess aversion. In the final assay, an air dilution olfactometer was used to administer volatile compounds to mice restrained in a double-chambered plethysmograph where respiratory reflexes were monitored. TRPV1 knockouts showed deficiencies in the detection of benzaldehyde, cyclohexanone and eugenol in at least one assay. However, cyclohexanone was the only substance tested that appears to act solely through TRPV1.

TRPV1 Antagonism by Capsazepine Modulates Innate Immune Response in Mice Infected with Plasmodium berghei ANKA

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Elizabeth S. Fernandes

2014-01-01

Full Text Available Thousands of people suffer from severe malaria every year. The innate immune response plays a determinant role in host’s defence to malaria. Transient receptor potential vanilloid 1 (TRPV1 modulates macrophage-mediated responses in sepsis, but its role in other pathogenic diseases has never been addressed. We investigated the effects of capsazepine, a TRPV1 antagonist, in malaria. C57BL/6 mice received 105 red blood cells infected with Plasmodium berghei ANKA intraperitoneally. Noninfected mice were used as controls. Capsazepine or vehicle was given intraperitoneally for 6 days. Mice were culled on day 7 after infection and blood and spleen cell phenotype and activation were evaluated. Capsazepine decreased circulating but not spleen F4/80+Ly6G+ cell numbers as well as activation of both F4/80+and F4/80+Ly6G+ cells in infected animals. In addition, capsazepine increased circulating but not spleen GR1+ and natural killer (NK population, without interfering with natural killer T (NKT cell numbers and blood NK and NKT activation. However, capsazepine diminished CD69 expression in spleen NKT but not NK cells. Infection increased lipid peroxidation and the release of TNFα and IFNγ, although capsazepine-treated group exhibited lower levels of lipid peroxidation and TNFα. Capsazepine treatment did not affect parasitaemia. Overall, TRPV1 antagonism modulates the innate immune response to malaria.

Asynchronous control for networked systems

CERN Document Server

Rubio, Francisco; Bencomo, Sebastián

2015-01-01

This book sheds light on networked control systems; it describes different techniques for asynchronous control, moving away from the periodic actions of classical control, replacing them with state-based decisions and reducing the frequency with which communication between subsystems is required. The text focuses specially on event-based control. Split into two parts, Asynchronous Control for Networked Systems begins by addressing the problems of single-loop networked control systems, laying out various solutions which include two alternative model-based control schemes (anticipatory and predictive) and the use of H2/H∞ robust control to deal with network delays and packet losses. Results on self-triggering and send-on-delta sampling are presented to reduce the need for feedback in the loop. In Part II, the authors present solutions for distributed estimation and control. They deal first with reliable networks and then extend their results to scenarios in which delays and packet losses may occur. The novel ...

Generalized Asynchronous Systems

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E. S. Kudryashova

2012-01-01

Full Text Available The paper consider a mathematical model of a concurrent system, the special case of which is an asynchronous system. Distributed asynchronous automata are introduced here. It is proved that Petri nets and transition systems with independence can be considered as distributed asynchronous automata. Time distributed asynchronous automata are defined in a standard way by correspondence which relates events with time intervals. It is proved that the time distributed asynchronous automata generalize time Petri nets and asynchronous systems.

TRPV4 Regulates Tight Junctions and Affects Differentiation in a Cell Culture Model of the Corneal Epithelium.

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Martínez-Rendón, Jacqueline; Sánchez-Guzmán, Erika; Rueda, Angélica; González, James; Gulias-Cañizo, Rosario; Aquino-Jarquín, Guillermo; Castro-Muñozledo, Federico; García-Villegas, Refugio

2017-07-01

TRPV4 (transient receptor potential vanilloid 4) is a cation channel activated by hypotonicity, moderate heat, or shear stress. We describe the expression of TRPV4 during the differentiation of a corneal epithelial cell model, RCE1(5T5) cells. TRPV4 is a late differentiation feature that is concentrated in the apical membrane of the outmost cell layer of the stratified epithelia. Ca 2+ imaging experiments showed that TRPV4 activation with GSK1016790A produced an influx of calcium that was blunted by the specific TRPV4 blocker RN-1734. We analyzed the involvement of TRPV4 in RCE1(5T5) epithelial differentiation by measuring the development of transepithelial electrical resistance (TER) as an indicator of the tight junction (TJ) assembly. We showed that TRPV4 activity was necessary to establish the TJ. In differentiated epithelia, activation of TRPV4 increases the TER and the accumulation of claudin-4 in cell-cell contacts. Epidermal Growth Factor (EGF) up-regulates the TER of corneal epithelial cultures, and we show here that TRPV4 activation mimicked this EGF effect. Conversely, TRPV4 inhibition or knock down by specific shRNA prevented the increase in TER. Moreover, TRPP2, an EGF-activated channel that forms heteromeric complexes with TRPV4, is also concentrated in the outmost cell layer of differentiated RCE1(5T5) sheets. This suggests that the EGF regulation of the TJ may involve a heterotetrameric TRPV4-TRPP2 channel. These results demonstrated TRPV4 activity was necessary for the correct establishment of TJ in corneal epithelia and as well as the regulation of both the barrier function of TJ and its ability to respond to EGF. J. Cell. Physiol. 232: 1794-1807, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Asynchronous LMS adaptive equalization

NARCIS (Netherlands)

Bergmans, J.W.M.; Lin, M.Y.; Modrie, D.; Otte, R.

2005-01-01

Digital data receivers often operate at a fixed sampling rate 1/Ts that is asynchronous to the baud rate 1/T. A digital equalizer that processes the incoming signal will also operate in the asynchronous clock domain. Existing adaptation techniques for this equalizer involve an error sequence ek that

Transient receptor potential vanilloid-3 (TRPV3) activation plays a central role in cardiac fibrosis induced by pressure overload in rats via TGF-β1 pathway.

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Liu, Yan; Qi, Hanping; E, Mingyao; Shi, Pilong; Zhang, Qianhui; Li, Shuzhi; Wang, Ye; Cao, Yonggang; Chen, Yunping; Ba, Lina; Gao, Jingquan; Huang, Wei; Sun, Hongli

2018-02-01

Cardiac fibrosis is a common pathologic change along with pressure overload. Recent studies indicated that transient receptor potential (TRP) channels played multiple roles in heart. However, the functional role of transient receptor potential vanilloid-3 (TRPV3) in cardiac fibrosis remained unclear. The present study was designed to investigate the relationship between TRPV3 activation and pressure overload-induced cardiac fibrosis. Pressure overload rats were successfully established by abdominal aortic constriction (AAC), and cardiac fibrosis was simulated by 100 nM angiotensin II (Ang II) in neonatal cardiac fibroblasts. Echocardiographic parameters, cardiac fibroblast proliferation, cell cycle, intracellular calcium concentration ([Ca 2+ ] i ), and the protein expressions of collagen I, collagen III, transforming growth factor beta 1 (TGF-β 1 ), cyclin E, and cyclin-dependent kinase 2 (CDK2) were measured. Echocardiographic and histological measurements suggested that the activation of TRPV3 exacerbated the cardiac dysfunction and increased interstitial fibrosis in pressure overload rats. Further results showed that TRPV3 activation upregulated the expressions of collagen I, collagen III, TGF-β 1 , cyclin E, and CDK2 in vivo and in vitro. At the same time, blocking TGF-β 1 pathway could partially reverse the effect of TRPV3 activation. These results suggested that TRPV3 activation exacerbated cardiac fibrosis by promoting cardiac fibroblast proliferation through TGF-β 1 /CDK2/cyclin E pathway in the pressure-overloaded rat hearts.

Reduced tissue osmolarity increases TRPV4 expression and pro-inflammatory cytokines in intervertebral disc cells

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BA Walter

2016-07-01

Full Text Available The mechanical behaviour and cellular metabolism of intervertebral discs (IVDs and articular cartilage are strongly influenced by their proteoglycan content and associated osmotic properties. This osmotic environment is a biophysical signal that changes with disease and may contribute to the elevated matrix breakdown and altered biologic response to loading observed in IVD degeneration and osteoarthritis. This study tested the hypothesis that changes in osmo-sensation by the transient receptor potential vallinoid-4 (TRPV4 ion channel occur with disease and contribute to the inflammatory environment found during degeneration. Immunohistochemistry on bovine IVDs from an inflammatory organ culture model were used to investigate if TRPV4 is expressed in the IVD and how expression changes with degeneration. Western blot, live-cell calcium imaging, and qRT-PCR were used to investigate whether osmolarity changes or tumour necrosis factor α (TNFα regulate TRPV4 expression, and how altered TRPV4 expression influences calcium signalling and pro-inflammatory cytokine expression. TRPV4 expression correlated with TNFα expression, and was increased when cultured in reduced medium osmolarity and unaltered with TNFα-stimulation. Increased TRPV4 expression increased the calcium flux following TRPV4 activation and increased interleukin-1β (IL-1β and IL-6 gene expression in IVD cells. TRPV4 expression was qualitatively elevated in regions of aggrecan depletion in degenerated human IVDs. Collectively, results suggest that reduced tissue osmolarity, likely following proteoglycan degradation, can increase TRPV4 signalling and enhance pro-inflammatory cytokine production, suggesting changes in TRPV4 mediated osmo-sensation may contribute to the progressive matrix breakdown in disease.

Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.

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Nellie Y Loh

Full Text Available Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1. Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5 and 6 (Trpv6 genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P. Compared to wild-type littermates, heterozygous (Trpv5(682P/+ and homozygous (Trpv5(682P/682P mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+ and Trpv5(682P/682P mice consistent with a trafficking defect. In addition, Trpv5(682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings

The contribution of the endogenous TRPV1 ligands 9-HODE and 13-HODE to nociceptive processing and their role in peripheral inflammatory pain mechanisms.

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Alsalem, Mohammad; Wong, Amy; Millns, Paul; Arya, Pallavi Huma; Chan, Michael Siang Liang; Bennett, Andrew; Barrett, David A; Chapman, Victoria; Kendall, David A

2013-04-01

The transient receptor potential vanilloid type 1 (TRPV1) plays a fundamental role in the detection of heat and inflammatory pain responses. Here we investigated the contribution of two potential endogenous ligands [9- and 13- hydroxyoctadecadienoic acid (HODE)] to TRPV1-mediated noxious responses and inflammatory pain responses. 9- and 13-HODE, and their precursor, linoleic acid, were measured in dorsal root ganglion (DRG) neurons and in the hindpaws of control and carrageenan-inflamed rats by liquid chromatography/tandem electrospray mass spectrometry. Calcium imaging studies of DRG neurons were employed to determine the role of TRPV1 in mediating linoleic acid, 9-HODE- and 13-HODE-evoked responses, and the contribution of 15-lipoxygenase to the generation of the HODEs. Behavioural studies investigated the contribution of 9- and 13-HODE and 15-lipoxygenase to inflammatory pain behaviour. 9-HODE (35 ± 7 pmol g(-1)) and 13-HODE (32 ± 6 pmol g(-1)) were detected in hindpaw tissue, but were below the limits of detection in DRGs. Following exposure to linoleic acid, 9- and 13-HODE were detected in DRGs and TRPV1 antagonist-sensitive calcium responses evoked, which were blocked by the 15-lipoxygenase inhibitor PD146176 and an anti-13-HODE antibody. Levels of linoleic acid were significantly increased in the carrageenan-inflamed hindpaw (P PD146176 significantly (P < 0.01) attenuated carrageenan-induced hyperalgesia. This study demonstrates that, although 9- and 13-HODE can activate TRPV1 in DRG cell bodies, the evidence for a role of these lipids as endogenous peripheral TRPV1 ligands in a model of inflammatory pain is at best equivocal. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Asynchronous L1-gain control of uncertain switched positive linear systems with dwell time.

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Li, Yang; Zhang, Hongbin

2018-04-01

In this paper, dwell time (DT) stability, L 1 -gain performance analysis and asynchronous L 1 -gain controller design problems of uncertain switched positive linear systems (SPLSs) are investigated. Via a time-scheduled multiple linear co-positive Lyapunov function (TSMLCLF) approach, convex sufficient conditions of DT stability and L 1 -gain performance of SPLSs with interval and polytopic uncertainties are presented. Furthermore, by utilizing the feature that the TSMLCLF keeps decreasing even if the controller is running asynchronously with the system, the asynchronous L 1 -gain controller design problem of SPLSs with interval and polytopic uncertainties is investigated. Convex sufficient conditions of the existence of time-varying asynchronous state-feedback controller which can ensure the closed-loop system's positivity, stability and L 1 -gain performance are established, and the controller gain matrices can be calculated instantaneously online. The obtained L 1 -gain in the paper is standard. All the results are presented in terms of linear programming. A practical example is provided to show the effectiveness of the results. Copyright © 2018 ISA. Published by Elsevier Ltd. All rights reserved.

Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice.

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Liao, Hsien-Yin; Hsieh, Ching-Liang; Huang, Chun-Ping; Lin, Yi-Wen

2017-02-13

Pain is associated with several conditions, such as inflammation, that result from altered peripheral nerve properties. Electroacupuncture (EA) is a common Chinese clinical medical technology used for pain management. Using an inflammatory pain mouse model, we investigated the effects of EA on the regulation of neurons, microglia, and related molecules. Complete Freund's adjuvant (CFA) injections produced a significant mechanical and thermal hyperalgesia that was reversed by EA or a transient receptor potential V1 (TRPV1) gene deletion. The expression of the astrocytic marker glial fibrillary acidic protein (GFAP), the microglial marker Iba-1, S100B, receptor for advanced glycation end-products (RAGE), TRPV1, and other related molecules was dramatically increased in the dorsal root ganglion (DRG) and spinal cord dorsal horn (SCDH) of CFA-treated mice. This effect was reversed by EA and TRPV1 gene deletion. In addition, endomorphin (EM) and N 6 -cyclopentyladenosine (CPA) administration reliably reduced mechanical and thermal hyperalgesia, thereby suggesting the involvement of opioid and adenosine receptors. Furthermore, blocking of opioid and adenosine A1 receptors reversed the analgesic effects of EA. Our study illustrates the substantial therapeutic effects of EA against inflammatory pain and provides a novel and detailed mechanism underlying EA-mediated analgesia via neuronal and non-neuronal pathways.

Update on the role of spinal cord TRPV1 receptors in pain modulation

Czech Academy of Sciences Publication Activity Database

Špicarová, Diana; Nerandžič, Vladimír; Paleček, Jiří

2014-01-01

Roč. 63, Suppl.1 (2014), S225-S236 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA305/09/1228; GA MŠk(CZ) LH12058; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GPP303/12/P510 Grant - others:Univerzita Karlova(CZ) 309211 Institutional support: RVO:67985823 Keywords : hyperalgesia * capsaicin * TRPV1 * Spinal cord Subject RIV: FH - Neurology Impact factor: 1.293, year: 2014

TRPV6 determines the effect of vitamin D3 on prostate cancer cell growth.

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V'yacheslav Lehen'kyi

Full Text Available Despite remarkable advances in the therapy and prevention of prostate cancer it is still the second cause of death from cancer in industrialized countries. Many therapies initially shown to be beneficial for the patients were abandoned due to the high drug resistance and the evolution rate of the tumors. One of the prospective therapeutical agents even used in the first stage clinical trials, 1,25-dihydroxyvitamin D3, was shown to be either unpredictable or inefficient in many cases. We have already shown that TRPV6 calcium channel, which is the direct target of 1,25-dihydroxyvitamin D3 receptor, positively controls prostate cancer proliferation and apoptosis resistance (Lehen'kyi et al., Oncogene, 2007. However, how the known 1,25-dihydroxyvitamin D3 antiproliferative effects may be compatible with the upregulation of pro-oncogenic TRPV6 channel remains a mystery. Here we demonstrate that in low steroid conditions 1,25-dihydroxyvitamin D3 upregulates the expression of TRPV6, enhances the proliferation by increasing the number of cells entering into S-phase. We show that these pro-proliferative effects of 1,25-dihydroxyvitamin D3 are directly mediated via the overexpression of TRPV6 channel which increases calcium uptake into LNCaP cells. The apoptosis resistance of androgen-dependent LNCaP cells conferred by TRPV6 channel is drastically inversed when 1,25-dihydroxyvitamin D3 effects were combined with the successful TRPV6 knockdown. In addition, the use of androgen-deficient DU-145 and androgen-insensitive LNCaP C4-2 cell lines allowed to suggest that the ability of 1,25-dihydroxyvitamin D3 to induce the expression of TRPV6 channel is a crucial determinant of the success or failure of 1,25-dihydroxyvitamin D3-based therapies.

Interaction with phosphoinositides confers adaptation onto the TRPV1 pain receptor.

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Jing Yao

2009-02-01

Full Text Available Adaptation is a common feature of many sensory systems. But its occurrence to pain sensation has remained elusive. Here we address the problem at the receptor level and show that the capsaicin ion channel TRPV1, which mediates nociception at the peripheral nerve terminals, possesses properties essential to the adaptation of sensory responses. Ca(2+ influx following the channel opening caused a profound shift (approximately 14-fold of the agonist sensitivity, but did not alter the maximum attainable current. The shift was adequate to render the channel irresponsive to normally saturating concentrations, leaving the notion that the channel became no longer functional after desensitization. By simultaneous patch-clamp recording and total internal reflection fluorescence (TIRF imaging, it was shown that the depletion of phosphatidylinositol 4,5-bisphosphate (PIP2 induced by Ca(2+ influx had a rapid time course synchronous to the desensitization of the current. The extent of the depletion was comparable to that by rapamycin-induced activation of a PIP2 5-phosphatase, which also caused a significant reduction of the agonist sensitivity without affecting the maximum response. These results support a prominent contribution of PIP2 depletion to the desensitization of TRPV1 and suggest the adaptation as a possible physiological function for the Ca(2+ influx through the channel.

A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats.

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Kirkedal, Christian; Wegener, Gregers; Moreira, Fabricio; Joca, Sâmia Regiane Lourenco; Liebenberg, Nico

2017-12-01

The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1-R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models. We investigated this assumption by administering the dual inhibitor of AEA hydrolysis and TRPV1 activation N-arachidonoyl-serotonin (AA-5HT) into the medial prefrontal cortex of rats. AA-5HT was given in three different doses (0.125, 0.250, 0.500 nmol/0.4 µl/side) and rat behaviour was assessed in the forced swim test. Our results show significant antidepressant-like effect of AA-5HT (0.250 nmol) but no effects of low or high doses. The effect of 0.250 nmol AA-5HT was partially attenuated when coadministering the inverse CB1-agonist rimonabant (1.6 µg). A 0.250 nmol of AA-5HT administration into the medial prefrontal cortex induced a significant antidepressant-like effect that was partially attenuated by locally blocking CB1-receptor.

Structural mechanism underlying capsaicin binding and activation of TRPV1 ion channel

OpenAIRE

Yang, Fan; Xiao, Xian; Cheng, Wei; Yang, Wei; Yu, Peilin; Song, Zhenzhen; Yarov-Yarovoy, Vladimir; Zheng, Jie

2015-01-01

Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2-to-4.5 ? resolution, however important details required for mechanistic understandings are unavailable: capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions. We obtained the missing atomic-level details by iterative computation, which were c...

TRP channels in calcium homeostasis: from hormonal control to structure-function relationship of TRPV5 and TRPV6.

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van Goor, Mark K C; Hoenderop, Joost G J; van der Wijst, Jenny

2017-06-01

Maintaining plasma calcium levels within a narrow range is of vital importance for many physiological functions. Therefore, calcium transport processes in the intestine, bone and kidney are tightly regulated to fine-tune the rate of absorption, storage and excretion. The TRPV5 and TRPV6 calcium channels are viewed as the gatekeepers of epithelial calcium transport. Several calciotropic hormones control the channels at the level of transcription, membrane expression, and function. Recent technological advances have provided the first near-atomic resolution structural models of several TRPV channels, allowing insight into their architecture. While this field is still in its infancy, it has increased our understanding of molecular channel regulation and holds great promise for future structure-function studies of these ion channels. This review will summarize the mechanisms that control the systemic calcium balance, as well as extrapolate structural views to the molecular functioning of TRPV5/6 channels in epithelial calcium transport. Copyright © 2016. Published by Elsevier B.V.

Arterial response to shear stress critically depends on endothelial TRPV4 expression.

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Veronika Hartmannsgruber

Full Text Available BACKGROUND: In blood vessels, the endothelium is a crucial signal transduction interface in control of vascular tone and blood pressure to ensure energy and oxygen supply according to the organs' needs. In response to vasoactive factors and to shear stress elicited by blood flow, the endothelium secretes vasodilating or vasocontracting autacoids, which adjust the contractile state of the smooth muscle. In endothelial sensing of shear stress, the osmo- and mechanosensitive Ca(2+-permeable TRPV4 channel has been proposed to be candidate mechanosensor. Using TRPV4(-/- mice, we now investigated whether the absence of endothelial TRPV4 alters shear-stress-induced arterial vasodilation. METHODOLOGY/PRINCIPAL FINDINGS: In TRPV4(-/- mice, loss of the TRPV4 protein was confirmed by Western blot, immunohistochemistry and by in situ-patch-clamp techniques in carotid artery endothelial cells (CAEC. Endothelium-dependent vasodilation was determined by pressure myography in carotid arteries (CA from TRPV4(-/- mice and wild-type littermates (WT. In WT CAEC, TRPV4 currents could be elicited by TRPV4 activators 4alpha-phorbol-12,13-didecanoate (4alphaPDD, arachidonic acid (AA, and by hypotonic cell swelling (HTS. In striking contrast, in TRPV4(-/- mice, 4alphaPDD did not produce currents and currents elicited by AA and HTS were significantly reduced. 4alphaPDD caused a robust and endothelium-dependent vasodilation in WT mice, again conspicuously absent in TRPV4(-/- mice. Shear stress-induced vasodilation could readily be evoked in WT, but was completely eliminated in TRPV4(-/- mice. In addition, flow/reperfusion-induced vasodilation was significantly reduced in TRPV4(-/- vs. WT mice. Vasodilation in response to acetylcholine, vasoconstriction in response to phenylephrine, and passive mechanical compliance did not differ between genotypes, greatly underscoring the specificity of the above trpv4-dependent phenotype for physiologically relevant shear stress

Arterial Response to Shear Stress Critically Depends on Endothelial TRPV4 Expression

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Kacik, Michael; Kaistha, Anuradha; Grgic, Ivica; Harteneck, Christian; Liedtke, Wolfgang; Hoyer, Joachim; Köhler, Ralf

2007-01-01

Background In blood vessels, the endothelium is a crucial signal transduction interface in control of vascular tone and blood pressure to ensure energy and oxygen supply according to the organs' needs. In response to vasoactive factors and to shear stress elicited by blood flow, the endothelium secretes vasodilating or vasocontracting autacoids, which adjust the contractile state of the smooth muscle. In endothelial sensing of shear stress, the osmo- and mechanosensitive Ca2+-permeable TRPV4 channel has been proposed to be candidate mechanosensor. Using TRPV4−/− mice, we now investigated whether the absence of endothelial TRPV4 alters shear-stress-induced arterial vasodilation. Methodology/Principal Findings In TRPV4−/− mice, loss of the TRPV4 protein was confirmed by Western blot, immunohistochemistry and by in situ-patch–clamp techniques in carotid artery endothelial cells (CAEC). Endothelium-dependent vasodilation was determined by pressure myography in carotid arteries (CA) from TRPV4−/− mice and wild-type littermates (WT). In WT CAEC, TRPV4 currents could be elicited by TRPV4 activators 4α-phorbol-12,13-didecanoate (4αPDD), arachidonic acid (AA), and by hypotonic cell swelling (HTS). In striking contrast, in TRPV4−/− mice, 4αPDD did not produce currents and currents elicited by AA and HTS were significantly reduced. 4αPDD caused a robust and endothelium-dependent vasodilation in WT mice, again conspicuously absent in TRPV4−/− mice. Shear stress-induced vasodilation could readily be evoked in WT, but was completely eliminated in TRPV4−/− mice. In addition, flow/reperfusion-induced vasodilation was significantly reduced in TRPV4−/− vs. WT mice. Vasodilation in response to acetylcholine, vasoconstriction in response to phenylephrine, and passive mechanical compliance did not differ between genotypes, greatly underscoring the specificity of the above trpv4-dependent phenotype for physiologically relevant shear stress. Conclusions

TRPV4 is associated with central rather than nephrogenic osmoregulation.

NARCIS (Netherlands)

Janas, S.; Seghers, F.; Schakman, O.; Alsady, M.; Deen, P.M.; Vriens, J.; Tissir, F.; Nilius, B.; Loffing, J.; Gailly, P.; Devuyst, O.

2016-01-01

TRPV4 is a polymodal cation channel expressed in osmosensitive neurons of the hypothalamus and in the mammalian nephron. The segmental distribution and role(s) of TRPV4 in osmoregulation remain debated. We investigated the renal distribution pattern of TRPV4 and the functional consequences of its

Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis.

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Fonseca, B M; Correia-da-Silva, G; Teixeira, N A

2018-05-01

Among a variety of phytocannabinoids, Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most promising therapeutic compounds. Besides the well-known palliative effects in cancer patients, cannabinoids have been shown to inhibit in vitro growth of tumor cells. Likewise, the major endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), induce tumor cell death. The purpose of the present study was to characterize cannabinoid elements and evaluate the effect of cannabinoids in endometrial cancer cell viability. The presence of cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1), and endocannabinoid-metabolizing enzymes were determined by qRT-PCR and Western blot. We also examined the effects and the underlying mechanisms induced by eCBs and phytocannabinoids in endometrial cancer cell viability. Besides TRPV1, both EC cell lines express all the constituents of the endocannabinoid system. We observed that at concentrations higher than 5 μM, eCBs and CBD induced a significant reduction in cell viability in both Ishikawa and Hec50co cells, whereas THC did not cause any effect. In Ishikawa cells, contrary to Hec50co, treatment with AEA and CBD resulted in an increase in the levels of activated caspase -3/-7, in cleaved PARP, and in reactive oxygen species generation, confirming that the reduction in cell viability observed in the MTT assay was caused by the activation of the apoptotic pathway. Finally, these effects were dependent on TRPV1 activation and intracellular calcium levels. These data indicate that cannabinoids modulate endometrial cancer cell death. Selective targeting of TPRV1 by AEA, CBD, or other stable analogues may be an attractive research area for the treatment of estrogen-dependent endometrial carcinoma. Our data further support the evaluation of CBD and CBD-rich extracts for the potential treatment of endometrial cancer, particularly, that has become non-responsive to common therapies.

Asynchronous data change notification between database server and accelerator controls system

International Nuclear Information System (INIS)

Fu, W.; Morris, J.; Nemesure, S.

2011-01-01

Database data change notification (DCN) is a commonly used feature. Not all database management systems (DBMS) provide an explicit DCN mechanism. Even for those DBMS's which support DCN (such as Oracle and MS SQL server), some server side and/or client side programming may be required to make the DCN system work. This makes the setup of DCN between database server and interested clients tedious and time consuming. In accelerator control systems, there are many well established software client/server architectures (such as CDEV, EPICS, and ADO) that can be used to implement data reflection servers that transfer data asynchronously to any client using the standard SET/GET API. This paper describes a method for using such a data reflection server to set up asynchronous DCN (ADCN) between a DBMS and clients. This method works well for all DBMS systems which provide database trigger functionality. Asynchronous data change notification (ADCN) between database server and clients can be realized by combining the use of a database trigger mechanism, which is supported by major DBMS systems, with server processes that use client/server software architectures that are familiar in the accelerator controls community (such as EPICS, CDEV or ADO). This approach makes the ADCN system easy to set up and integrate into an accelerator controls system. Several ADCN systems have been set up and used in the RHIC-AGS controls system.

Asynchronous zero-forcing adaptive equalization

NARCIS (Netherlands)

Bergmans, J.W.M.; Pozidis, H.; Lin, M.Y.

2005-01-01

Digital data receivers often operate at a fixed sampling rate 1/Ts that is asynchronous to the baud rate 1/T. A digital equalizer that processes the incoming signal will also be asynchronous, and its adaptation is commonly based on extensions of the LMS algorithm. In this paper, we develop and

Supercooling Agent Icilin Blocks a Warmth-Sensing Ion Channel TRPV3

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Muhammad Azhar Sherkheli

2012-01-01

Full Text Available Transient receptor potential vanilloid subtype 3 (TRPV3 is a thermosensitive ion channel expressed in a variety of neural cells and in keratinocytes. It is activated by warmth (33–39°C, and its responsiveness is dramatically increased at nociceptive temperatures greater than 40°C. Monoterpenoids and 2-APB are chemical activators of TRPV3 channels. We found that Icilin, a known cooling substance and putative ligand of TRPM8, reversibly inhibits TRPV3 activity at nanomolar concentrations in expression systems like Xenopus laeves oocytes, HEK-293 cells, and in cultured human keratinocytes. Our data show that icilin's antagonistic effects for the warm-sensitive TRPV3 ion channel occurs at very low concentrations. Therefore, the cooling effect evoked by icilin may at least in part be due to TRPV3 inhibition in addition to TRPM8 potentiation. Blockade of TRPV3 activity by icilin at such low concentrations might have important implications for overall cooling sensations detected by keratinocytes and free nerve endings in skin. We hypothesize that blockage of TRPV3 might be a signal for cool-sensing systems (like TRPM8 to beat up the basal activity resulting in increased cold perception when warmth sensors (like TRPV3 are shut off.

Heavy metal cations permeate the TRPV6 epithelial cation channel.

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Kovacs, Gergely; Danko, Tamas; Bergeron, Marc J; Balazs, Bernadett; Suzuki, Yoshiro; Zsembery, Akos; Hediger, Matthias A

2011-01-01

TRPV6 belongs to the vanilloid family of the transient receptor potential channel (TRP) superfamily. This calcium-selective channel is highly expressed in the duodenum and the placenta, being responsible for calcium absorption in the body and fetus. Previous observations have suggested that TRPV6 is not only permeable to calcium but also to other divalent cations in epithelial tissues. In this study, we tested whether TRPV6 is indeed also permeable to cations such as zinc and cadmium. We found that the basal intracellular calcium concentration was higher in HEK293 cells transfected with hTRPV6 than in non-transfected cells, and that this difference almost disappeared in nominally calcium-free solution. Live cell imaging experiments with Fura-2 and NewPort Green DCF showed that overexpression of human TRPV6 increased the permeability for Ca(2+), Ba(2+), Sr(2+), Mn(2+), Zn(2+), Cd(2+), and interestingly also for La(3+) and Gd(3+). These results were confirmed using the patch clamp technique. (45)Ca uptake experiments showed that cadmium, lanthanum and gadolinium were also highly efficient inhibitors of TRPV6-mediated calcium influx at higher micromolar concentrations. Our results suggest that TRPV6 is not only involved in calcium transport but also in the transport of other divalent cations, including heavy metal ions, which may have toxicological implications. Copyright © 2010 Elsevier Ltd. All rights reserved.

Radiosynthesis of [11C]SB-705498, a selective transient receptor potential Vanilloid 1 (TRPV1) receptor antagonist

International Nuclear Information System (INIS)

Dolle, F.; Bramoulle, Y.; Deverre, J.R.; Bottlaender, M.; Passchier, J.

2011-01-01

Complete text of publication follows: Objectives: The transient receptor potential vanilloid 1 (TRPV1) receptor, previously known as the vanilloid receptor 1 (VR1), is a non-selective cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptor is involved in pain and sensitisation associated with tissue injury and inflammation and therefore represents a pharmacological target of choice for the development of novel therapeutic agents for the treatment of chronic pain, migraine and gastrointestinal disorders. Among a novel series of pyrrolidinyl ureas recently discovered by GSK, SB-705498 (1, namely 1-(2-bromophenyl)-3-[(R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-yl]urea) has been identified as a potent, selective and orally bioavailable TRPV1 antagonist and considered for positron emission tomography studies. SB-705498 (1) has therefore been isotopically labelled with the short-lived positron-emitter carbon-11 (t1/2: 20.38 min) at its urea site using [ 11 C]phosgene in a one-pot two-step process, via the intermediate preparation of 2-bromophenyl [ 11 C]isocyanate. Methods: Carbon-11-labeling of SB-705498 comprises: (A) Trapping of [ 11 C]phosgene (radio-synthesized from cyclotron-produced [ 11 C]methane via [ 11 C]carbon tetrachloride using minor modifications of published processes) at room temperature for 1 to 2 minutes in 250 μL of acetonitrile containing 0.6 μmole of 2-bromoaniline (2) giving 2-bromophenyl [ 11 C]isocyanate ([ 11 C]-3), followed by (B) addition of an excess of chiral (R)-1-(5- trifluoromethylpyridin-2-yl)pyrrolidin-3-ylamine (4, 40 μmoles in 500 μL of acetonitrile) as the second amine and reaction at room temperature for an additional one minute giving the desired urea derivative ([ 11 C]SB-705498 ([ 11 C]-1)), (C) dilution of the crude reaction mixture with water (500 μL) containing 4% (v:v) of DEA, injection and purification on a semi-preparative Waters Symmetry R C18 HPLC

Loss of TRPV2 Homeostatic Control of Cell Proliferation Drives Tumor Progression

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Sonia Liberati

2014-02-01

Full Text Available Herein we evaluate the involvement of the TRPV2 channel, belonging to the Transient Receptor Potential Vanilloid channel family (TRPVs, in development and progression of different tumor types. In normal cells, the activation of TRPV2 channels by growth factors, hormones, and endocannabinoids induces a translocation of the receptor from the endosomal compartment to the plasma membrane, which results in abrogation of cell proliferation and induction of cell death. Consequently, loss or inactivation of TRPV2 signaling (e.g., glioblastomas, induces unchecked proliferation, resistance to apoptotic signals and increased resistance to CD95-induced apoptotic cell death. On the other hand, in prostate cancer cells, Ca2+-dependent activation of TRPV2 induced by lysophospholipids increases the invasion of tumor cells. In addition, the progression of prostate cancer to the castration-resistant phenotype is characterized by de novo TRPV2 expression, with higher TRPV2 transcript levels in patients with metastatic cancer. Finally, TRPV2 functional expression in tumor cells can also depend on the presence of alternative splice variants of TRPV2 mRNA that act as dominant-negative mutant of wild-type TRPV2 channels, by inhibiting its trafficking and translocation to the plasma membrane. In conclusion, as TRP channels are altered in human cancers, and their blockage impair tumor progression, they appear to be a very promising targets for early diagnosis and chemotherapy.

Increased Expression Of Toll-Like Receptor 2 Mrna Following Permanent Middle Cerebral Artery Occlusion In Rat: Role Of TRPV1 Receptors

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Amir Moghadam Ahmadi

2017-02-01

Full Text Available Background: Stroke is a major cause of mortality and long term disability in adults. TRPV1 has a pivotal role in neuroinflammation. Among TLRs, TLR2 significantly participate in induction of inflammation in brain. In this study, the effect of TRPV1 receptor agonist and antagonist on outcome and gene expression of TLR2 in a rat model of permanent middle cerebral artery occlusion (MCAO was investigated. Methods: Forty male rats were assigned to the following groups: sham, vehicle stroke, AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke, and capsaicin (1 mg/kg; 3 h after stroke. Stroke was induced by permanent middle cerebral artery occlusion and behavioral functions were assessed 1, 3, and 7 days after stroke. Infarct volume, brain edema and mRNA expression of TLR2 were also evaluated at the end of the study. Results: While stroke animals showed infarctions and behavioral functions, we did not observe any cerebral infarction and behavioral functions in sham-operated animals. AMG9810 decreased neurological deficits 7 days after cerebral ischemia (P<0.01. In the ledged beam-walking test, the slip ratio was increased following ischemia (*P < 0.05. AMG9810 improved this index in animals undergone stroke. However, capsaicin enhanced the slip ratio 3 and 7 days after cerebral ischemia (#P<0.05. TLR2 P<0.05(mRNA expression was elevated in ischemic rats.   Conclusion: Our data indicate that pharmacological blockade of TRPV1 by AMG9810 attenuates behavioral function and mRNA expression of TLR2. Therefore, it might be useful as a potential target for the treatment of ischemic stroke.

Acidic microenvironments induce lymphangiogenesis and IL-8 production via TRPV1 activation in human lymphatic endothelial cells

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Nakanishi, Masako, E-mail: n-masako@wakayama-med.ac.jp [Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509 (Japan); Morita, Yoshihiro [Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871 (Japan); Department of Oral and Maxillofacial Surgery, Seichokai Hannan Municipal Hospital, Hannan, Osaka 599-0202 (Japan); Hata, Kenji [Department of Molecular and Cellular Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871 (Japan); Muragaki, Yasuteru, E-mail: ymuragak@wakayama-med.ac.jp [Department of Pathology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509 (Japan)

2016-07-15

Local acidosis is one of the characteristic features of the cancer microenvironment. Many reports indicate that acidosis accelerates the proliferation and invasiveness of cancer cells. However, whether acidic conditions affect lymphatic metastasis is currently unknown. In the present study, we focused on the effects of acidosis on lymphatic endothelial cells (LECs) to assess the relationship between acidic microenvironments and lymph node metastasis. We demonstrated that normal human LECs express various acid receptors by immunohistochemistry and reverse transcriptase-polymerase chain reaction (PCR). Acidic stimulation with low pH medium induced morphological changes in LECs to a spindle shape, and significantly promoted cellular growth and tube formation. Moreover, real-time PCR revealed that acidic conditions increased the mRNA expression of interleukin (IL)-8. Acidic stimulation increased IL-8 production in LECs, whereas a selective transient receptor potential vanilloid subtype 1 (TRPV1) antagonist, 5′-iodoresiniferatoxin, decreased IL-8 production. IL-8 accelerated the proliferation of LECs, and inhibition of IL-8 diminished tube formation and cell migration. In addition, phosphorylation of nuclear factor (NF)-κB was induced by acidic conditions, and inhibition of NF-κB activation reduced acid-induced IL-8 expression. These results suggest that acidic microenvironments in tumors induce lymphangiogenesis via TRPV1 activation in LECs, which in turn may promote lymphatic metastasis. - Highlights: • Acidity accelerates the growth, migration, and tube formation of LECs. • Acidic condition induces IL-8 expression in LECs. • IL-8 is critical for the changes of LECs. • IL-8 expression is induced via TRPV1 activation.

TRPV1 may increase the effectiveness of estrogen therapy on neuroprotection and neuroregeneration

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Ricardo Ramírez-Barrantes

2016-01-01

Full Text Available Aging induces physical deterioration, loss of the blood brain barrier, neuronal loss-induced mental and neurodegenerative diseases. Hypotalamus-hypophysis-gonad axis aging precedes symptoms of menopause or andropause and is a major determinant of sensory and cognitive integrated function. Sexual steroids support important functions, exert pleiotropic effects in different sensory cells, promote regeneration, plasticity and health of the nervous system. Their diminution is associated with impaired cognitive and mental health and increased risk of neurodegenerative diseases. Then, restoring neuroendocrine axes during aging can be key to enhance brain health through neuroprotection and neuroregeneration, depending on the modulation of plasticity mechanisms. Estrogen-dependent transient receptor potential cation channel, subfamily V, member 1 (TRPV1 expression induces neuroprotection, neurogenesis and regeneration on damaged tissues. Agonists of TRPV1 can modulate neuroprotection and repair of sensitive neurons, while modulators as other cognitive enhancers may improve the survival rate, differentiation and integration of neural stem cell progenitors in functional neural network. Menopause constitutes a relevant clinical model of steroidal production decline associated with progressive cognitive and mental impairment, which allows exploring the effects of hormone therapy in health outcomes such as dysfunction of CNS. Simulating the administration of hormone therapy to virtual menopausal individuals allows assessing its hypothetical impact and sensitivity to conditions that modify the effectiveness and efficiency.

Comparison of P2X and TRPV1 receptors in ganglia or primary culture of trigeminal neurons and their modulation by NGF or serotonin

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Giniatullin Rashid

2006-03-01

Full Text Available Abstract Background Cultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated. Results Rat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization, while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist α, β-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491 and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors. Conclusion Comparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception

The thermosensitive TRPV3 channel contributes to rapid wound healing in oral epithelia.

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Aijima, Reona; Wang, Bing; Takao, Tomoka; Mihara, Hiroshi; Kashio, Makiko; Ohsaki, Yasuyoshi; Zhang, Jing-Qi; Mizuno, Atsuko; Suzuki, Makoto; Yamashita, Yoshio; Masuko, Sadahiko; Goto, Masaaki; Tominaga, Makoto; Kido, Mizuho A

2015-01-01

The oral cavity provides an entrance to the alimentary tract to serve as a protective barrier against harmful environmental stimuli. The oral mucosa is susceptible to injury because of its location; nonetheless, it has faster wound healing than the skin and less scar formation. However, the molecular pathways regulating this wound healing are unclear. Here, we show that transient receptor potential vanilloid 3 (TRPV3), a thermosensitive Ca(2+)-permeable channel, is more highly expressed in murine oral epithelia than in the skin by quantitative RT-PCR. We found that temperatures above 33°C activated TRPV3 and promoted oral epithelial cell proliferation. The proliferation rate in the oral epithelia of TRPV3 knockout (TRPV3KO) mice was less than that of wild-type (WT) mice. We investigated the contribution of TRPV3 to wound healing using a molar tooth extraction model and found that oral wound closure was delayed in TRPV3KO mice compared with that in WT mice. TRPV3 mRNA was up-regulated in wounded tissues, suggesting that TRPV3 may contribute to oral wound repair. We identified TRPV3 as an essential receptor in heat-induced oral epithelia proliferation and wound healing. Our findings suggest that TRPV3 activation could be a potential therapeutic target for wound healing in skin and oral mucosa. © FASEB.

Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas.

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Yuka Okada

Full Text Available In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4 channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT mice are different than those in their TRPV4-null (KO counterpart. Stromal opacification due to fibrosis in KO (n = 128 mice was markedly reduced after 20 days relative to that in WT (n = 157 mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and α-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor β, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice.

Loss of TRPV4 Function Suppresses Inflammatory Fibrosis Induced by Alkali-Burning Mouse Corneas.

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Okada, Yuka; Shirai, Kumi; Miyajima, Masayasu; Reinach, Peter S; Yamanaka, Osamu; Sumioka, Takayoshi; Kokado, Masahide; Tomoyose, Katsuo; Saika, Shizuya

2016-01-01

In humans suffering from pulmonary disease and a mouse model, transient receptor potential vanilloid 4 (TRPV4) channel activation contributes to fibrosis. As a corneal alkali burn induces the same response, we determined if such an effect is also attributable to TRPV4 activation in mice. Accordingly, we determined if the alkali burn wound healing responses in wild-type (WT) mice are different than those in their TRPV4-null (KO) counterpart. Stromal opacification due to fibrosis in KO (n = 128) mice was markedly reduced after 20 days relative to that in WT (n = 157) mice. Immunohistochemistry revealed that increases in polymorphonuclear leukocytes and macrophage infiltration declined in KO mice. Semi-quantitative real time RT-PCR of ocular KO fibroblast cultures identified increases in proinflammatory and monocyte chemoattractant protein-1 chemoattractant gene expression after injury. Biomarker gene expression of fibrosis, collagen1a1 and α-smooth muscle actin were attenuated along with macrophage release of interleukin-6 whereas transforming growth factor β, release was unchanged. Tail vein reciprocal bone marrow transplantation between WT and KO chimera mouse models mice showed that reduced scarring and inflammation in KO mice are due to loss of TRPV4 expression on both corneal resident immune cells, fibroblasts and infiltrating polymorphonuclear leukocytes and macrophages. Intraperitoneal TRPV4 receptor antagonist injection of HC-067047 (10 mg/kg, daily) into WT mice reproduced the KO-phenotype. Taken together, alkali-induced TRPV4 activation contributes to inducing fibrosis and inflammation since corneal transparency recovery was markedly improved in KO mice.

Oncostatin M induces heat hypersensitivity by gp130-dependent sensitization of TRPV1 in sensory neurons

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Langeslag Michiel

2011-12-01

Full Text Available Abstract Oncostatin M (OSM is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130-/- and gp130 floxed (gp130fl/fl mice. Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo. The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.

Activation of TRPV1 channels inhibits mechanosensitive Piezo channel activity by depleting membrane phosphoinositides

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Borbiro, Istvan; Badheka, Doreen; Rohacs, Tibor

2015-01-01

Capsaicin is an activator of the heat-sensitive TRPV1 (transient receptor potential vanilloid 1) ion channels and has been used as a local analgesic. We found that activation of TRPV1 channels with capsaicin either in dorsal root ganglion neurons or in a heterologous expression system inhibited the mechanosensitive Piezo1 and Piezo2 channels by depleting phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and its precursor PI(4)P from the plasma membrane through Ca2+-induced phospholipase Cδ (PLCδ) activation. Experiments with chemically inducible phosphoinositide phosphatases and receptor-induced activation of PLCβ indicated that inhibition of Piezo channels required depletion of both PI(4)P and PI(4,5)P2. The mechanically activated current amplitudes decreased substantially in the excised inside-out configuration, where the membrane patch containing Piezo1 channels is removed from the cell. PI(4,5)P2 and PI(4)P applied to these excised patches inhibited this decrease. Thus, we concluded that Piezo channel activity requires the presence of phosphoinositides, and the combined depletion of PI(4,5)P2 or PI(4)P reduces channel activity. In addition to revealing a role for distinct membrane lipids in mechanosensitive ion channel regulation, these data suggest that inhibition of Piezo2 channels may contribute to the analgesic effect of capsaicin. PMID:25670203

Identifying the Integrated Neural Networks Involved in Capsaicin-Induced Pain Using fMRI in Awake TRPV1 Knockout and Wild-Type Rats

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Jason Richard Yee

2015-02-01

Full Text Available In the present study, we used functional MRI in awake rats to investigate the pain response that accompanies intradermal injection of capsaicin into the hindpaw. To this end, we used BOLD imaging together with a 3D segmented, annotated rat atlas and computational analysis to identify the integrated neural circuits involved in capsaicin-induced pain. The specificity of the pain response to capsaicin was tested in a transgenic model that contains a biallelic deletion of the gene encoding for the transient receptor potential cation channel subfamily V member 1 (TRPV1. Capsaicin is an exogenous ligand for the TRPV1 receptor, and in wild-type rats, activated the putative pain neural circuit. In addition, capsaicin-treated wild-type rats exhibited activation in brain regions comprising the Papez circuit and habenular system, systems that play important roles in the integration of emotional information, and learning and memory of aversive information, respectively. As expected, capsaicin administration to TRPV1-KO rats failed to elicit the robust BOLD activation pattern observed in wild-type controls. However, the intradermal injection of formalin elicited a significant activation of the putative pain pathway as represented by such areas as the anterior cingulate, somatosensory cortex, parabrachial nucleus, and periaqueductal gray. Notably, comparison of neural responses to capsaicin in wild-type versus knock-out rats uncovered evidence that capsaicin may function in an antinociceptive capacity independent of TRPV1 signaling. Our data suggest that neuroimaging of pain in awake, conscious animals has the potential to inform the neurobiological basis of full and integrated perceptions of pain.

Low latency asynchronous interface circuits

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Sadowski, Greg

2017-06-20

In one form, a logic circuit includes an asynchronous logic circuit, a synchronous logic circuit, and an interface circuit coupled between the asynchronous logic circuit and the synchronous logic circuit. The asynchronous logic circuit has a plurality of asynchronous outputs for providing a corresponding plurality of asynchronous signals. The synchronous logic circuit has a plurality of synchronous inputs corresponding to the plurality of asynchronous outputs, a stretch input for receiving a stretch signal, and a clock output for providing a clock signal. The synchronous logic circuit provides the clock signal as a periodic signal but prolongs a predetermined state of the clock signal while the stretch signal is active. The asynchronous interface detects whether metastability could occur when latching any of the plurality of the asynchronous outputs of the asynchronous logic circuit using said clock signal, and activates the stretch signal while the metastability could occur.

The Protective Role of Selenium on Scopolamine-Induced Memory Impairment, Oxidative Stress, and Apoptosis in Aged Rats: The Involvement of TRPM2 and TRPV1 Channels.

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Balaban, Hasan; Nazıroğlu, Mustafa; Demirci, Kadir; Övey, İshak Suat

2017-05-01

Inhibition of Ca 2+ entry into the hippocampus and dorsal root ganglion (DRG) through inhibition of N-methyl-D-aspartate (NMDA) receptor antagonist drugs is the current standard of care in neuronal diseases such as Alzheimer's disease, dementia, and peripheral pain. Oxidative stress activates Ca 2+ -permeable TRPM2 and TRPV1, and recent studies indicate that selenium (Se) is a potent TRPM2 and TRPV1 channel antagonist in the hippocampus and DRG. In this study, we investigated the neuroprotective properties of Se in primary hippocampal and DRG neuron cultures of aged rats when given alone or in combination with scopolamine (SCOP). Thirty-two aged (18-24 months old) rats were divided into four groups. The first and second groups received a placebo and SCOP (1 mg/kg/day), respectively. The third and fourth groups received intraperitoneal Se (1.5 mg/kg/ over day) and SCOP + Se, respectively. The hippocampal and DRG neurons also were stimulated in vitro with a TRPV1 channel agonist (capsaicin) and a TRPM2 channel agonist (cumene hydroperoxide). We found that Se was fully effective in reversing SCOP-induced TRPM2 and TRPV1 current densities as well as errors in working memory and reference memory. In addition, Se completely reduced SCOP-induced oxidative toxicity by modulating lipid peroxidation, reducing glutathione and glutathione peroxidase. The Se and SCOP + Se treatments also decreased poly (ADP-ribose) polymerase activity, intracellular free Ca 2+ concentrations, apoptosis, and caspase 3, caspase 9, and mitochondrial membrane depolarization values in the hippocampus. In conclusion, the current study reports on the cellular level for SCOP and Se on the different endocytotoxic cascades for the first time. Notably, the research indicates that Se can result in remarkable neuroprotective and memory impairment effects in the hippocampal neurons of rats. Graphical abstract Possible molecular pathways of involvement of selenium (Se) in scopolamine (SCOP) induced

Derived (mutated)-types of TRPV6 channels elicit greater Ca²+ influx into the cells than ancestral-types of TRPV6: evidence from Xenopus oocytes and mammalian cell expression system.

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Sudo, Yuka; Matsuo, Kiyotaka; Tetsuo, Tomoyuki; Tsutsumi, Satoshi; Ohkura, Masamichi; Nakai, Junichi; Uezono, Yasuhito

2010-01-01

The frequency of the allele containing three derived nonsynonymous SNPs (157C, 378M, 681M) of the gene encoding calcium permeable TRPV6 channels expressed in the intestine has been increased by positive selection in non-African populations. To understand the nature of these SNPs, we compared the properties of Ca²+ influx of ancestral (in African populations) and derived-TRPV6 (in non-African populations) channels with electrophysiological, Ca²+-imaging, and morphological methods using both the Xenopus oocyte and mammalian cell expression systems. Functional electrophysiological and Ca²+-imaging analyses indicated that the derived-TRPV6 elicited more Ca²+ influx than the ancestral one in TRPV6-expressing cells where both channels were equally expressed in the cells. Ca²+-inactivation properties in the ancestral- and derived-TRPV6 were almost the same. Furthermore, fluorescence resonance energy transfer (FRET) analysis showed that both channels have similar multimeric formation properties, suggesting that derived-TRPV6 itself could cause higher Ca²+ influx. These findings suggest that populations having derived-TRPV6 in non-African areas may absorb higher Ca²+ from the intestine than ancestral-TRPV6 in the African area.

Functional interaction of TRPV4 channel protein with annexin A2 in DRG.

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Ning, Liping; Wang, Chuanwei; Ding, Xinli; Zhang, Yang; Wang, Xuping; Yue, Shouwei

2012-09-01

Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable, non-selective cation channel that is involved in the transmission of pain signals mediated by dorsal root ganglion (DRG). Annexin A2 belongs to a class of membrane-binding proteins that plays an important role in the regulation of ion channels. Nevertheless, little is known about the interaction between them in DRG. In this paper, we evaluated the functional interaction of TRPV4 with annexin A2 in DRG. We have used immunocytochemistry and co-immunoprecipitation assays to investigate the interaction between annexin A2 and TRPV4 in DRG. The role of annexin A2 in the regulation of TRPV4 activity in DRG was further verified by measurement of intracellular free calcium concentrations ([Ca(2+)](i)) and substance P (SP) release. First, annexin A2 was showed partial co-localization with TRPV4 in DRG neurons. Then, annexin A2 and TRPV4 were co-precipitated with each other in DRG lysates. Furthermore, the downregulation of annexin A2 using specific small interfering RNA significantly inhibited Ca(2+) influx and SP mediated by TRPV4. Our results provide evidence that annexin A2 is associated with TRPV4 and regulates TRPV4-mediated Ca(2+) influx and SP release in DRG neurons. The objective of this work is to determine the influence of annexin A2 on TRPV4 in DRG neurons, which may be the basis for treatment of pain relief.

The human TRPV6 channel protein is associated with cyclophilin B in human placenta.

Science.gov (United States)

Stumpf, Tobias; Zhang, Qi; Hirnet, Daniela; Lewandrowski, Urs; Sickmann, Albert; Wissenbach, Ulrich; Dörr, Janka; Lohr, Christian; Deitmer, Joachim W; Fecher-Trost, Claudia

2008-06-27

Transcellular calcium transport in the kidney, pancreas, small intestine, and placenta is partly mediated by transient receptor potential (TRP) channels. The highly selective TRPV6 calcium channel protein is most likely important for the calcium transfer in different specialized epithelial cells. In the human placenta the protein is expressed in trophoblast tissue, where it is implicated in the transepithelial calcium transfer from mother to the fetus. We enriched the TRPV6 channel protein endogenously expressed in placenta together with annexin A2 and cyclophilin B (CypB), which is a member of the huge immunophilin family. In the human placenta TRPV6 and CypB are mainly located intracellularly in the syncytiotrophoblast layer, but a small amount of the mature glycosylated TRPV6 channel protein and CypB is also expressed in microvilli apical membranes, the fetomaternal barrier. To understand the role of CypB on the TRPV6 channel function, we evaluated the effect of CypB co-expression on TRPV6-mediated calcium uptake into Xenopus laevis oocytes expressing TRPV6. A significant increase of TRPV6-mediated calcium uptake was observed after CypB/TRPV6 co-expression. This stimulatory effect of CypB was reversed by the immunosuppressive drug cyclosporin A, which inhibits the enzymatic activity of CypB. Cyclosporin A had no significant effect on TRPV6 and CypB protein expression levels in the oocytes. In summary, our results establish CypB as a new TRPV6 accessory protein with potential involvement in TRPV6 channel activation through its peptidyl-prolyl cis/trans isomerase activity.

Hypotonic stress promotes ATP release, reactive oxygen species production and cell proliferation via TRPV4 activation in rheumatoid arthritis rat synovial fibroblasts

International Nuclear Information System (INIS)

Hu, Fen; Hui, Zhenhai; Wei, Wei; Yang, Jianyu; Chen, Ziyuan; Guo, Bu; Xing, Fulin; Zhang, Xinzheng; Pan, Leiting; Xu, Jingjun

2017-01-01

Rheumatoid arthritis (RA) is a chronic and systemic autoimmune-disease with complex and unclear etiology. Hypotonicity of synovial fluid is a typical characteristic of RA, which may play pivotal roles in RA pathogenesis. In this work, we studied the responses of RA synovial fibroblasts to hypotonic stress in vitro and further explored the underlying mechanisms. Data showed that hyposmotic solutions significantly triggered increases in cytosolic calcium concentration ([Ca 2+ ] c ) of synoviocytes. Subsequently, it caused rapid release of ATP, as well as remarkable production of intracellular reactive oxygen species (ROS). Meanwhile, hypotonic stimulus promoted the proliferation of synovial fibroblasts. These effects were almost abolished by calcium-free buffer and significantly inhibited by gadolinium (III) chloride (a mechanosensitive Ca 2+ channel blocker) and ruthenium red (a transient receptor potential vanilloid 4 (TRPV4) blocker). 4α-phorbol 12,13-didecanoate, a specific agonist of TRPV4, also mimicked hypotonic shock-induced responses shown above. In contrast, voltage-gated channel inhibitors verapamil and nifedipine had little influences on these responses. Furthermore, RT-PCR and western blotting evidently detected TRPV4 expression at mRNA and protein level in isolated synoviocytes. Taken together, our results indicated that hypotonic stimulus resulted in ATP release, ROS production, and cell proliferation depending on Ca 2+ entry through activation of TRPV4 channel in synoviocytes. - Highlights: • Hypotonic stress evokes Ca 2+ entry in rheumatoid arthritis synovial fibroblasts. • Hypotonic stress induces rapid ATP release and ROS production in synoviocytes. • Hypotonic stimulation promotes the proliferation of synovial fibroblasts. • TRPV4 controls hypotonic-induced responses in synoviocytes.

Reciprocal positive regulation between TRPV6 and NUMB in PTEN-deficient prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Kim, Sung-Young; Hong, Chansik; Wie, Jinhong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Kim, Euiyong [Department of Physiology, College of Medicine, Inje University, Busan 614-735 (Korea, Republic of); Kim, Byung Joo [Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan 626-870 (Korea, Republic of); Ha, Kotdaji [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Cho, Nam-Hyuk; Kim, In-Gyu [Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Jeon, Ju-Hong [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); So, Insuk, E-mail: insuk@snu.ac.kr [Department of Physiology, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of)

2014-04-25

Highlights: • TRPV6 interacts with tumor suppressor proteins. • Numb has a selective effect on TRPV6, depending on the prostate cancer cell line. • PTEN is a novel regulator of TRPV6–Numb complex. - Abstract: Calcium acts as a second messenger and plays a crucial role in signaling pathways involved in cell proliferation. Recently, calcium channels related to calcium influx into the cytosol of epithelial cells have attracted attention as a cancer therapy target. Of these calcium channels, TRPV6 is overexpressed in prostate cancer and is considered an important molecule in the process of metastasis. However, its exact role and mechanism is unclear. NUMB, well-known tumor suppressor gene, is a novel interacting partner of TRPV6. We show that NUMB and TRPV6 have a reciprocal positive regulatory relationship in PC-3 cells. We repeated this experiment in two other prostate cancer cell lines, DU145 and LNCaP. Interestingly, there were no significant changes in TRPV6 expression following NUMB knockdown in DU145. We revealed that the presence or absence of PTEN was the cause of NUMB–TRPV6 function. Loss of PTEN caused a positive correlation of TRPV6–NUMB expression. Collectively, we determined that PTEN is a novel interacting partner of TRPV6 and NUMB. These results demonstrated a novel relationship of NUMB–TRPV6 in prostate cancer cells, and show that PTEN is a novel regulator of this complex.

Antinociceptive Effect of Ghrelin in a Rat Model of Irritable Bowel Syndrome Involves TRPV1/Opioid Systems

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Yuqing Mao

2017-09-01

Full Text Available Background/Aims: Irritable bowel syndrome (IBS, defined as recurrent abdominal pain and changes in bowel habits, seriously affects quality of life and ability to work. Ghrelin is a brain-gut hormone, which has been reported to show antinociceptive effects in peripheral pain. We investigated the effect of ghrelin on visceral hypersensitivity and pain in a rat model of IBS. Methods: Maternal deprivation (MD was used to provide a stress-induced model of IBS in Wistar rats. Colorectal distension (CRD was used to detect visceral sensitivity, which was evaluated by abdominal withdrawal reflex (AWR scores. Rats that were confirmed to have visceral hypersensitivity after MD were injected with ghrelin (10 µg/kg subcutaneously twice a week from weeks 7 to 8. [D-Lys3]-GHRP-6 (100 nmol/L and naloxone (100 nmol/L were administered subcutaneously to block growth hormone secretagogue receptor 1α (GHS-R1α and opioid receptors, respectively. Expression of transient receptor potential vanilloid type 1 (TRPV1 and µ and κ opioid receptors (MOR and KOR in colon, dorsal root ganglion (DRG and cerebral cortex tissues were detected by western blotting, quantitative real-time polymerase chain reaction (qRT-PCR, immunohistochemical analyses and immunofluorescence. Results: Ghrelin treatment increased expression of opioid receptors and inhibited expression of TRPV1 in colon, dorsal root ganglion (DRG and cerebral cortex. The antinociceptive effect of ghrelin in the rat model of IBS was partly blocked by both the ghrelin antagonist [D-Lys3]-GHRP-6 and the opioid receptor antagonist naloxone. Conclusion: The results indicate that ghrelin exerted an antinociceptive effect, which was mediated via TRPV1/opioid systems, in IBS-induced visceral hypersensitivity. Ghrelin might potentially be used as a new treatment for IBS.

A Gate Hinge Controls the Epithelial Calcium Channel TRPV5

OpenAIRE

van der Wijst, Jenny; Leunissen, Elizabeth H.; Blanchard, Maxime G.; Venselaar, Hanka; Verkaart, Sjoerd; Paulsen, Candice E.; Bindels, Ren? J.; Hoenderop, Joost G.

2017-01-01

TRPV5 is unique within the large TRP channel family for displaying a high Ca2+ selectivity together with Ca2+-dependent inactivation. Our study aims to uncover novel insights into channel gating through in-depth structure-function analysis. We identify an exceptional tryptophan (W583) at the terminus of the intracellular pore that is unique for TRPV5 (and TRPV6). A combination of site-directed mutagenesis, biochemical and electrophysiological analysis, together with homology modeling, demonst...

Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes.

Science.gov (United States)

Rajasekhar, Pradeep; Poole, Daniel P; Veldhuis, Nicholas A

2017-01-01

Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic conditions of metabolism, inflammation, peripheral neuropathies, musculoskeletal development, and cardiovascular regulation. Mechanosensory and receptor- or lipid-mediated signaling functions of TRPV4 have historically been attributed to central and peripheral neurons. However, with the development of potent and selective pharmacological tools, transgenic mice and improved molecular and imaging techniques, many new roles for TRPV4 have been revealed in nonneuronal cells. In this chapter, we discuss these recent findings and highlight the need for greater characterization of TRPV4-mediated signaling in nonneuronal cell types that are either directly associated with neurons or indirectly control their excitability through release of sensitizing cellular factors. We address the integral role of these cells in sensory and inflammatory processes as well as their importance when considering undesirable on-target effects that may be caused by systemic delivery of TRPV4-selective pharmaceutical agents for treatment of chronic diseases. In future, this will drive a need for targeted drug delivery strategies to regulate such a diverse and promiscuous protein. © 2017 Elsevier Inc. All rights reserved.

TRPV1 receptors contribute to mediate paclitaxel-induced c-Fos expression in spinal cord dorsal horn neurons

Czech Academy of Sciences Publication Activity Database

Kalynovska, Nataliia; Adámek, Pavel; Paleček, Jiří

2017-01-01

Roč. 66, č. 3 (2017), s. 549-532 ISSN 0862-8408 R&D Projects: GA ČR(CZ) GA15-11138S; GA MŠk(CZ) LH15279; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:67985823 Keywords : c-Fos * paclitaxel * TRPV1 * neuropathy * spinal cord Subject RIV: FH - Neurology OBOR OECD: Neurosciences (including psychophysiology Impact factor: 1.461, year: 2016

The C-terminal domain of TRPV4 is essential for plasma membrane localization.

Science.gov (United States)

Becker, Daniel; Müller, Margarethe; Leuner, Kristina; Jendrach, Marina

2008-02-01

Many members of the TRP superfamily oligomerize in the ER before trafficking to the plasma membrane. For membrane localization of the non-selective cation channel TRPV4 specific domains in the N-terminus are required, but the role of the C-terminus in the oligomerization and trafficking process has been not determined until now. Therefore, the localization of recombinant TRPV4 in two cell models was analyzed: HaCaT keratinocytes that express TRPV4 endogenously were compared to CHO cells that are devoid of endogenous TRPV4. When deletions were introduced in the C-terminal domain three states of TRPV4 localization were defined: a truncated TRPV4 protein of 855 amino acids was exported to the plasma membrane like the full-length channel (871 aa) and was also functional. Mutants with a length of 828 to 844 amino acids remained in the ER of CHO cells, but in HaCaT cells plasma membrane localization was partially rescued by oligomerization with endogenous TRPV4. This was confirmed by coexpression of recombinant full-length TRPV4 together with these deletion mutants, which resulted in an almost complete plasma membrane localization of both proteins and significant FRET in the plasma membrane and the ER. All deletions upstream of amino acid 828 resulted in total ER retention that could not rescued by coexpression with the full-length protein. However, these deletion mutants did not impair export of full-length TRPV4, implying that no oligomerization took place. These data indicate that the C-terminus of TRPV4 is required for oligomerization, which takes place in the ER and precedes plasma membrane trafficking.

Omega-3 Fatty Acids Modulate TRPV4 Function through Plasma Membrane Remodeling.

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Caires, Rebeca; Sierra-Valdez, Francisco J; Millet, Jonathan R M; Herwig, Joshua D; Roan, Esra; Vásquez, Valeria; Cordero-Morales, Julio F

2017-10-03

Dietary consumption of ω-3 polyunsaturated fatty acids (PUFAs), present in fish oils, is known to improve the vascular response, but their molecular targets remain largely unknown. Activation of the TRPV4 channel has been implicated in endothelium-dependent vasorelaxation. Here, we studied the contribution of ω-3 PUFAs to TRPV4 function by precisely manipulating the fatty acid content in Caenorhabditis elegans. By genetically depriving the worms of PUFAs, we determined that the metabolism of ω-3 fatty acids is required for TRPV4 activity. Functional, lipid metabolome, and biophysical analyses demonstrated that ω-3 PUFAs enhance TRPV4 function in human endothelial cells and support the hypothesis that lipid metabolism and membrane remodeling regulate cell reactivity. We propose a model whereby the eicosanoid's epoxide group location increases membrane fluidity and influences the endothelial cell response by increasing TRPV4 channel activity. ω-3 PUFA-like molecules might be viable antihypertensive agents for targeting TRPV4 to reduce systemic blood pressure. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Network evolution induced by asynchronous stimuli through spike-timing-dependent plasticity.

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Wu-Jie Yuan

Full Text Available In sensory neural system, external asynchronous stimuli play an important role in perceptual learning, associative memory and map development. However, the organization of structure and dynamics of neural networks induced by external asynchronous stimuli are not well understood. Spike-timing-dependent plasticity (STDP is a typical synaptic plasticity that has been extensively found in the sensory systems and that has received much theoretical attention. This synaptic plasticity is highly sensitive to correlations between pre- and postsynaptic firings. Thus, STDP is expected to play an important role in response to external asynchronous stimuli, which can induce segregative pre- and postsynaptic firings. In this paper, we study the impact of external asynchronous stimuli on the organization of structure and dynamics of neural networks through STDP. We construct a two-dimensional spatial neural network model with local connectivity and sparseness, and use external currents to stimulate alternately on different spatial layers. The adopted external currents imposed alternately on spatial layers can be here regarded as external asynchronous stimuli. Through extensive numerical simulations, we focus on the effects of stimulus number and inter-stimulus timing on synaptic connecting weights and the property of propagation dynamics in the resulting network structure. Interestingly, the resulting feedforward structure induced by stimulus-dependent asynchronous firings and its propagation dynamics reflect both the underlying property of STDP. The results imply a possible important role of STDP in generating feedforward structure and collective propagation activity required for experience-dependent map plasticity in developing in vivo sensory pathways and cortices. The relevance of the results to cue-triggered recall of learned temporal sequences, an important cognitive function, is briefly discussed as well. Furthermore, this finding suggests a potential

Synaptotagmin-7 is an asynchronous calcium sensor for synaptic transmission in neurons expressing SNAP-23.

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Jens P Weber

Full Text Available Synchronization of neurotransmitter release with the presynaptic action potential is essential for maintaining fidelity of information transfer in the central nervous system. However, synchronous release is frequently accompanied by an asynchronous release component that builds up during repetitive stimulation, and can even play a dominant role in some synapses. Here, we show that substitution of SNAP-23 for SNAP-25 in mouse autaptic glutamatergic hippocampal neurons results in asynchronous release and a higher frequency of spontaneous release events (mEPSCs. Use of neurons from double-knock-out (SNAP-25, synaptotagmin-7 mice in combination with viral transduction showed that SNAP-23-driven release is triggered by endogenous synaptotagmin-7. In the absence of synaptotagmin-7 release became even more asynchronous, and the spontaneous release rate increased even more, indicating that synaptotagmin-7 acts to synchronize release and suppress spontaneous release. However, compared to synaptotagmin-1, synaptotagmin-7 is a both leaky and asynchronous calcium sensor. In the presence of SNAP-25, consequences of the elimination of synaptotagmin-7 were small or absent, indicating that the protein pairs SNAP-25/synaptotagmin-1 and SNAP-23/synaptotagmin-7 might act as mutually exclusive calcium sensors. Expression of fusion proteins between pHluorin (pH-sensitive GFP and synaptotagmin-1 or -7 showed that vesicles that fuse using the SNAP-23/synaptotagmin-7 combination contained synaptotagmin-1, while synaptotagmin-7 barely displayed activity-dependent trafficking between vesicle and plasma membrane, implying that it acts as a plasma membrane calcium sensor. Overall, these findings support the idea of alternative syt∶SNARE combinations driving release with different kinetics and fidelity.

Swelling and eicosanoid metabolites differentially gate TRPV4 channels in retinal neurons and glia

DEFF Research Database (Denmark)

Ryskamp, Daniel A; Jo, Andrew O; Frye, Amber M

2014-01-01

that were inhibited by TRPV4 antagonists and absent in TRPV4(-/-) Müller cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca(2+) waves, and, in excess, were sufficient to induce reactive gliosis. In contrast, neurons responded to TRPV4 agonists...... and swelling with fast, inactivating Ca(2+) signals that were independent of phospholipase A2. Our results support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with potentially significant consequences...

The bovine TRPV3 as a pathway for the uptake of Na+, Ca2+, and NH4.

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Schrapers, Katharina T; Sponder, Gerhard; Liebe, Franziska; Liebe, Hendrik; Stumpff, Friederike

2018-01-01

Absorption of ammonia from the gastrointestinal tract results in problems that range from hepatic encephalopathy in humans to poor nitrogen efficiency of cattle with consequences for the global climate. Previous studies on epithelia and cells from the native ruminal epithelium suggest functional involvement of the bovine homologue of TRPV3 (bTRPV3) in ruminal NH4+ transport. Since the conductance of TRP channels to NH4+ has never been studied, bTRPV3 was overexpressed in HEK-293 cells and investigated using the patch-clamp technique and intracellular calcium imaging. Control cells contained the empty construct. Divalent cations blocked the conductance for monovalent cations in both cell types, with effects higher in cells expressing bTRPV3. In bTRPV3 cells, but not in controls, menthol, thymol, carvacrol, or 2-APB stimulated whole cell currents mediated by Na+, Cs+, NH4+, and K+, with a rise in intracellular Ca2+ observed in response to menthol. While only 25% of control patches showed single-channel events (with a conductance of 40.8 ± 11.9 pS for NH4+ and 25.0 ± 5.8 pS for Na+), 90% of bTRPV3 patches showed much larger conductances of 127.8 ± 4.2 pS for Na+, 240.1 ± 3.6 pS for NH4+, 34.0 ± 1.7 pS for Ca2+, and ~ 36 pS for NMDG+. Open probability, but not conductance, rose with time after patch excision. In conjunction with previous research, we suggest that bTRPV3 channels may play a role in the transport of Na+, K+, Ca2+ and NH4+ across the rumen with possible repercussions for understanding the function of TRPV3 in other epithelia.

The bovine TRPV3 as a pathway for the uptake of Na+, Ca2+, and NH4+

Science.gov (United States)

Liebe, Franziska; Liebe, Hendrik

2018-01-01

Absorption of ammonia from the gastrointestinal tract results in problems that range from hepatic encephalopathy in humans to poor nitrogen efficiency of cattle with consequences for the global climate. Previous studies on epithelia and cells from the native ruminal epithelium suggest functional involvement of the bovine homologue of TRPV3 (bTRPV3) in ruminal NH4+ transport. Since the conductance of TRP channels to NH4+ has never been studied, bTRPV3 was overexpressed in HEK-293 cells and investigated using the patch-clamp technique and intracellular calcium imaging. Control cells contained the empty construct. Divalent cations blocked the conductance for monovalent cations in both cell types, with effects higher in cells expressing bTRPV3. In bTRPV3 cells, but not in controls, menthol, thymol, carvacrol, or 2-APB stimulated whole cell currents mediated by Na+, Cs+, NH4+, and K+, with a rise in intracellular Ca2+ observed in response to menthol. While only 25% of control patches showed single-channel events (with a conductance of 40.8 ± 11.9 pS for NH4+ and 25.0 ± 5.8 pS for Na+), 90% of bTRPV3 patches showed much larger conductances of 127.8 ± 4.2 pS for Na+, 240.1 ± 3.6 pS for NH4+, 34.0 ± 1.7 pS for Ca2+, and ~ 36 pS for NMDG+. Open probability, but not conductance, rose with time after patch excision. In conjunction with previous research, we suggest that bTRPV3 channels may play a role in the transport of Na+, K+, Ca2+ and NH4+ across the rumen with possible repercussions for understanding the function of TRPV3 in other epithelia. PMID:29494673

Crystal structure of the epithelial calcium channel TRPV6.

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Saotome, Kei; Singh, Appu K; Yelshanskaya, Maria V; Sobolevsky, Alexander I

2016-06-23

Precise regulation of calcium homeostasis is essential for many physiological functions. The Ca(2+)-selective transient receptor potential (TRP) channels TRPV5 and TRPV6 play vital roles in calcium homeostasis as Ca(2+) uptake channels in epithelial tissues. Detailed structural bases for their assembly and Ca(2+) permeation remain obscure. Here we report the crystal structure of rat TRPV6 at 3.25 Å resolution. The overall architecture of TRPV6 reveals shared and unique features compared with other TRP channels. Intracellular domains engage in extensive interactions to form an intracellular 'skirt' involved in allosteric modulation. In the K(+) channel-like transmembrane domain, Ca(2+) selectivity is determined by direct coordination of Ca(2+) by a ring of aspartate side chains in the selectivity filter. On the basis of crystallographically identified cation-binding sites at the pore axis and extracellular vestibule, we propose a Ca(2+) permeation mechanism. Our results provide a structural foundation for understanding the regulation of epithelial Ca(2+) uptake and its role in pathophysiology.

Electromagnetic radiation (Wi-Fi) and epilepsy induce calcium entry and apoptosis through activation of TRPV1 channel in hippocampus and dorsal root ganglion of rats.

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Ghazizadeh, Vahid; Nazıroğlu, Mustafa

2014-09-01

Incidence rates of epilepsy and use of Wi-Fi worldwide have been increasing. TRPV1 is a Ca(2+) permeable and non-selective channel, gated by noxious heat, oxidative stress and capsaicin (CAP). The hyperthermia and oxidant effects of Wi-Fi may induce apoptosis and Ca(2+) entry through activation of TRPV1 channel in epilepsy. Therefore, we tested the effects of Wi-Fi (2.45 GHz) exposure on Ca(2+) influx, oxidative stress and apoptosis through TRPV1 channel in the murine dorsal root ganglion (DRG) and hippocampus of pentylentetrazol (PTZ)-induced epileptic rats. Rats in the present study were divided into two groups as controls and PTZ. The PTZ groups were divided into two subgroups namely PTZ + Wi-Fi and PTZ + Wi-Fi + capsazepine (CPZ). The hippocampal and DRG neurons were freshly isolated from the rats. The DRG and hippocampus in PTZ + Wi-Fi and PTZ + Wi-Fi + CPZ groups were exposed to Wi-Fi for 1 hour before CAP stimulation. The cytosolic free Ca(2+), reactive oxygen species production, apoptosis, mitochondrial membrane depolarization, caspase-3 and -9 values in hippocampus were higher in the PTZ group than in the control although cell viability values decreased. The Wi-Fi exposure induced additional effects on the cytosolic Ca(2+) increase. However, pretreatment of the neurons with CPZ, results in a protection against epilepsy-induced Ca(2+) influx, apoptosis and oxidative damages. In results of whole cell patch-clamp experiments, treatment of DRG with Ca(2+) channel antagonists [thapsigargin, verapamil + diltiazem, 2-APB, MK-801] indicated that Wi-Fi exposure induced Ca(2+) influx via the TRPV1 channels. In conclusion, epilepsy and Wi-Fi in our experimental model is involved in Ca(2+) influx and oxidative stress-induced hippocampal and DRG death through activation of TRPV1 channels, and negative modulation of this channel activity by CPZ pretreatment may account for the neuroprotective activity against oxidative stress.

Dorsal root ganglion neurons innervating skeletal muscle respond to physiological combinations of protons, ATP, and lactate mediated by ASIC, P2X, and TRPV1.

Science.gov (United States)

Light, Alan R; Hughen, Ronald W; Zhang, Jie; Rainier, Jon; Liu, Zhuqing; Lee, Jeewoo

2008-09-01

The adequate stimuli and molecular receptors for muscle metaboreceptors and nociceptors are still under investigation. We used calcium imaging of cultured primary sensory dorsal root ganglion (DRG) neurons from C57Bl/6 mice to determine candidates for metabolites that could be the adequate stimuli and receptors that could detect these stimuli. Retrograde DiI labeling determined that some of these neurons innervated skeletal muscle. We found that combinations of protons, ATP, and lactate were much more effective than individually applied compounds for activating rapid calcium increases in muscle-innervating dorsal root ganglion neurons. Antagonists for P2X, ASIC, and TRPV1 receptors suggested that these three receptors act together to detect protons, ATP, and lactate when presented together in physiologically relevant concentrations. Two populations of muscle-innervating DRG neurons were found. One responded to low metabolite levels (likely nonnoxious) and used ASIC3, P2X5, and TRPV1 as molecular receptors to detect these metabolites. The other responded to high levels of metabolites (likely noxious) and used ASIC3, P2X4, and TRPV1 as their molecular receptors. We conclude that a combination of ASIC, P2X5 and/or P2X4, and TRPV1 are the molecular receptors used to detect metabolites by muscle-innervating sensory neurons. We further conclude that the adequate stimuli for muscle metaboreceptors and nociceptors are combinations of protons, ATP, and lactate.

Acid and stretch, but not capsaicin, are effective stimuli for ATP release in the porcine bladder mucosa: Are ASIC and TRPV1 receptors involved?

Science.gov (United States)

Sadananda, Prajni; Kao, Felicity C L; Liu, Lu; Mansfield, Kylie J; Burcher, Elizabeth

2012-05-15

Stretch-evoked ATP release from the bladder mucosa is a key event in signaling bladder fullness. Our aim was to examine whether acid and capsaicin can also release ATP and to determine the receptors involved, using agonists and antagonists at TRPV1 and acid-sensing ion channels (ASICs). Strips of porcine bladder mucosa were exposed to acid, capsaicin or stretch. Strip tension was monitored. Bath fluid was collected for ATP measurement. Gene expression of ASICs and TRPV1 in porcine bladders was quantified using quantitative real-time PCR (qRT-PCR). Stretch stimulus (150% of original length) repeatedly and significantly increased ATP release to approximately 45 times basal release. Acid (pH 6.5, 6.0, 5.6) contracted mucosal strips and also increased ATP release up to 30-fold, without evidence of desensitization. Amiloride (0.3 μM) reduced the acid-evoked ATP release by approximately 70%, while capsazepine (10 μM) reduced acid-evoked ATP release at pH 6.0 and pH 5.6 (by 68% and 61%, respectively). Capsaicin (0.1-10 μM) was ineffective in causing ATP release, and also failed to contract porcine mucosal or detrusor strips. Gene expression for ASIC1, ASIC2, ASIC3 and TRPV1 was seen in the lateral wall, dome, trigone and neck of both detrusor and mucosa. In conclusion, stretch and acid induce ATP release in the porcine bladder mucosa, but capsaicin is ineffective. The pig bladder is a well-known model for the human bladder, however these data suggest that it should be used with caution, particularly for TRPV1 related studies. Copyright © 2012 Elsevier B.V. All rights reserved.

A dominant TRPV4 variant underlies osteochondrodysplasia in Scottish fold cats.

Science.gov (United States)

Gandolfi, B; Alamri, S; Darby, W G; Adhikari, B; Lattimer, J C; Malik, R; Wade, C M; Lyons, L A; Cheng, J; Bateman, J F; McIntyre, P; Lamandé, S R; Haase, B

2016-08-01

Scottish fold cats, named for their unique ear shape, have a dominantly inherited osteochondrodysplasia involving malformation in the distal forelimbs, distal hindlimbs and tail, and progressive joint destruction. This study aimed to identify the gene and the underlying variant responsible for the osteochondrodysplasia. DNA samples from 44 Scottish fold and 54 control cats were genotyped using a feline DNA array and a case-control genome-wide association analysis conducted. The gene encoding a calcium permeable ion channel, transient receptor potential cation channel, subfamily V, member 4 (TRPV4) was identified as a candidate within the associated region and sequenced. Stably transfected HEK293 cells were used to compare wild-type and mutant TRPV4 expression, cell surface localisation and responses to activation with a synthetic agonist GSK1016709A, hypo-osmolarity, and protease-activated receptor 2 stimulation. The dominantly inherited folded ear and osteochondrodysplasia in Scottish fold cats is associated with a p.V342F substitution (c.1024G>T) in TRPV4. The change was not found in 648 unaffected cats. Functional analysis in HEK293 cells showed V342F mutant TRPV4 was poorly expressed at the cell surface compared to wild-type TRPV4 and as a consequence the maximum response to a synthetic agonist was reduced. Mutant TRPV4 channels had a higher basal activity and an increased response to hypotonic conditions. Access to a naturally-occurring TRPV4 mutation in the Scottish fold cat will allow further functional studies to identify how and why the mutations affect cartilage and bone development. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Thy1.2 YFP-16 transgenic mouse labels a subset of large-diameter sensory neurons that lack TRPV1 expression.

Directory of Open Access Journals (Sweden)

Thomas E Taylor-Clark

Full Text Available The Thy1.2 YFP-16 mouse expresses yellow fluorescent protein (YFP in specific subsets of peripheral and central neurons. The original characterization of this model suggested that YFP was expressed in all sensory neurons, and this model has been subsequently used to study sensory nerve structure and function. Here, we have characterized the expression of YFP in the sensory ganglia (DRG, trigeminal and vagal of the Thy1.2 YFP-16 mouse, using biochemical, functional and anatomical analyses. Despite previous reports, we found that YFP was only expressed in approximately half of DRG and trigeminal neurons and less than 10% of vagal neurons. YFP-expression was only found in medium and large-diameter neurons that expressed neurofilament but not TRPV1. YFP-expressing neurons failed to respond to selective agonists for TRPV1, P2X(2/3 and TRPM8 channels in Ca2+ imaging assays. Confocal analysis of glabrous skin, hairy skin of the back and ear and skeletal muscle indicated that YFP was expressed in some peripheral terminals with structures consistent with their presumed non-nociceptive nature. In summary, the Thy1.2 YFP-16 mouse expresses robust YFP expression in only a subset of sensory neurons. But this mouse model is not suitable for the study of nociceptive nerves or the function of such nerves in pain and neuropathies.

TRPV1 as a key determinant in ciguatera and neurotoxic shellfish poisoning

Science.gov (United States)

Cuypers, Eva; Yanagihara, Angel; Rainier, Jon D.; Tytgat, Jan

2007-01-01

Ciguatera fish poisoning and neurotoxic shellfish poisoning are distinct clinical entities characterized by gastrointestinal and neurological disturbances, following the consumption of certain reef fish and shellfish containing toxic polyether compounds sporadically present in certain toxic marine dinoflagellates. The biotransformation and bioaccumulation of gambierol and brevetoxin, and their congeners, are believed to be involved in the pathogenesis of these “food-chain diseases”, for which no effective treatments are available. Here, we describe for the first time the potent effect of gambierol and brevetoxin on TRPV1 channels, a key player in thermal and pain sensation. Our findings may lead to promising new therapeutic interventions. PMID:17659256

TRPV3, a thermosensitive channel is expressed in mouse distal colon epithelium

International Nuclear Information System (INIS)

Ueda, Takashi; Yamada, Takahiro; Ugawa, Shinya; Ishida, Yusuke; Shimada, Shoichi

2009-01-01

The thermo-transient receptor potential (thermoTRP) subfamily is composed of channels that are important in nociception and thermo-sensing. Here, we show a selective expression of TRPV3 channel in the distal colon throughout the gastrointestinal tract. Expression analyses clearly revealed that TRPV3 mRNA and proteins were expressed in the superficial epithelial cells of the distal colon, but not in those of the stomach, duodenum or proximal colon. In a subset of primary epithelial cells cultured from the distal colon, carvacrol, an agonist for TRPV3, elevated cytosolic Ca 2+ concentration in a concentration-dependent manner. This response was inhibited by ruthenium red, a TRPV channel antagonist. Organotypic culture supported that the carvacrol-responsive cells were present in superficial epithelial cells. Moreover, application of carvacrol evoked ATP release in primary colonic epithelial cells. We conclude that TRPV3 is present in absorptive cells in the distal colon and may be involved in a variety of cellular functions.

POTENTIATION OF PULMONARY REFLEX RESPONSE TO CAPSAICIN 24 HOURS FOLLOWING WHOLE-BODY ACROLEIN EXPOSURE IS MEDIATED BY TRPV1

Science.gov (United States)

Pulmonary C-fibers are stimulated by irritant air pollutants producing apnea, bronchospasm, and decrease in HR. C-fiber chemoreflex activation is mediated by TRPV1 and release of substance P. While acrolein has been shown to stimulate C-fibers, the persistence of acrolein effect...

A BMI-based occupational therapy assist suit: asynchronous control by SSVEP.

Science.gov (United States)

Sakurada, Takeshi; Kawase, Toshihiro; Takano, Kouji; Komatsu, Tomoaki; Kansaku, Kenji

2013-01-01

A brain-machine interface (BMI) is an interface technology that uses neurophysiological signals from the brain to control external machines. Recent invasive BMI technologies have succeeded in the asynchronous control of robot arms for a useful series of actions, such as reaching and grasping. In this study, we developed non-invasive BMI technologies aiming to make such useful movements using the subject's own hands by preparing a BMI-based occupational therapy assist suit (BOTAS). We prepared a pre-recorded series of useful actions-a grasping-a-ball movement and a carrying-the-ball movement-and added asynchronous control using steady-state visual evoked potential (SSVEP) signals. A SSVEP signal was used to trigger the grasping-a-ball movement and another SSVEP signal was used to trigger the carrying-the-ball movement. A support vector machine was used to classify EEG signals recorded from the visual cortex (Oz) in real time. Untrained, able-bodied participants (n = 12) operated the system successfully. Classification accuracy and time required for SSVEP detection were ~88% and 3 s, respectively. We further recruited three patients with upper cervical spinal cord injuries (SCIs); they also succeeded in operating the system without training. These data suggest that our BOTAS system is potentially useful in terms of rehabilitation of patients with upper limb disabilities.

Parallel selection on TRPV6 in human populations

OpenAIRE

Hughes, David A; Tang, Kun; Strotmann, Rainer; Schöneberg, Torsten; Prenen, Jean; Nilius, Bernd; Stoneking, Mark

2008-01-01

We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH) test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians an...

Parallel selection on TRPV6 in human populations.

Science.gov (United States)

Hughes, David A; Tang, Kun; Strotmann, Rainer; Schöneberg, Torsten; Prenen, Jean; Nilius, Bernd; Stoneking, Mark

2008-02-27

We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH) test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians and African-Americans, as well as in newly-obtained sequence data for additional populations. We find that all non-African populations carry a signature of selection on the same haplotype at the TRPV6 locus. The selective footprints, however, are significantly differentiated between non-African populations and estimated to be younger than an ancestral population of non-Africans. The possibility of a single selection event occurring in an ancestral population of non-Africans was tested by simulations and rejected. The putatively-selected TRPV6 haplotype contains three candidate sites for functional differences, namely derived non-synonymous substitutions C157R, M378V and M681T. Potential functional differences between the ancestral and derived TRPV6 proteins were investigated by cloning the ancestral and derived forms, transfecting cell lines, and carrying out electrophysiology experiments via patch clamp analysis. No statistically-significant differences in biophysical channel function were found, although one property of the protein, namely Ca(2+) dependent inactivation, may show functionally relevant differences between the ancestral and derived forms. Although the reason for selection on this locus remains elusive, this is the first demonstration of a widespread parallel selection event acting on standing genetic variation in humans, and highlights the utility of between population EHH statistics.

Parallel selection on TRPV6 in human populations.

Directory of Open Access Journals (Sweden)

David A Hughes

Full Text Available We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians and African-Americans, as well as in newly-obtained sequence data for additional populations. We find that all non-African populations carry a signature of selection on the same haplotype at the TRPV6 locus. The selective footprints, however, are significantly differentiated between non-African populations and estimated to be younger than an ancestral population of non-Africans. The possibility of a single selection event occurring in an ancestral population of non-Africans was tested by simulations and rejected. The putatively-selected TRPV6 haplotype contains three candidate sites for functional differences, namely derived non-synonymous substitutions C157R, M378V and M681T. Potential functional differences between the ancestral and derived TRPV6 proteins were investigated by cloning the ancestral and derived forms, transfecting cell lines, and carrying out electrophysiology experiments via patch clamp analysis. No statistically-significant differences in biophysical channel function were found, although one property of the protein, namely Ca(2+ dependent inactivation, may show functionally relevant differences between the ancestral and derived forms. Although the reason for selection on this locus remains elusive, this is the first demonstration of a widespread parallel selection event acting on standing genetic variation in humans, and highlights the utility of between population EHH statistics.

TRPV4 activation mediates flow-induced nitric oxide production in the rat thick ascending limb

Science.gov (United States)

Garvin, Jeffrey L.

2014-01-01

Nitric oxide (NO) regulates renal function. Luminal flow stimulates NO production in the thick ascending limb (TAL). Transient receptor potential vanilloid 4 (TRPV4) is a mechano-sensitive channel activated by luminal flow in different types of cells. We hypothesized that TRPV4 mediates flow-induced NO production in the rat TAL. We measured NO production in isolated, perfused rat TALs using the fluorescent dye DAF FM. Increasing luminal flow from 0 to 20 nl/min stimulated NO from 8 ± 3 to 45 ± 12 arbitrary units (AU)/min (n = 5; P < 0.05). The TRPV4 antagonists, ruthenium red (15 μmol/l) and RN 1734 (10 μmol/l), blocked flow-induced NO production. Also, luminal flow did not increase NO production in the absence of extracellular calcium. We also studied the effect of luminal flow on NO production in TALs transduced with a TRPV4shRNA. In nontransduced TALs luminal flow increased NO production by 47 ± 17 AU/min (P < 0.05; n = 5). Similar to nontransduced TALs, luminal flow increased NO production by 39 ± 11 AU/min (P < 0.03; n = 5) in TALs transduced with a control negative sequence-shRNA while in TRPV4shRNA-transduced TALs, luminal flow did not increase NO production (Δ10 ± 15 AU/min; n = 5). We then tested the effect of two different TRPV4 agonists on NO production in the absence of luminal flow. 4α-Phorbol 12,13-didecanoate (1 μmol/l) enhanced NO production by 60 ± 11 AU/min (P < 0.002; n = 7) and GSK1016790A (10 ηmol/l) increased NO production by 52 ± 15 AU/min (P < 0.03; n = 5). GSK1016790A (10 ηmol/l) did not stimulate NO production in TRPV4shRNA-transduced TALs. We conclude that activation of TRPV4 channels mediates flow-induced NO production in the rat TAL. PMID:24966090

Flexible trigger menu implementation on the Global Trigger for the CMS Level-1 trigger upgrade

Science.gov (United States)

MATSUSHITA, Takashi; CMS Collaboration

2017-10-01

The CMS experiment at the Large Hadron Collider (LHC) has continued to explore physics at the high-energy frontier in 2016. The integrated luminosity delivered by the LHC in 2016 was 41 fb-1 with a peak luminosity of 1.5 × 1034 cm-2s-1 and peak mean pile-up of about 50, all exceeding the initial estimations for 2016. The CMS experiment has upgraded its hardware-based Level-1 trigger system to maintain its performance for new physics searches and precision measurements at high luminosities. The Global Trigger is the final step of the CMS Level-1 trigger and implements a trigger menu, a set of selection requirements applied to the final list of objects from calorimeter and muon triggers, for reducing the 40 MHz collision rate to 100 kHz. The Global Trigger has been upgraded with state-of-the-art FPGA processors on Advanced Mezzanine Cards with optical links running at 10 GHz in a MicroTCA crate. The powerful processing resources of the upgraded system enable implementation of more algorithms at a time than previously possible, allowing CMS to be more flexible in how it handles the available trigger bandwidth. Algorithms for a trigger menu, including topological requirements on multi-objects, can be realised in the Global Trigger using the newly developed trigger menu specification grammar. Analysis-like trigger algorithms can be represented in an intuitive manner and the algorithms are translated to corresponding VHDL code blocks to build a firmware. The grammar can be extended in future as the needs arise. The experience of implementing trigger menus on the upgraded Global Trigger system will be presented.

Environmental toxin acrolein alters levels of endogenous lipids, including TRP agonists: A potential mechanism for headache driven by TRPA1 activation

Directory of Open Access Journals (Sweden)

Emma Leishman

2017-01-01

Full Text Available Exposure to airborne toxins can trigger headaches, but the mechanisms are not well understood. Some environmental toxins, such as acrolein, activate transient receptor potential ankyrin 1 (TRPA1, a receptor involved in pain sensation that is highly expressed in the trigeminovascular system. It has been shown in rat models that repeated exposure to acrolein induces trigeminovascular sensitization to both TRPA1 and TRP vanilloid 1 (TRPV1 agonists, a phenomenon linked to headache. In this study, we test the hypothesis that the sensitization of trigeminovascular responses in rats after acrolein exposure via inhalation is associated with changes in levels of endogenous lipids, including TRPV1 agonists, in the trigeminal ganglia, trigeminal nucleus, and cerebellum. Lipidomics analysis of 80 lipids was performed on each tissue after acute acrolein, chronic acrolein, or room air control. Both acute and chronic acrolein exposure drove widespread alterations in lipid levels. After chronic acrolein exposure, levels of all 6 N-acyl ethanolamines in the screening library, including the endogenous cannabinoid and TRPV1 agonist, N-arachidonoyl ethanolamine, were elevated in trigeminal tissue and in the cerebellum. This increase in TRPV1 ligands by acrolein exposure may indicate further downstream signaling, in that we also show here that a combination of these TRPV1 endogenous agonists increases the potency of the individual ligands in TRPV1-HEK cells. In addition to these TRPV1 agonists, 3 TRPV3 antagonists, 4 TRPV4 agonists, and 25 orphan lipids were up and down regulated after acrolein exposure. These data support the hypothesis that lipid signaling may represent a mechanism by which repeated exposure to the TRPA1 agonist and environmental toxin, acrolein, drives trigeminovascular sensitization. Keywords: Lipidomics, Endogenous cannabinoid, TRPA1, TRPV1, Lipoamine, Acrolein, Migraine

Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium

Science.gov (United States)

Monaghan, Kevin; McNaughten, Jennifer; McGahon, Mary K.; Kelly, Catriona; Kyle, Daniel; Yong, Phaik Har

2015-01-01

Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4α-phorbol 12,13-didecanoate (4-αPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-αPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4αPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months’ streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the

An asynchronous data-driven event-building scheme based on ATM switching fabrics

International Nuclear Information System (INIS)

Letheren, M.; Christiansen, J.; Mandjavidze, I.; Verhille, H.; De Prycker, M.; Pauwels, B.; Petit, G.; Wright, S.; Lumley, J.

1994-01-01

The very high data rates expected in experiments at the next generation of high luminosity hadron colliders will be handled by pipelined front-end readout electronics and multiple levels (2 or 3) of triggering. A variety of data acquisition architectures have been proposed for use downstream of the first level trigger. Depending on the architecture, the aggregate bandwidths required for event building are expected to be of the order 10--100 Gbit/s. Here, an Asynchronous Transfer Mode (ATM) packet-switching network technology is proposed as the interconnect for building high-performance, scalable data acquisition architectures. This paper introduces the relevant characteristics of ATM and describes components for the construction of an ATM-based event builder: (1) a multi-path, self-routing, scalable ATM switching fabric, (2) an experimental high performance workstation ATM-interface, and (3) a VMEbus ATM-interface. The requirement for traffic shaping in ATM-based event-builders is discussed and an analysis of the performance of several such schemes is presented

Asynchronous machines. Direct torque control; Machines asynchrones. Commande par controle direct de couple

Energy Technology Data Exchange (ETDEWEB)

Fornel, B. de [Institut National Polytechnique, 31 - Toulouse (France)

2006-05-15

The asynchronous machine, with its low cost and robustness, is today the most widely used motor to make speed variators. However, its main drawback is that the same current generates both the magnetic flux and the torque, and thus any torque variation creates a flux variation. Such a coupling gives to the asynchronous machine a nonlinear behaviour which makes its control much more complex. The direct self control (DSC) method has been developed to improve the low efficiency of the scalar control method and for the specific railway drive application. The direct torque control (DTC) method is derived from the DSC method but corresponds to other type of applications. The DSC and DTC algorithms for asynchronous motors are presented in this article: 1 - direct control of the stator flux (DSC): principle, flux control, torque control, switching frequency of the inverter, speed estimation; 2 - direct torque control (DTC): principle, electromagnetic torque derivative, signals shape and switching frequency, some results, DTC speed variator without speed sensor, DTC application to multi-machine multi-converter systems; 3 - conclusion. (J.S.)

A BMI-based occupational therapy assist suit: asynchronous control by SSVEP

Directory of Open Access Journals (Sweden)

Takeshi eSakurada

2013-09-01

Full Text Available A brain-machine interface (BMI is an interface technology that uses neurophysiological signals from the brain to control external machines. Recent invasive BMI technologies have succeeded in the asynchronous control of robot arms for a useful series of actions, such as reaching and grasping. In this study, we developed non-invasive BMI technologies aiming to make such useful movements using the subject's own hands by preparing a BMI-based occupational therapy assist suit (BOTAS. We prepared a pre-recorded series of useful actionsa grasping-a-ball movement and a carrying-the-ball movementand added asynchronous control using steady-state visual evoked potential (SSVEP signals. A SSVEP signal was used to trigger the grasping-a-ball movement and another SSVEP signal was used to trigger the carrying-the-ball movement. A support vector machine was used to classify EEG signals recorded from the visual cortex (Oz in real time. Untrained, able-bodied participants (n = 12 operated the system successfully. Classification accuracy and time required for SSVEP detection were approximately 88% and 3 s, respectively. We further recruited three patients with upper cervical spinal cord injuries; they also succeeded in operating the system without training. These data suggest that our BOTAS system is potentially useful in terms of rehabilitation of patients with upper limb disabilities.

Involvement of TRPV3 and TRPM8 ion channel proteins in induction of mammalian cold-inducible proteins.

Science.gov (United States)

Fujita, Takanori; Liu, Yu; Higashitsuji, Hiroaki; Itoh, Katsuhiko; Shibasaki, Koji; Fujita, Jun; Nishiyama, Hiroyuki

2018-01-01

Cold-inducible RNA-binding protein (CIRP), RNA-binding motif protein 3 (RBM3) and serine and arginine rich splicing factor 5 (SRSF5) are RNA-binding proteins that are transcriptionally upregulated in response to moderately low temperatures and a variety of cellular stresses in mammalian cells. Induction of these cold-inducible proteins (CIPs) is dependent on transient receptor potential (TRP) V4 channel protein, but seems independent of its ion channel activity. We herein report that in addition to TRPV4, TRPV3 and TRPM8 are necessary for the induction of CIPs. We established cell lines from the lung of TRPV4-knockout (KO) mouse, and observed induction of CIPs in them by western blot analysis. A TRPV4 antagonist RN1734 suppressed the induction in wild-type mouse cells, but not in TRPV4-KO cells. A TRPV3 channel blocker S408271 and a TRPM8 channel blocker AMTB as well as siRNAs against TRPV3 and TRPM8 suppressed the CIP induction in mouse TRPV4-KO cells and human U-2 OS cells. A TRPV3 channel agonist 2-APB induced CIP expression, but camphor did not. Neither did a TRPM8 channel agonist WS-12. These results suggest that TRPV4, TRPV3 and TRPM8 proteins, but not their ion channel activities are necessary for the induction of CIPs at 32 °C. Identification of proteins that differentially interact with these TRP channels at 37 °C and 32 °C would help elucidate the underlying mechanisms of CIP induction by hypothermia. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The depressor response to intracerebroventricular hypotonic saline is sensitive to TRPV4 antagonist RN1734

Directory of Open Access Journals (Sweden)

Claire H Feetham

2015-04-01

Full Text Available Several reports have shown that the periventricular region of the brain, including the paraventricular nucleus (PVN, is critical to sensing and responding to changes in plasma osmolality. Further studies also implicate the transient receptor potential ion channel, type V4 (TRPV4 channel in this homeostatic behaviour. In previous work we have shown that TRPV4 ion channels couple to calcium-activated potassium channels in the PVN to decrease action potential firing frequency in response to hypotonicity. In the present study we investigated whether, similarly, intracerebroventricular (ICV application of hypotonic solutions modulated cardiovascular parameters, and if so whether this was sensitive to a TRPV4 channel inhibitor. We found that ICV injection of 270mOsmol artificial cerebrospinal fluid (ACSF decreased mean blood pressure, but not heart rate, compared to naïve mice or mice injected with 300mOsmol ACSF. This effect was abolished by treatment with the TRPV4 inhibitor RN1734. These data suggest that periventricular targets within the brain are capable of generating depressor action in response to TRPV4 ion channel activation. Potentially, in the future, the TRPV4 channel, or the TRPV4–KCa coupling mechanism, may serve as a therapeutic target for treatment of cardiovascular disease.

Flexible trigger menu implementation on the Global Trigger for the CMS Level-1 trigger upgrade

CERN Document Server

Matsushita, Takashi

2017-01-01

The CMS experiment at the Large Hadron Collider (LHC) has continued to explore physics at the high-energy frontier in 2016. The integrated luminosity delivered by the LHC in 2016 was 41~fb$^{-1}$ with a peak luminosity of 1.5 $\\times$ 10$^{34}$ cm$^{-2}$s$^{-1}$ and peak mean pile-up of about 50, all exceeding the initial estimations for 2016. The CMS experiment has upgraded its hardware-based Level-1 trigger system to maintain its performance for new physics searches and precision measurements at high luminosities. The Global Trigger is the final step of the CMS \\mbox{Level-1} trigger and implements a trigger menu, a set of selection requirements applied to the final list of objects from calorimeter and muon triggers, for reducing the 40 MHz collision rate to 100 kHz. The Global Trigger has been upgraded with state-of-the-art FPGA processors on Advanced Mezzanine Cards with optical links running at 10 GHz in a MicroTCA crate. The powerful processing resources of the upgraded system enable implemen...

AKAP localizes in a specific subset of TRPV1 and CaV1.2 positive nociceptive rat DRG neurons

Science.gov (United States)

Brandao, Katherine E.; Dell’Acqua, Mark L.; Levinson, Simon R.

2016-01-01

Modulation of phosphorylation states of ion channels is a critical step in the development of hyperalgesia during inflammation. Modulatory enhancement of channel activity may increase neuronal excitability and affect downstream targets such as gene transcription. The specificity required for such regulation of ion channels quickly occurs via targeting of protein kinases and phosphatases by the scaffolding A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/150 has been implicated in inflammatory pain by targeting PKA and PKC to the TRPV1 channel in peripheral sensory neurons, thus lowering threshold for activation by multiple inflammatory reagents. However, the expression pattern of AKAP79/150 in peripheral sensory neurons is unknown. In this study we use immunofluorescence microscopy to identify in DRG sections the peripheral neuron subtypes that express the rodent isoform AKAP150, as well as the subcellular distribution of AKAP150 and its potential target ion channels. We found that AKAP150 is predominantly expressed in a subset of small DRG sensory neurons where it is localized at the plasma membrane of the soma, axon initial segment and small fibers. The majority of these neurons is peripherin positive and produces c-fibers, though a small portion produces Aδ-fibers. Furthermore, we demonstrate that AKAP79/150 colocalizes with TRPV1 and CaV1.2 in the soma and axon initial segment. Thus AKAP150 is expressed in small, nociceptive DRG neurons where it is targeted to membrane regions and where it may play a role in the modulation of ion channel phosphorylation states required for hyperalgesia. PMID:21674494

Asynchronous data change notification between database server and accelerator control systems

International Nuclear Information System (INIS)

Wenge Fu; Seth Nemesure; Morris, J.

2012-01-01

Database data change notification (DCN) is a commonly used feature, it allows to be informed when the data has been changed on the server side by another client. Not all database management systems (DBMS) provide an explicit DCN mechanism. Even for those DBMS's which support DCN (such as Oracle and MS SQL server), some server side and/or client side programming may be required to make the DCN system work. This makes the setup of DCN between database server and interested clients tedious and time consuming. In accelerator control systems, there are many well established software client/server architectures (such as CDEV, EPICS, and ADO) that can be used to implement data reflection servers that transfer data asynchronously to any client using the standard SET/GET API. This paper describes a method for using such a data reflection server to set up asynchronous DCN (ADCN) between a DBMS and clients. This method works well for all DBMS systems which provide database trigger functionality. (authors)

Expression of the transient receptor potential channels TRPV1, TRPA1 and TRPM8 in mouse trigeminal primary afferent neurons innervating the dura

Science.gov (United States)

2012-01-01

Background Migraine and other headache disorders affect a large percentage of the population and cause debilitating pain. Activation and sensitization of the trigeminal primary afferent neurons innervating the dura and cerebral vessels is a crucial step in the “headache circuit”. Many dural afferent neurons respond to algesic and inflammatory agents. Given the clear role of the transient receptor potential (TRP) family of channels in both sensing chemical stimulants and mediating inflammatory pain, we investigated the expression of TRP channels in dural afferent neurons. Methods We used two fluorescent tracers to retrogradely label dural afferent neurons in adult mice and quantified the abundance of peptidergic and non-peptidergic neuron populations using calcitonin gene-related peptide immunoreactivity (CGRP-ir) and isolectin B4 (IB4) binding as markers, respectively. Using immunohistochemistry, we compared the expression of TRPV1 and TRPA1 channels in dural afferent neurons with the expression in total trigeminal ganglion (TG) neurons. To examine the distribution of TRPM8 channels, we labeled dural afferent neurons in mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from a TRPM8 locus. We used nearest-neighbor measurement to predict the spatial association between dural afferent neurons and neurons expressing TRPA1 or TRPM8 channels in the TG. Results and conclusions We report that the size of dural afferent neurons is significantly larger than that of total TG neurons and facial skin afferents. Approximately 40% of dural afferent neurons exhibit IB4 binding. Surprisingly, the percentage of dural afferent neurons containing CGRP-ir is significantly lower than those of total TG neurons and facial skin afferents. Both TRPV1 and TRPA1 channels are expressed in dural afferent neurons. Furthermore, nearest-neighbor measurement indicates that TRPA1-expressing neurons are clustered around a subset of dural afferent neurons. Interestingly, TRPM

CCS, locations and asynchronous transition systems

DEFF Research Database (Denmark)

Mukund, Madhavan; Nielsen, Mogens

1992-01-01

We provide a simple non-interleaved operational semantics for CCS in terms of asynchronous transition systems. We identify the concurrency present in the system in a natural way, in terms of events occurring at independent locations in the system. We extend the standard interleaving transition...... system for CCS by introducing labels on the transitions with information about the locations of events. We then show that the resulting transition system is an asynchronous transition system which has the additional property of being elementary, which means that it can also be represented by a 1-safe net....... We also introduce a notion of bisimulation on asynchronous transition systems which preserves independence. We conjecture that the induced equivalence on CCS processes coincides with the notion of location equivalence proposed by Boudol et al....

Performance of the ATLAS Muon Trigger and Phase-1 Upgrade of Level-1 Endcap Muon Trigger

CERN Document Server

Mizukami, Atsushi; The ATLAS collaboration

2017-01-01

The ATLAS experiment utilises a trigger system to efficiently record interesting events. It consists of first-level and high-level triggers. The first-level trigger is implemented with custom-built hardware to reduce the event rate from 40 MHz to100 kHz. Then the software-based high-level triggers refine the trigger decisions reducing the output rate down to 1 kHz. Events with muons in the final state are an important signature for many physics topics at the LHC. An efficient trigger on muons and a detailed understanding of its performance are required. Trigger efficiencies are, for example, obtained from the muon decay of Z boson, with a Tag&Probe method, using proton-proton collision data collected in 2016 at a centre-of-mass energy of 13 TeV. The LHC is expected to increase its instantaneous luminosity to $3\\times10^{34} \\rm{cm^{-2}s^{-1}}$ after the phase-1 upgrade between 2018-2020. The upgrade of the ATLAS trigger system is mandatory to cope with this high-luminosity. In the phase-1 upgrade, new det...

TRPV1, TRPA1, and TRPM8 channels in inflammation, energy redirection, and water retention: role in chronic inflammatory diseases with an evolutionary perspective.

Science.gov (United States)

Straub, Rainer H

2014-09-01

Chronic inflammatory diseases are accompanied by a systemic response of the body, necessary to redirect energy-rich fuels to the activated immune system and to induce volume expansion. The systemic response is switched on by two major pathways: (a) circulating cytokines enter the brain, and (b) signals via sensory nerve fibers are transmitted to the brain. Concerning item b, sensory nerve terminals are equipped with a multitude of receptors that sense temperature, inflammation, osmolality, and pain. Thus, they can be important to inform the brain about peripheral inflammation. Central to these sensory modalities are transient receptor potential channels (TRP channels) on sensory nerve endings. For example, TRP vanilloid 1 (TRPV1) can be activated by heat, inflammatory factors (e.g., protons, bradykinin, anandamide), hyperosmolality, pungent irritants, and others. TRP channels are multimodal switches that transmit peripheral signals to the brain, thereby inducing a systemic response. It is demonstrated how and why these TRP channels (TRPV1, TRP ankyrin type 1 (TRPA1), and TRP melastatin type 8 (TRPM8)) are important to start up a systemic response of energy expenditure, energy allocation, and water retention and how this is linked to a continuously activated immune system in chronic inflammatory diseases.

Asynchronous design of Networks-on-Chip

DEFF Research Database (Denmark)

Sparsø, Jens

2007-01-01

-synchronous, mesochronous, globally-asynchronous locally-synchronous and fully asynchronous), discusses the circuitry needed to implement these timing methodologies, and provides some implementation details for a couple of asynchronous NoCs designed at the Technical University of Denmark (DTU). The paper is written...... to support an invited talk at the NORCHIP’2007 conference....

Acid solution is a suitable medium for introducing QX-314 into nociceptors through TRPV1 channels to produce sensory-specific analgesic effects.

Directory of Open Access Journals (Sweden)

He Liu

Full Text Available BACKGROUND: Previous studies have demonstrated that QX-314, an intracellular sodium channel blocker, can enter into nociceptors through capsaicin-activated TRPV1 or permeation of the membrane by chemical enhancers to produce a sensory-selective blockade. However, the obvious side effects of these combinations limit the application of QX-314. A new strategy for targeting delivery of QX-314 into nociceptors needs further investigation. The aim of this study is to test whether acidic QX-314, when dissolves in acidic solution directly, can enter into nociceptors through acid-activated TRPV1 and block sodium channels from the intracellular side to produce a sensory-specific analgesic effect. METHODOLOGY/PRINCIPAL FINDINGS: Acidic solution or noradrenaline was injected intraplantarly to induce acute pain behavior in mice. A chronic constrictive injury model was performed to induce chronic neuropathic pain. A sciatic nerve blockade model was used to evaluate the sensory-specific analgesic effects of acidic QX-314. Thermal and mechanical hyperalgesia were measured by using radiant heat and electronic von Frey filaments test. Spinal Fos protein expression was determined by immunohistochemistry. The expression of p-ERK was detected by western blot assay. Whole cell clamp recording was performed to measure action potentials and total sodium current in rats DRG neurons. We found that pH 5.0 PBS solution induced behavioral hyperalgesia accompanied with the increased expression of spinal Fos protein and p-ERK. Pretreatment with pH 5.0 QX-314, and not pH 7.4 QX-314, alleviated pain behavior, inhibited the increased spinal Fos protein and p-ERK expression induced by pH 5.0 PBS or norepinephrine, blocked sodium currents and abolished the production of action potentials evoked by current injection. The above effects were prevented by TRPV1 channel inhibitor SB366791, but not by ASIC channel inhibitor amiloride. Furthermore, acidic QX-314 employed adjacent to the

Behavioral synthesis of asynchronous circuits

DEFF Research Database (Denmark)

Nielsen, Sune Fallgaard

2005-01-01

This thesis presents a method for behavioral synthesis of asynchronous circuits, which aims at providing a synthesis flow which uses and tranfers methods from synchronous circuits to asynchronous circuits. We move the synchronous behavioral synthesis abstraction into the asynchronous handshake...... is idle. This reduces unnecessary switching activity in the individual functional units and therefore the energy consumption of the entire circuit. A collection of behavioral synthesis algorithms have been developed allowing the designer to perform time and power constrained design space exploration...

Angiotensin-2-mediated Ca2+ signaling in the retinal pigment epithelium: role of angiotensin-receptor-associated-protein and TRPV2 channel.

Directory of Open Access Journals (Sweden)

Rene Barro-Soria

Full Text Available Angiotensin II (AngII receptor (ATR is involved in pathologic local events such as neovascularisation and inflammation including in the brain and retina. The retinal pigment epithelium (RPE expresses ATR in its AT1R form, angiotensin-receptor-associated protein (Atrap, and transient-receptor-potential channel-V2 (TRPV2. AT1R and Atrap co-localize to the basolateral membrane of the RPE, as shown by immunostaining. Stimulation of porcine RPE (pRPE cells by AngII results in biphasic increases in intracellular free Ca(2+inhibited by losartan. Xestospongin C (xest C and U-73122, blockers of IP3R and PLC respectively, reduced AngII-evoked Ca(2+response. RPE cells from Atrap(-/- mice showed smaller AngII-evoked Ca(2+peak (by 22% and loss of sustained Ca(2+elevation compared to wild-type. The TRPV channel activator cannabidiol (CBD at 15 µM stimulates intracellular Ca(2+-rise suggesting that porcine RPE cells express TRPV2 channels. Further evidence supporting the functional expression of TRPV2 channels comes from experiments in which 100 µM SKF96365 (a TRPV channel inhibitor reduced the cannabidiol-induced Ca(2+-rise. Application of SKF96365 or reduction of TRPV2 expression by siRNA reduced the sustained phase of AngII-mediated Ca(2+transients by 53%. Thus systemic AngII, an effector of the local renin-angiotensin system stimulates biphasic Ca(2+transients in the RPE by releasing Ca(2+from cytosolic IP3-dependent stores and activating ATR/Atrap and TRPV2 channels to generate a sustained Ca(2+elevation.

Design Considerations for an Upgraded Track-Finding Processor in the Level-1 Endcap Muon Trigger of CMS for SLHC operations

CERN Document Server

Acosta, D; Furic, I; Gartner, J; Di Giovanni, G P; Hammar, A; Kotov, K; Madorsky, A; Matveev, M; Padley, P; Uvarov, L; Wang, D

2009-01-01

The conceptual design for a Level-1 muon track-finder trigger for the CMS endcap muon system is proposed that can accommodate the increased particle occupancy and system constraints of the proposed SLHC accelerator upgrade and the CMS detector upgrades. A brief review of the architecture of the current track-finder for LHC trigger operation is given, with potential bottlenecks indicated for SLHC operation. The upgraded track-finding processors described here would receive as many as two track segments detected from every cathode strip chamber comprising the endcap muon system, up to a total of 18 per 60° azimuthal sector. This would dramatically improve the efficiency of the track reconstruction in a high occupancy environment over the current design. However, such an improvement would require significantly higher bandwidth and logic resources. We propose to use the fastest available serial links, running asynchronously to the machine clock to use their full bandwidth. The work of creating a firmware model f...

Modulation of the transient receptor potential vanilloid channel TRPV4 by 4alpha-phorbol esters: a structure-activity study

DEFF Research Database (Denmark)

Klausen, Thomas Kjaer; Pagani, Alberto; Minassi, Alberto

2009-01-01

The mechanism of activation of the transient receptor potential vanilloid 4 (TRPV4) channel by 4alpha-phorbol esters was investigated by combining information from chemical modification of 4alpha-phorbol-didecanoate (4alpha-PDD, 2a), site-directed mutagenesis, Ca(2+) imaging, and electrophysiology....... Binding of 4alpha-phorbol esters occurs in a loop in the TM3-TM4 domain of TRPV4 that is analogous to the capsaicin binding site of TRPV1, and the ester decoration of ring C and the A,B ring junction are critical for activity. The lipophilic ester groups on ring C serve mainly as a steering element...

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

Directory of Open Access Journals (Sweden)

Debebe Gebremedhin

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

Characterization of a Madin-Darby canine kidney cell line stably expressing TRPV5.

NARCIS (Netherlands)

Dekker, E. den; Schoeber, J.P.H.; Topala, C.N.; Graaf, S.F.J. van de; Hoenderop, J.G.J.; Bindels, R.J.M.

2005-01-01

To provide a cell model for studying specifically the regulation of Ca2+ entry by the epithelial calcium channel transient receptor potential-vanilloid-5 (TRPV5), green fluorescent protein (GFP)-tagged TRPV5 was expressed stably in Madin-Darby canine kidney type I (MDCK) cells. The localization of

Workshop on data acquisition and trigger system simulations for high energy physics

Energy Technology Data Exchange (ETDEWEB)

NONE

1992-12-31

This report discusses the following topics: DAQSIM: A data acquisition system simulation tool; Front end and DCC Simulations for the SDC Straw Tube System; Simulation of Non-Blocklng Data Acquisition Architectures; Simulation Studies of the SDC Data Collection Chip; Correlation Studies of the Data Collection Circuit & The Design of a Queue for this Circuit; Fast Data Compression & Transmission from a Silicon Strip Wafer; Simulation of SCI Protocols in Modsim; Visual Design with vVHDL; Stochastic Simulation of Asynchronous Buffers; SDC Trigger Simulations; Trigger Rates, DAQ & Online Processing at the SSC; Planned Enhancements to MODSEM II & SIMOBJECT -- an Overview -- R.; DAGAR -- A synthesis system; Proposed Silicon Compiler for Physics Applications; Timed -- LOTOS in a PROLOG Environment: an Algebraic language for Simulation; Modeling and Simulation of an Event Builder for High Energy Physics Data Acquisition Systems; A Verilog Simulation for the CDF DAQ; Simulation to Design with Verilog; The DZero Data Acquisition System: Model and Measurements; DZero Trigger Level 1.5 Modeling; Strategies Optimizing Data Load in the DZero Triggers; Simulation of the DZero Level 2 Data Acquisition System; A Fast Method for Calculating DZero Level 1 Jet Trigger Properties and Physics Input to DAQ Studies.

Workshop on data acquisition and trigger system simulations for high energy physics

International Nuclear Information System (INIS)

1992-01-01

This report discusses the following topics: DAQSIM: A data acquisition system simulation tool; Front end and DCC Simulations for the SDC Straw Tube System; Simulation of Non-Blocklng Data Acquisition Architectures; Simulation Studies of the SDC Data Collection Chip; Correlation Studies of the Data Collection Circuit ampersand The Design of a Queue for this Circuit; Fast Data Compression ampersand Transmission from a Silicon Strip Wafer; Simulation of SCI Protocols in Modsim; Visual Design with vVHDL; Stochastic Simulation of Asynchronous Buffers; SDC Trigger Simulations; Trigger Rates, DAQ ampersand Online Processing at the SSC; Planned Enhancements to MODSEM II ampersand SIMOBJECT -- an Overview -- R.; DAGAR -- A synthesis system; Proposed Silicon Compiler for Physics Applications; Timed -- LOTOS in a PROLOG Environment: an Algebraic language for Simulation; Modeling and Simulation of an Event Builder for High Energy Physics Data Acquisition Systems; A Verilog Simulation for the CDF DAQ; Simulation to Design with Verilog; The DZero Data Acquisition System: Model and Measurements; DZero Trigger Level 1.5 Modeling; Strategies Optimizing Data Load in the DZero Triggers; Simulation of the DZero Level 2 Data Acquisition System; A Fast Method for Calculating DZero Level 1 Jet Trigger Properties and Physics Input to DAQ Studies

TRPV4 calcium-permeable channel is a novel regulator of oxidized LDL-induced macrophage foam cell formation.

Science.gov (United States)

Goswami, Rishov; Merth, Michael; Sharma, Shweta; Alharbi, Mazen O; Aranda-Espinoza, Helim; Zhu, Xiaoping; Rahaman, Shaik O

2017-09-01

Cardiovascular disease is the number one cause of death in United States, and atherosclerosis, a chronic inflammatory arterial disease, is the most dominant underlying pathology. Macrophages are thought to orchestrate atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators. Emerging data support a role for a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. However, the identity of the plasma membrane mechanosensor and the mechanisms by which pro-atherogenic signals are transduced/maintained are unknown. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family and a known mechanosensor, is the likely mediator of oxidized low-density lipoprotein (oxLDL)-dependent macrophage foam cell formation, a critical process in atherogenesis. Specifically, we found that: i) genetic ablation of TRPV4 or pharmacologic inhibition of TRPV4 activity by a specific antagonist blocked oxLDL-induced macrophage foam cell formation, and ii) TRPV4 deficiency prevented pathophysiological range matrix stiffness or scratch-induced exacerbation of oxLDL-induced foam cell formation. Mechanistically, we found that: i) plasma membrane localization of TRPV4 was sensitized to the increasing level of matrix stiffness, ii) lack of foam cell formation in TRPV4 null cells was not due to lack of expression of CD36, a major receptor for oxLDL, and iii) TRPV4 channel activity regulated oxLDL uptake but not its binding on macrophages. Altogether, these findings identify a novel role for TRPV4 in regulating macrophage foam cell formation by modulating uptake of oxLDL. These findings suggest that therapeutic targeting of TRPV4 may provide a selective approach to the treatment of atherosclerosis. Copyright © 2017. Published by Elsevier Inc.

The ATLAS Level-1 Topological Trigger Performance

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00371751; The ATLAS collaboration

2016-01-01

The LHC will collide protons in the ATLAS detector with increasing luminosity through 2016, placing stringent operational and physical requirements to the ATLAS trigger system in order to reduce the 40 MHz collision rate to a manageable event storage rate of 1 kHz, while not rejecting interesting physics events. The Level-1 trigger is the first rate-reducing step in the ATLAS trigger system with an output rate of 100 kHz and decision latency smaller than 2.5 μs. It consists of a calorimeter trigger, muon trigger and a central trigger processor. During the LHC shutdown after the Run 1 finished in 2013, the Level-1 trigger system was upgraded including hardware, firmware and software updates. In particular, new electronics modules were introduced in the real-time data processing path: the Topological Processor System (L1Topo). It consists of a single AdvancedCTA shelf equipped with two Level-1 topological processor blades. They receive real-time information from the Level-1 calorimeter and muon triggers, which...

Pro asynchronous programming with .NET

CERN Document Server

Blewett, Richard; Ltd, Rock Solid Knowledge

2014-01-01

Pro Asynchronous Programming with .NET teaches the essential skill of asynchronous programming in .NET. It answers critical questions in .NET application development, such as: how do I keep my program responding at all times to keep my users happy how do I make the most of the available hardware how can I improve performanceIn the modern world, users expect more and more from their applications and devices, and multi-core hardware has the potential to provide it. But it takes carefully crafted code to turn that potential into responsive, scalable applications.With Pro Asynchronous Programming

Asynchronized synchronous machines

CERN Document Server

Botvinnik, M M

1964-01-01

Asynchronized Synchronous Machines focuses on the theoretical research on asynchronized synchronous (AS) machines, which are "hybrids” of synchronous and induction machines that can operate with slip. Topics covered in this book include the initial equations; vector diagram of an AS machine; regulation in cases of deviation from the law of full compensation; parameters of the excitation system; and schematic diagram of an excitation regulator. The possible applications of AS machines and its calculations in certain cases are also discussed. This publication is beneficial for students and indiv

Ethanol attenuation of long-term depression in the nucleus accumbens can be overcome by activation of TRPV1 receptors.

Science.gov (United States)

Renteria, Rafael; Jeanes, Zachary M; Morrisett, Richard A

2014-11-01

Altered expression of synaptic plasticity within the nucleus accumbens (NAc) constitutes a critical neuroadaptive response to ethanol (EtOH) and other drugs of abuse. We have previously reported that N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) is markedly affected by chronic intermittent ethanol exposure in vivo; however, endocannabinoid (eCB)-dependent synaptic depression, despite being very well-documented in the dorsal striatum, is much less well understood in the NAc. Whole cell patch clamp electrophysiology was used to investigate interactions between these different plasticity-induction systems. Excitatory postsynaptic currents (EPSCs) were measured in the NAc shell and NMDAR-LTD was induced by a pairing protocol (500 stimuli at 1 Hz stimulation [low-frequency stimulation (LFS)] paired with postsynaptic depolarization to -50 mV). AM251, a CB1 receptor antagonist, was used to determine whether this form of LTD is modulated by eCBs. To determine the effect of EtOH on a purely eCB-dependent response in the NAc, depolarization-induced suppression of excitation (DSE) was used in the presence of 40 mM EtOH. Finally, we determined whether the enhancement of eCB signaling with URB597, a fatty acid amide hydrolase inhibitor, and AM404, an anandamide re-uptake inhibitor would also modulate LFS LTD in the presence of NMDAR blockade or EtOH. In the presence of AM251, the LFS pairing protocol resulted in NMDAR-dependent long-term potentiation that was blocked with either EtOH or DL-APV. We also found that DSE in the NAc shell was blocked by AM251 and suppressed by EtOH. Enhanced eCB signaling rescued NAc-LTD expression in the presence of EtOH through a distinct mechanism requiring activation of TRPV1 receptors. EtOH modulation of synaptic plasticity in the NAc is dependent upon a complex interplay between NMDARs, eCBs, and TRPV1 receptors. These findings demonstrate a novel form of TRPV1-dependent LTD in the NAc shell that may be critical

The use of flow cytometry to examine calcium signalling by TRPV1 in mixed cell populations.

Science.gov (United States)

Assas, Bakri M; Abdulaal, Wesam H; Wakid, Majed H; Zakai, Haytham A; Miyan, J; Pennock, J L

2017-06-15

Flow cytometric analysis of calcium mobilisation has been in use for many years in the study of specific receptor engagement or isolated cell:cell communication. However, calcium mobilisation/signaling is key to many cell functions including apoptosis, mobility and immune responses. Here we combine multiplex surface staining of whole spleen with Indo-1 AM to visualise calcium mobilisation and examine calcium signaling in a mixed immune cell culture over time. We demonstrate responses to a TRPV1 agonist in distinct cell subtypes without the need for cell separation. Multi parameter staining alongside Indo-1 AM to demonstrate calcium mobilization allows the study of real time calcium signaling in a complex environment. Copyright © 2017. Published by Elsevier Inc.

Error characterization for asynchronous computations: Proxy equation approach

Science.gov (United States)

Sallai, Gabriella; Mittal, Ankita; Girimaji, Sharath

2017-11-01

Numerical techniques for asynchronous fluid flow simulations are currently under development to enable efficient utilization of massively parallel computers. These numerical approaches attempt to accurately solve time evolution of transport equations using spatial information at different time levels. The truncation error of asynchronous methods can be divided into two parts: delay dependent (EA) or asynchronous error and delay independent (ES) or synchronous error. The focus of this study is a specific asynchronous error mitigation technique called proxy-equation approach. The aim of this study is to examine these errors as a function of the characteristic wavelength of the solution. Mitigation of asynchronous effects requires that the asynchronous error be smaller than synchronous truncation error. For a simple convection-diffusion equation, proxy-equation error analysis identifies critical initial wave-number, λc. At smaller wave numbers, synchronous error are larger than asynchronous errors. We examine various approaches to increase the value of λc in order to improve the range of applicability of proxy-equation approach.

Damage to lens fiber cells causes TRPV4-dependent Src family kinase activation in the epithelium.

Science.gov (United States)

Shahidullah, M; Mandal, A; Delamere, N A

2015-11-01

The bulk of the lens consists of tightly packed fiber cells. Because mature lens fibers lack mitochondria and other organelles, lens homeostasis relies on a monolayer of epithelial cells at the anterior surface. The detection of various signaling pathways in lens epithelial cells suggests they respond to stimuli that influence lens function. Focusing on Src Family Kinases (SFKs) and Transient Receptor Potential Vanilloid 4 (TRPV4), we tested whether the epithelium can sense and respond to an event that occurs in fiber mass. The pig lens was subjected to localized freeze-thaw (FT) damage to fibers at posterior pole then the lens was incubated for 1-10 min in Krebs solution at 37 °C. Transient SFK activation in the epithelium was detectable at 1 min. Using a western blot approach, the ion channel TRPV4 was detected in the epithelium but was sparse or absent in fiber cells. Even though TRPV4 expression appears low at the actual site of FT damage to the fibers, SFK activation in the epithelium was suppressed in lenses subjected to FT damage then incubated with the TRPV4 antagonist HC067047 (10 μM). Na,K-ATPase activity was examined because previous studies report changes of Na,K-ATPase activity associated with SFK activation. Na,K-ATPase activity doubled in the epithelium removed from FT-damaged lenses and the response was prevented by HC067047 or the SFK inhibitor PP2 (10 μM). Similar changes were observed in response to fiber damage caused by injection of 5 μl hyperosmotic NaCl or mannitol solution beneath the surface of the posterior pole. The findings point to a TRPV4-dependent mechanism that enables the epithelial cells to detect remote damage in the fiber mass and respond within minutes by activating SFK and increasing Na,K-ATPase activity. Because TRPV4 channels are mechanosensitive, we speculate they may be stimulated by swelling of the lens structure caused by damage to the fibers. Increased Na,K-ATPase activity gives the lens greater capacity to

Tissue transglutaminase inhibits the TRPV5-dependent calcium transport in an N-glycosylation-dependent manner

DEFF Research Database (Denmark)

Boros, Sandor; Xi, Qi; Dimke, Henrik Anthony

2011-01-01

Tissue transglutaminase (tTG) is a multifunctional Ca(2+)-dependent enzyme, catalyzing protein crosslinking. The transient receptor potential vanilloid (TRPV) family of cation channels was recently shown to contribute to the regulation of TG activities in keratinocytes and hence skin barrier form......, these observations imply that tTG is a novel extracellular enzyme inhibiting the activity of TRPV5. The inhibition of TRPV5 occurs in an N-glycosylation-dependent manner, signifying a common final pathway by which distinct extracellular factors regulate channel activity....

Rapid effects of 17beta-estradiol on TRPV5 epithelial Ca2+ channels in rat renal cells.

LENUS (Irish Health Repository)

Irnaten, Mustapha

2009-08-01

The renal distal tubules and collecting ducts play a key role in the control of electrolyte and fluid homeostasis. The discovery of highly calcium selective channels, Transient Receptor Potential Vanilloid 5 (TRPV5) of the TRP superfamily, has clarified the nature of the calcium entry channels. It has been proposed that this channel mediates the critical Ca(2+) entry step in transcellular Ca(2+) re-absorption in the kidney. The regulation of transmembrane Ca(2+) flux through TRPV5 is of particular importance for whole body calcium homeostasis.In this study, we provide evidence that the TRPV5 channel is present in rat cortical collecting duct (RCCD(2)) cells at mRNA and protein levels. We demonstrate that 17beta-estradiol (E(2)) is involved in the regulation of Ca(2+) influx in these cells via the epithelial Ca(2+) channels TRPV5. By combining whole-cell patch-clamp and Ca(2+)-imaging techniques, we have characterized the electrophysiological properties of the TRPV5 channel and showed that treatment with 20-50nM E(2) rapidly (<5min) induced a transient increase in inward whole-cell currents and intracellular Ca(2+) via TRPV5 channels. This rise was significantly prevented when cells were pre-treated with ruthenium red and completely abolished in cells treated with siRNA specifically targeting TRPV5.These data demonstrate for the first time, a novel rapid modulation of endogenously expressed TRPV5 channels by E(2) in kidney cells. Furthermore, the results suggest calcitropic effects of E(2). The results are discussed in relation to present concepts of non-genomic actions of E(2) in Ca(2+) homeostasis.

Rapid effects of 17beta-estradiol on epithelial TRPV6 Ca2+ channel in human T84 colonic cells.

LENUS (Irish Health Repository)

Irnaten, Mustapha

2008-11-01

The control of calcium homeostasis is essential for cell survival and is of crucial importance for several physiological functions. The discovery of the epithelial calcium channel Transient Receptor Potential Vaniloid (TRPV6) in intestine has uncovered important Ca(2+) absorptive pathways involved in the regulation of whole body Ca(2+) homeostasis. The role of steroid hormone 17beta-estradiol (E(2)), in [Ca(2+)](i) regulation involving TRPV6 has been only limited at the protein expression levels in over-expressing heterologous systems. In the present study, using a combination of calcium-imaging, whole-cell patch-clamp techniques and siRNA technology to specifically knockdown TRPV6 protein expression, we were able to (i) show that TRPV6 is natively, rather than exogenously, expressed at mRNA and protein levels in human T84 colonic cells, (ii) characterize functional TRPV6 channels and (iii) demonstrate, for the first time, the rapid effects of E(2) in [Ca(2+)](i) regulation involving directly TRPV6 channels in T84 cells. Treatment with E(2) rapidly (<5 min) enhanced [Ca(2+)](i) and this increase was partially but significantly prevented when cells were pre-treated with ruthenium red and completely abolished in cells treated with siRNA specifically targeting TRPV6 protein expression. These results indicate that when cells are stimulated by E(2), Ca(2+) enters the cell through TRPV6 channels. TRPV6 channels in T84 cells contribute to the Ca(2+) entry\\/signalling pathway that is sensitive to 17beta-estradiol.

The Aeolian Asynchronous Generator

Directory of Open Access Journals (Sweden)

Ionel Dragomirescu

2008-10-01

Full Text Available The production of the electric energy with lower costs could be realized with the help of the aeolian electric central. In these centrals we can use the squirrel cage asynchronous generators, because these machines are the most safety in function and easy exploited. This work show the function analyzing of the asynchronous generator having on involving torque depending on the square wind speed, the air-density and on the construction of the wing spiral.

Triggers in UA2 and UA1

International Nuclear Information System (INIS)

Dorenbosch, J.

1985-01-01

The UA2 and UA1 trigger systems are described as they will be used after the upgrade of the CERN SPPS. The luminosity of the collider will increase to 3x10 30 . The bunch spacing is 4 microseconds, comparable to the time available for a second level trigger at the SSC. The first level triggers are very powerful and deliver trigger rates of about 100 Hz. The UA1 second level trigger operates on the final digitizings with a combination of special and general purpose processors. At the highest trigger levels a small farm of processors performs the final reduction. (orig.)

[Effect of bee venom injection on TrkA and TRPV1 expression in the dorsal root ganglion of rats with collagen-induced arthritis].

Science.gov (United States)

Xian, Pei-Feng; Chen, Ying; Yang, Lu; Liu, Guo-Tao; Peng, Peng; Wang, Sheng-Xu

2016-06-01

To investigate the therapeutic effect of acupoint injection of bee venom on collagen-induced arthritis (CIA) in rats and explore the mechanism of bee venom therapy in the treatment of rheumatoid arthritis. Fifteen male Wistar rats were randomly divided into bee venom treatment group (BV group), CIA model group, and control group. In the former two groups, CIA was induced by injections of collagen II+IFA (0.2 mL) via the tail vein, and in the control group, normal saline was injected instead. The rats in BV group received daily injection of 0.1 mL (3 mg/mL) bee venom for 7 consecutive days. All the rats were assessed for paw thickness and arthritis index from days 14 to 21, and the pain threshold was determined on day 21. The expressions of TRPV1 and TrkA in the dorsal root ganglion at the level of L4-6 were detected using immunohistochemistry and Western blotting, respectively. The rats in CIA model group started to show paw swelling on day 10, and by day 14, all the rats in this group showed typical signs of CIA. In BV group, the rats receiving been venom therapy for 7 days showed a significantly smaller paw thickness and a low arthritis index than those in the model group. The pain threshold was the highest in the control group and the lowest in the model group. TRPV1-positive cells and TrkA expression in the dorsal root ganglion was significantly reduced in BV group as compared with that in the model group. s Injection of bee venom can decrease expression of TRPV1 and TrkA in the dorsal root ganglion to produce anti-inflammatory and analgesic effects, suggesting the potential value of bee venom in the treatment of rheumatoid arthritis.

The ATLAS Level-1 Calorimeter Trigger

International Nuclear Information System (INIS)

Achenbach, R; Andrei, V; Adragna, P; Apostologlou, P; Barnett, B M; Brawn, I P; Davis, A O; Edwards, J P; Asman, B; Bohm, C; Ay, C; Bauss, B; Bendel, M; Dahlhoff, A; Eckweiler, S; Booth, J R A; Thomas, P Bright; Charlton, D G; Collins, N J; Curtis, C J

2008-01-01

The ATLAS Level-1 Calorimeter Trigger uses reduced-granularity information from all the ATLAS calorimeters to search for high transverse-energy electrons, photons, τ leptons and jets, as well as high missing and total transverse energy. The calorimeter trigger electronics has a fixed latency of about 1 μs, using programmable custom-built digital electronics. This paper describes the Calorimeter Trigger hardware, as installed in the ATLAS electronics cavern

The ATLAS Level-1 Calorimeter Trigger

Energy Technology Data Exchange (ETDEWEB)

Achenbach, R; Andrei, V [Kirchhoff-Institut fuer Physik, University of Heidelberg, D-69120 Heidelberg (Germany); Adragna, P [Physics Department, Queen Mary, University of London, London E1 4NS (United Kingdom); Apostologlou, P; Barnett, B M; Brawn, I P; Davis, A O; Edwards, J P [STFC Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Didcot, Oxon OX11 0QX (United Kingdom); Asman, B; Bohm, C [Fysikum, Stockholm University, SE-106 91 Stockholm (Sweden); Ay, C; Bauss, B; Bendel, M; Dahlhoff, A; Eckweiler, S [Institut fuer Physik, University of Mainz, D-55099 Mainz (Germany); Booth, J R A; Thomas, P Bright; Charlton, D G; Collins, N J; Curtis, C J [School of Physics and Astronomy, University of Birmingham, Birmingham B15 2TT (United Kingdom)], E-mail: e.eisenhandler@qmul.ac.uk (and others)

2008-03-15

The ATLAS Level-1 Calorimeter Trigger uses reduced-granularity information from all the ATLAS calorimeters to search for high transverse-energy electrons, photons, {tau} leptons and jets, as well as high missing and total transverse energy. The calorimeter trigger electronics has a fixed latency of about 1 {mu}s, using programmable custom-built digital electronics. This paper describes the Calorimeter Trigger hardware, as installed in the ATLAS electronics cavern.

TRPV2 activation induces apoptotic cell death in human T24 bladder cancer cells: a potential therapeutic target for bladder cancer.

Science.gov (United States)

Yamada, Takahiro; Ueda, Takashi; Shibata, Yasuhiro; Ikegami, Yosuke; Saito, Masaki; Ishida, Yusuke; Ugawa, Shinya; Kohri, Kenjiro; Shimada, Shoichi

2010-08-01

To investigate the functional expression of the transient receptor potential vanilloid 2 (TRPV2) channel protein in human urothelial carcinoma (UC) cells and to determine whether calcium influx into UC cells through TRPV2 is involved in apoptotic cell death. The expression of TRPV2 mRNA in bladder cancer cell lines (T24, a poorly differentiated UC cell line and RT4, a well-differentiated UC cell line) was analyzed using reverse transcriptase-polymerase chain reaction. The calcium permeability of TRPV2 channels in T24 cells was investigated using a calcium imaging assay that used cannabidiol (CBD), a relatively selective TRPV2 agonist, and ruthenium red (RuR), a nonselective TRPV channel antagonist. The death of T24 or RT4 cells in the presence of CBD was evaluated using a cellular viability assay. Apoptosis of T24 cells caused by CBD was confirmed using an annexin-V assay and small interfering RNA (siRNA) silencing of TRPV2. TRPV2 mRNA was abundantly expressed in T24 cells. The expression level in UC cells was correlated with high-grade disease. The administration of CBD increased intracellular calcium concentrations in T24 cells. In addition, the viability of T24 cells progressively decreased with increasing concentrations of CBD, whereas RT4 cells were mostly unaffected. Cell death occurred via apoptosis caused by continuous influx of calcium through TRPV2. TRPV2 channels in UC cells are calcium-permeable and the regulation of calcium influx through these channels leads directly to the death of UC cells. TRPV2 channels in UC cells may be a potential new therapeutic target, especially in higher-grade UC cells. Copyright 2010 Elsevier Inc. All rights reserved.

Level Zero Trigger Processor for the NA62 experiment

Science.gov (United States)

Soldi, D.; Chiozzi, S.

2018-05-01

The NA62 experiment is designed to measure the ultra-rare decay K+ arrow π+ ν bar nu branching ratio with a precision of ~ 10% at the CERN Super Proton Synchrotron (SPS). The trigger system of NA62 consists in three different levels designed to select events of physics interest in a high beam rate environment. The L0 Trigger Processor (L0TP) is the lowest level system of the trigger chain. It is hardware implemented using programmable logic. The architecture of the NA62 L0TP system is a new approach compared to existing systems used in high-energy physics experiments. It is fully digital, based on a standard gigabit Ethernet communication between detectors and the L0TP Board. The L0TP Board is a commercial development board, mounting a programmable logic device (FPGA). The primitives generated by sub-detectors are sent asynchronously using the UDP protocol to the L0TP during the entire beam spill period. The L0TP realigns in time the primitives coming from seven different sources and performs a data selection based on the characteristics of the event such as energy, multiplicity and topology of hits in the sub-detectors. It guarantees a maximum latency of 1 ms. The maximum input rate is about 10 MHz for each sub-detector, while the design maximum output trigger rate is 1 MHz. A description of the trigger algorithm is presented here.

Psychophysiological effects of synchronous versus asynchronous music during cycling.

Science.gov (United States)

Lim, Harry B T; Karageorghis, Costas I; Romer, Lee M; Bishop, Daniel T

2014-02-01

Synchronizing movement to a musical beat may reduce the metabolic cost of exercise, but findings to date have been equivocal. Our aim was to examine the degree to which the synchronous application of music moderates the metabolic demands of a cycle ergometer task. Twenty-three recreationally active men made two laboratory visits. During the first visit, participants completed a maximal incremental ramp test on a cycle ergometer. At the second visit, they completed four randomized 6-min cycling bouts at 90% of ventilatory threshold (control, metronome, synchronous music, and asynchronous music). Main outcome variables were oxygen uptake, HR, ratings of dyspnea and limb discomfort, affective valence, and arousal. No significant differences were evident for oxygen uptake. HR was lower under the metronome condition (122 ± 15 bpm) compared to asynchronous music (124 ± 17 bpm) and control (125 ± 16 bpm). Limb discomfort was lower while listening to the metronome (2.5 ± 1.2) and synchronous music (2.3 ± 1.1) compared to control (3.0 ± 1.5). Both music conditions, synchronous (1.9 ± 1.2) and asynchronous (2.1 ± 1.3), elicited more positive affective valence compared to metronome (1.2 ± 1.4) and control (1.2 ± 1.2), while arousal was higher with synchronous music (3.4 ± 0.9) compared to metronome (2.8 ± 1.0) and control (2.8 ± 0.9). Synchronizing movement to a rhythmic stimulus does not reduce metabolic cost but may lower limb discomfort. Moreover, synchronous music has a stronger effect on limb discomfort and arousal when compared to asynchronous music.

Burst-Mode Asynchronous Controllers on FPGA

Directory of Open Access Journals (Sweden)

Duarte L. Oliveira

2008-01-01

Full Text Available FPGAs have been mainly used to design synchronous circuits. Asynchronous design on FPGAs is difficult because the resulting circuit may suffer from hazard problems. We propose a method that implements a popular class of asynchronous circuits, known as burst mode, on FPGAs based on look-up table architectures. We present two conditions that, if satisfied, guarantee essential hazard-free implementation on any LUT-based FPGA. By doing that, besides all the intrinsic advantages of asynchronous over synchronous circuits, they also take advantage of the shorter design time and lower cost associated with FPGA designs.

TRPV6 exhibits unusual patterns of polymorphism and divergence in worldwide populations.

Science.gov (United States)

Akey, Joshua M; Swanson, Willie J; Madeoy, Jennifer; Eberle, Michael; Shriver, Mark D

2006-07-01

A striking footprint of positive selection was recently identified on chromosome 7q34-35 that spans at least 115 kb and encompasses four known genes (KEL, TRPV5, TRPV6, EPHB6). The signature of selection was observed in only one of the two populations analyzed suggesting the action of geographically restricted selective pressures. However, as only two populations were analyzed, it remains unknown whether the signature of selection extends to additional populations. To address this issue and begin to dissect the evolutionary history of this region in more detail, we performed an in-depth population genetic analysis on TRPV6, which is a calcium-permeable ion channel thought to mediate the rate-limiting step of dietary calcium absorption. We demonstrate that the rate of TRPV6 protein evolution is significantly accelerated in the human lineage, but only for a haplotype defined by three non-synonymous SNPs (C157R, M378V and M681T) that are nearly fixed for the derived alleles in non-African populations. Interestingly, we found that these three non-synonymous SNPs have high posterior probabilities for being targets of positive selection and are therefore strong candidates for mediating the population-specific signatures of selection in this region. In addition, we resequenced the exons corresponding to the C157R, M378V and M681T polymorphisms in 90 geographically diverse individuals and characterized their global allele frequency distribution by genotyping them in 1064 individuals from 52 populations. These data strongly suggest that the TRPV6 haplotype defined by the derived alleles at C157R, M378V and M681T conferred a selective advantage that varied spatially, and perhaps temporally, during human history.

BTeV trigger/DAQ innovations

International Nuclear Information System (INIS)

Votava, Margaret

2005-01-01

The BTeV experiment was a collider based high energy physics (HEP) B-physics experiment proposed at Fermilab. It included a large-scale, high speed trigger/data acquisition (DAQ) system, reading data off the detector at 500 Gbytes/sec and writing to mass storage at 200 Mbytes/sec. The online design was considered to be highly credible in terms of technical feasibility, schedule and cost. This paper will give an overview of the overall trigger/DAQ architecture, highlight some of the challenges, and describe the BTeV approach to solving some of the technical challenges. At the time of termination in early 2005, the experiment had just passed its baseline review. Although not fully implemented, many of the architecture choices, design, and prototype work for the online system (both trigger and DAQ) were well on their way to completion. Other large, high-speed online systems may have interest in the some of the design choices and directions of BTeV, including (a) a commodity-based tracking trigger running asynchronously at full rate, (b) the hierarchical control and fault tolerance in a large real time environment, (c) a partitioning model that supports offline processing on the online farms during idle periods with plans for dynamic load balancing, and (d) an independent parallel highway architecture

TRPV5: an ingeniously controlled calcium channel.

NARCIS (Netherlands)

Groot, T. de; Bindels, R.J.M.; Hoenderop, J.G.J.

2008-01-01

Body Ca(2+) homeostasis is tightly controlled and slight disturbances in renal Ca(2+) reabsorption can lead to excessive urine Ca(2+) excretion and promote kidney stone formation. The epithelial Ca(2+) channel TRPV5 constitutes the rate-limiting step of active Ca(2+) reabsorption in the kidney.

1 Commande multivariable du moteur asynchrone triphasé à cage ...

African Journals Online (AJOL)

AKA BOKO

Correspondance, courriel : rabenarivo.michel@yahoo.fr. Résumé. La commande du moteur asynchrone triphasé à ... synthèse du système à l'aide du logiciel MATLAB. Mots-clés : commande, système multivariable, variation de ... of the system by MATLAB software. Keywords : control, MIMO system, frequency variation, ...

Ablation of rat TRPV1-expressing Adelta/C-fibers with resiniferatoxin: analysis of withdrawal behaviors, recovery of function and molecular correlates

Directory of Open Access Journals (Sweden)

Haspel Gal

2010-12-01

Full Text Available Abstract Background Ablation of TRPV1-expressing nociceptive fibers with the potent capsaicin analog resiniferatoxin (RTX results in long lasting pain relief. RTX is particularly adaptable to focal application, and the induced chemical axonopathy leads to analgesia with a duration that is influenced by dose, route of administration, and the rate of fiber regeneration. TRPV1 is expressed in a subpopulation of unmyelinated C- and lightly myelinated Adelta fibers that detect changes in skin temperature at low and high rates of noxious heating, respectively. Here we investigate fiber-type specific behaviors, their time course of recovery and molecular correlates of axon damage and nociception using infrared laser stimuli following an RTX-induced peripheral axonopathy. Results RTX was injected into rat hind paws (mid-plantar to produce thermal hypoalgesia. An infrared diode laser was used to stimulate Adelta fibers in the paw with a small-diameter (1.6 mm, high-energy, 100 msec pulse, or C-fibers with a wide-diameter (5 mm, long-duration, low-energy pulse. We monitored behavioral responses to indicate loss and regeneration of fibers. At the site of injection, responses to C-fiber stimuli were significantly attenuated for two weeks after 5 or 50 ng RTX. Responses to Adelta stimuli were significantly attenuated for two weeks at the highest intensity stimulus, and for 5 weeks to a less intense Adelta stimulus. Stimulation on the toe, a site distal to the injection, showed significant attenuation of Adelta responses for 7- 8 weeks after 5 ng, or 9-10 weeks after 50 ng RTX. In contrast, responses to C-fiber stimuli exhibited basically normal responses at 5 weeks after RTX. During the period of fiber loss and recovery, molecular markers for nerve regeneration (ATF3 and galanin are upregulated in the dorsal root ganglia (DRG when behavior is maximally attenuated, but markers of nociceptive activity (c-Fos in spinal cord and MCP-1 in DRG, although induced

Behavioral Synthesis of Asynchronous Circuits Using Syntax Directed Translation as Backend

DEFF Research Database (Denmark)

Nielsen, Sune Fallgaard; Sparsø, Jens; Madsen, Jan

2009-01-01

The current state-of-the art in high-level synthesis of asynchronous circuits is syntax directed translation, which performs a one-to-one mapping of a HDL-description into a corresponding circuit. This paper presents a method for behavioral synthesis of asynchronous circuits which builds on top...... description language Balsa [1]. This ”conventional” template architecture allows us to adapt traditional synchronous synthesis techniques for resource sharing, scheduling, binding etc, to the domain of asynchronous circuits. A prototype tool has been implemented on top of the Balsa framework, and the method...... is illustrated through the implementation of a set of example circuits. The main contributions of the paper are: the fundamental idea, the template architecture and its implementation using asynchronous handshake components, and the implementation of a prototype tool....

Progress on the Level-1 Calorimeter Trigger

CERN Multimedia

Eric Eisenhandler

The Level-1 Calorimeter Trigger (L1Calo) has recently passed a number of major hurdles. The various electronic modules that make up the trigger are either in full production or are about to be, and preparations in the ATLAS pit are well advanced. L1Calo has three main subsystems. The PreProcessor converts analogue calorimeter signals to digital, associates the rather broad trigger pulses with the correct proton-proton bunch crossing, and does a final calibration in transverse energy before sending digital data streams to the two algorithmic trigger processors. The Cluster Processor identifies and counts electrons, photons and taus, and the Jet/Energy-sum Processor looks for jets and also sums missing and total transverse energy. Readout drivers allow the performance of the trigger to be monitored online and offline, and also send region-of-interest information to the Level-2 Trigger. The PreProcessor (Heidelberg) is the L1Calo subsystem with the largest number of electronic modules (124), and most of its fu...

The ATLAS Level-1 Central Trigger Processor (CTP)

CERN Document Server

Spiwoks, Ralf; Ellis, Nick; Farthouat, P; Gällnö, P; Haller, J; Krasznahorkay, A; Maeno, T; Pauly, T; Pessoa-Lima, H; Resurreccion-Arcas, I; Schuler, G; De Seixas, J M; Torga-Teixeira, R; Wengler, T

2005-01-01

The ATLAS Level-1 Central Trigger Processor (CTP) combines information from calorimeter and muon trigger processors and makes the final Level-1 Accept (L1A) decision on the basis of lists of selection criteria (trigger menus). In addition to the event-selection decision, the CTP also provides trigger summary information to the Level-2 trigger and the data acquisition system. It further provides accumulated and bunch-by-bunch scaler data for monitoring of the trigger, detector and beam conditions. The CTP is presented and results are shown from tests with the calorimeter adn muon trigger processors connected to detectors in a particle beam, as well as from stand-alone full-system tests in the laboratory which were used to validate the CTP.

ATLAS Level-1 Topological Trigger

CERN Document Server

Zheng, Daniel; The ATLAS collaboration

2018-01-01

The ATLAS experiment has introduced and recently commissioned a completely new hardware sub-system of its first-level trigger: the topological processor (L1Topo). L1Topo consist of two AdvancedTCA blades mounting state-of-the-art FPGA processors, providing high input bandwidth (up to 4 Gb/s) and low latency data processing (200 ns). L1Topo is able to select collision events by applying kinematic and topological requirements on candidate objects (energy clusters, jets, and muons) measured by calorimeters and muon sub-detectors. Results from data recorded using the L1Topo trigger will be presented. These results demonstrate a significantly improved background event rejection, thus allowing for a rate reduction without efficiency loss. This improvement has been shown for several physics processes leading to low-pT leptons, including H->tau tau and J/Psi->mu mu. In addition to describing the L1Topo trigger system, we will discuss the use of an accurate L1Topo simulation as a powerful tool to validate and optimize...

Comparing the force ripple during asynchronous and conventional stimulation.

Science.gov (United States)

Downey, Ryan J; Tate, Mark; Kawai, Hiroyuki; Dixon, Warren E

2014-10-01

Asynchronous stimulation has been shown to reduce fatigue during electrical stimulation; however, it may also exhibit a force ripple. We quantified the ripple during asynchronous and conventional single-channel transcutaneous stimulation across a range of stimulation frequencies. The ripple was measured during 5 asynchronous stimulation protocols, 2 conventional stimulation protocols, and 3 volitional contractions in 12 healthy individuals. Conventional 40 Hz and asynchronous 16 Hz stimulation were found to induce contractions that were as smooth as volitional contractions. Asynchronous 8, 10, and 12 Hz stimulation induced contractions with significant ripple. Lower stimulation frequencies can reduce fatigue; however, they may also lead to increased ripple. Future efforts should study the relationship between force ripple and the smoothness of the evoked movements in addition to the relationship between stimulation frequency and NMES-induced fatigue to elucidate an optimal stimulation frequency for asynchronous stimulation. © 2014 Wiley Periodicals, Inc.

UA1 upgrade first-level calorimeter trigger processor

International Nuclear Information System (INIS)

Bains, N.; Charlton, D.; Ellis, N.; Garvey, J.; Gregory, J.; Jimack, M.P.; Jovanovic, P.; Kenyon, I.R.; Baird, S.A.; Campbell, D.; Cawthraw, M.; Coughlan, J.; Flynn, P.; Galagedera, S.; Grayer, G.; Halsall, R.; Shah, T.P.; Stephens, R.; Eisenhandler, E.; Fensome, I.; Landon, M.

1989-01-01

A new first-level trigger processor has been built for the UA1 experiment on the Cern SppS Collider. The processor exploits the fine granularity of the new UA1 uranium-TMP calorimeter to improve the selectivity of the trigger. The new electron trigger has improved hadron jet rejection, achieved by requiring low energy deposition around the electromagnetic cluster. A missing transverse energy trigger and a total energy trigger have also been implemented. (orig.)

Validation of ATLAS L1 Topological Triggers

CERN Document Server

Praderio, Marco

2017-01-01

The Topological trigger (L1Topo) is a new component of the ATLAS L1 (Level-1) trigger. Its purpose is that of reducing the otherwise too high rate of data collection from the LHC by rejecting those events considered “uninteresting” (meaning that they have already been studied). This event rate reduction is achieved by applying topological requirements to the physical objects present in each event. It is very important to make sure that this trigger does not reject any “interesting” event. Therefore we need to verify its correct functioning. The goal of this summer student project is to study the response of two L1Topo algorithms (concerning ∆R and invariant mass). To do so I will compare the trigger decisions produced by the L1Topo hardware with the ones produced by the “official” L1Topo simulation. This way I will be able to identify events that could be incorrectly rejected. Simultaneously I will produce an emulation of these triggers that will help me understand the cause of disagreements bet...

Novel endogenous N-acyl amides activate TRPV1-4 receptors, BV-2 microglia, and are regulated in brain in an acute model of inflammation

Science.gov (United States)

Raboune, Siham; Stuart, Jordyn M.; Leishman, Emma; Takacs, Sara M.; Rhodes, Brandon; Basnet, Arjun; Jameyfield, Evan; McHugh, Douglas; Widlanski, Theodore; Bradshaw, Heather B.

2014-01-01

A family of endogenous lipids, structurally analogous to the endogenous cannabinoid, N-arachidonoyl ethanolamine (Anandamide), and called N-acyl amides have emerged as a family of biologically active compounds at TRP receptors. N-acyl amides are constructed from an acyl group and an amine via an amide bond. This same structure can be modified by changing either the fatty acid or the amide to form potentially hundreds of lipids. More than 70 N-acyl amides have been identified in nature. We have ongoing studies aimed at isolating and characterizing additional members of the family of N-acyl amides in both central and peripheral tissues in mammalian systems. Here, using a unique in-house library of over 70 N-acyl amides we tested the following three hypotheses: (1) Additional N-acyl amides will have activity at TRPV1-4, (2) Acute peripheral injury will drive changes in CNS levels of N-acyl amides, and (3) N-acyl amides will regulate calcium in CNS-derived microglia. Through these studies, we have identified 20 novel N-acyl amides that collectively activate (stimulating or inhibiting) TRPV1-4. Using lipid extraction and HPLC coupled to tandem mass spectrometry we showed that levels of at least 10 of these N-acyl amides that activate TRPVs are regulated in brain after intraplantar carrageenan injection. We then screened the BV2 microglial cell line for activity with this N-acyl amide library and found overlap with TRPV receptor activity as well as additional activators of calcium mobilization from these lipids. Together these data provide new insight into the family of N-acyl amides and their roles as signaling molecules at ion channels, in microglia, and in the brain in the context of inflammation. PMID:25136293

The JET fast central acquisition and trigger system

International Nuclear Information System (INIS)

Blackler, K.; Edwards, A.W.

1994-01-01

This paper describes a new data acquisition system at JET which uses Texas TMS320C40 parallel digital signal processors and the HELIOS parallel operating system to reduce the large amounts of experimental data produced by fast diagnostics. This unified system features a two level trigger system which performs real-time activity detection together with asynchronous event classification and selection. This provides automated data reduction during an experiment. The system's application to future fusion machines which have almost continuous operation is discussed

Commissioning the ATLAS Level-1 Central Trigger System

CERN Document Server

Sherman, Daniel

2010-01-01

The ATLAS Level-1 central trigger is a critical part of ATLAS operation. It receives the 40 MHz bunch clock from the LHC and distributes it to all sub-detectors. It initiates their read-out by forming the Level-1 Accept decision, which is based on information from the calorimeter and muon trigger processors and a variety of additional trigger inputs from detectors in the forward region. It also provides trigger summary information to the data acquisition system and the Level-2 trigger system. In this paper, we present the completion of the installed central trigger system, its performance during cosmic-ray data taking and the experience gained with triggering on the first LHC beams.

Structural mechanism underlying capsaicin binding and activation of TRPV1 ion channel

Science.gov (United States)

Cheng, Wei; Yang, Wei; Yu, Peilin; Song, Zhenzhen; Yarov-Yarovoy, Vladimir; Zheng, Jie

2015-01-01

Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2-to-4.5 Å resolution, however important details required for mechanistic understandings are unavailable: capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions. We obtained the missing atomic-level details by iterative computation, which were confirmed by systematic site-specific functional tests. We observed that the bound capsaicin takes “tail-up, head-down” configurations. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes the open state by “pull-and-contact” interactions between the vanillyl group and the S4-S5 linker. Our study provided a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrated an effective approach to obtain atomic level information from cryo-EM structures. PMID:26053297

Modulatory effects of the fruits of Tribulus terrestris L. on the function of atopic dermatitis-related calcium channels, Orai1 and TRPV3

Directory of Open Access Journals (Sweden)

Joo Hyun Nam

2016-07-01

Conclusions: Our results suggest that T. terrestris extract may have a therapeutic potential for recovery of abnormal skin barrier pathologies in atopic dermatitis through modulating the activities of calcium ion channels, Orai1 and TRPV3. This is the first study to report the modulatory effect of a medicinal plant on the function of ion channels in skin barrier.

Computing by Temporal Order: Asynchronous Cellular Automata

Directory of Open Access Journals (Sweden)

Michael Vielhaber

2012-08-01

Full Text Available Our concern is the behaviour of the elementary cellular automata with state set 0,1 over the cell set Z/nZ (one-dimensional finite wrap-around case, under all possible update rules (asynchronicity. Over the torus Z/nZ (n<= 11,we will see that the ECA with Wolfram rule 57 maps any v in F_2^n to any w in F_2^n, varying the update rule. We furthermore show that all even (element of the alternating group bijective functions on the set F_2^n = 0,...,2^n-1, can be computed by ECA57, by iterating it a sufficient number of times with varying update rules, at least for n <= 10. We characterize the non-bijective functions computable by asynchronous rules.

The ATLAS Level-1 Trigger Timing Setup

CERN Document Server

Spiwoks, R; Ellis, Nick; Farthouat, P; Gällnö, P; Haller, J; Krasznahorkay, A; Maeno, T; Pauly, T; Pessoa-Lima, H; Resurreccion-Arcas, I; Schuler, G; De Seixas, J M; Torga-Teixeira, R; Wengler, T

2005-01-01

The ATLAS detector at CERN's LHC will be exposed to proton-proton collisions at a bunch-crossing rate of 40 MHz. In order to reduce the data rate, a three-level trigger system selects potentially interesting physics. The first trigger level is implemented in electronics and firmware. It aims at reducing the output rate to less than 100 kHz. The Central Trigger Processor combines information from the calorimeter and muon trigger processors and makes the final Level-1-Accept decision. It is a central element in the timing setup of the experiment. Three aspects are considered in this article: the timing setup with respect to the Level-1 trigger, with respect to the expriment, and with respect to the world.

Current Trends in High-Level Synthesis of Asynchronous Circuits

DEFF Research Database (Denmark)

Sparsø, Jens

2009-01-01

This paper is a survey paper presenting what the author sees as two major and promising trends in the current research in CAD-tools and design-methods for asynchronous circuits. One branch of research builds on top of existing asynchronous CAD-tools that perform syntax directed translation, e...... a conventional synchronous circuit as the starting point, and then adds some form of handshake-based flow-control. One approach keeps the global clock and implements discrete-time asynchronous operation. Another approach substitutes the clocked registers by asynchronous handshake-registers, thus creating truly...

Asynchronous communication in real space process algebra

NARCIS (Netherlands)

Baeten, J.C.M.; Bergstra, J.A.

1991-01-01

A version of classical real space process algebra is given in which messages travel with constant speed through a three-dimensional medium. It follows that communication is asynchronous and has a broadcasting character. A state operator is used to describe asynchronous message transfer and a

Asynchronous communication in real space process algebra

NARCIS (Netherlands)

Bergstra, J.A.; Baeten, J.C.M.

1992-01-01

A version of classical real space process algebra is given in which messages travel with constant speed through a three-dimensional medium. It follows that communication is asynchronous and has a broadcasting character. A state operator is used to describe asynchronous message transfer and a

Asynchronous and corrected-asynchronous numerical solutions of parabolic PDES on MIMD multiprocessors

Science.gov (United States)

Amitai, Dganit; Averbuch, Amir; Itzikowitz, Samuel; Turkel, Eli

1991-01-01

A major problem in achieving significant speed-up on parallel machines is the overhead involved with synchronizing the concurrent process. Removing the synchronization constraint has the potential of speeding up the computation. The authors present asynchronous (AS) and corrected-asynchronous (CA) finite difference schemes for the multi-dimensional heat equation. Although the discussion concentrates on the Euler scheme for the solution of the heat equation, it has the potential for being extended to other schemes and other parabolic partial differential equations (PDEs). These schemes are analyzed and implemented on the shared memory multi-user Sequent Balance machine. Numerical results for one and two dimensional problems are presented. It is shown experimentally that the synchronization penalty can be about 50 percent of run time: in most cases, the asynchronous scheme runs twice as fast as the parallel synchronous scheme. In general, the efficiency of the parallel schemes increases with processor load, with the time level, and with the problem dimension. The efficiency of the AS may reach 90 percent and over, but it provides accurate results only for steady-state values. The CA, on the other hand, is less efficient, but provides more accurate results for intermediate (non steady-state) values.

Level-1 Calorimeter Trigger starts firing

CERN Multimedia

Stephen Hillier

2007-01-01

L1Calo is one of the major components of ATLAS First Level trigger, along with the Muon Trigger and Central Trigger Processor. It forms all of the first-level calorimeter-based triggers, including electron, jet, tau and missing ET. The final system consists of over 250 custom designed 9U VME boards, most containing a dense array of FPGAs or ASICs. It is subdivided into a PreProcessor, which digitises the incoming trigger signals from the Liquid Argon and Tile calorimeters, and two separate processor systems, which perform the physics algorithms. All of these are highly flexible, allowing the possibility to adapt to beam conditions and luminosity. All parts of the system are read out through Read-Out Drivers, which provide monitoring data and Region of Interest (RoI) information for the Level-2 trigger. Production of the modules is now essentially complete, and enough modules exist to populate the full scale system in USA15. Installation is proceeding rapidly - approximately 90% of the final modules are insta...

TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells.

Directory of Open Access Journals (Sweden)

Zhi-Ren Zhang

Full Text Available Regulation of apical calcium entry is important for the function of principal cells of the collecting duct. However, the molecular identity and the regulators of the transporter/channel, which is responsible for apical calcium entry and what factors regulate the calcium conduction remain unclear.We report that endogenous TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal principal cells of the collecting duct. TRPP2\\TRPV4 channel complex was identified by patch-clamp, immunofluorescence and co-immunprecipitation studies in both principal cells that either possess normal cilia (cilia (+ or in which cilia are absent (cilia (-. This channel has distinct biophysical and pharmacological and regulatory profiles compared to either TRPP2 or TRPV4 channels. The rate of occurrence detected by patch clamp was higher in cilia (- compared to cilia (+ cells. In addition, shRNA knockdown of TRPP2 increased the prevalence of TRPV4 channel activity while knockdown of TRPV4 resulted in TRPP2 activity and knockdown of both proteins vastly decreased the 23-pS channel activity. Epidermal growth factor (EGF stimulated TRPP2\\TRPV4 channel through the EGF receptor (EGFR tyrosine kinase-dependent signaling. With loss of cilia, apical EGF treatment resulted in 64-fold increase in channel activity in cilia (- but not cilia (+ cells. In addition EGF increased cell proliferation in cilia (- cell that was dependent upon TRPP2\\TRPV4 channel mediated increase in intracellular calcium.We conclude that in the absence of cilia, an EGF activated TRPP2\\TRPV4 channel may play an important role in increased cell proliferation and cystogenesis.

Synchronization of Hierarchical Time-Varying Neural Networks Based on Asynchronous and Intermittent Sampled-Data Control.

Science.gov (United States)

Xiong, Wenjun; Patel, Ragini; Cao, Jinde; Zheng, Wei Xing

In this brief, our purpose is to apply asynchronous and intermittent sampled-data control methods to achieve the synchronization of hierarchical time-varying neural networks. The asynchronous and intermittent sampled-data controllers are proposed for two reasons: 1) the controllers may not transmit the control information simultaneously and 2) the controllers cannot always exist at any time . The synchronization is then discussed for a kind of hierarchical time-varying neural networks based on the asynchronous and intermittent sampled-data controllers. Finally, the simulation results are given to illustrate the usefulness of the developed criteria.In this brief, our purpose is to apply asynchronous and intermittent sampled-data control methods to achieve the synchronization of hierarchical time-varying neural networks. The asynchronous and intermittent sampled-data controllers are proposed for two reasons: 1) the controllers may not transmit the control information simultaneously and 2) the controllers cannot always exist at any time . The synchronization is then discussed for a kind of hierarchical time-varying neural networks based on the asynchronous and intermittent sampled-data controllers. Finally, the simulation results are given to illustrate the usefulness of the developed criteria.

The Design of Finite State Machine for Asynchronous Replication Protocol

Science.gov (United States)

Wang, Yanlong; Li, Zhanhuai; Lin, Wei; Hei, Minglei; Hao, Jianhua

Data replication is a key way to design a disaster tolerance system and to achieve reliability and availability. It is difficult for a replication protocol to deal with the diverse and complex environment. This means that data is less well replicated than it ought to be. To reduce data loss and to optimize replication protocols, we (1) present a finite state machine, (2) run it to manage an asynchronous replication protocol and (3) report a simple evaluation of the asynchronous replication protocol based on our state machine. It's proved that our state machine is applicable to guarantee the asynchronous replication protocol running in the proper state to the largest extent in the event of various possible events. It also can helpful to build up replication-based disaster tolerance systems to ensure the business continuity.

A first-level calorimeter trigger for the ATLAS experiment

International Nuclear Information System (INIS)

Perera, V.; Edwards, J.; Gee, N.

1995-01-01

In the RD27 collaboration the authors have carried out system studies on the implementation of the first level calorimeter trigger processor system for the ATLAS experiment to be mounted at the Large Hadron Collider (LHC) at CERN. A demonstrator trigger system operated successfully with the RD3 and RD33 calorimeters at the full 40 MHz LHC bunch crossing (BC) rate. The prototype application-specific integrated circuits (ASICs) in this system each processed data from only a single trigger cell and its environment, which would lead to an extremely large system for ATLAS. Using eight-bit parallel data even the use of ASICs, processing multiple trigger cells would demand unacceptably large numbers of input pins and module connections. Initial studies of this I/O problem produced a solution based on asynchronous transmission of zero-suppressed and BC-tagged data on 160 Mbit/s serial links. This approach appeared to be feasible but would have introduced additional latency of about 20 BCs. Further studies have led to the design of a fully-synchronous calorimeter trigger processor system using commercial high-speed optical links. The links will terminate in multi-chip modules (MCMs) incorporating custom-designed integrated optics, and the trigger algorithms will be implemented in ASICs

TRPV5, the gateway to Ca2+ homeostasis.

NARCIS (Netherlands)

Mensenkamp, A.R.; Hoenderop, J.G.J.; Bindels, R.J.M.

2007-01-01

Ca2+ homeostasis in the body is tightly controlled, and is a balance between absorption in the intestine, excretion via the urine, and exchange from bone. Recently, the epithelial Ca2+ channel (TRPV5) has been identified as the gene responsible for the Ca2+ influx in epithelial cells of the renal

Developing asynchronous online interprofessional education.

Science.gov (United States)

Sanborn, Heidi

2016-09-01

For many health programmes, developing interprofessional education (IPE) has been a challenge. Evidence on the best method for design and implementation of IPE has been slow to emerge, with little research on how to best incorporate IPE in the asynchronous online learning environment. This leaves online programmes with no clear guidance when embarking upon an initiative to integrate IPE into the curriculum. One tool that can be effective at guiding the incorporation of IPE across all learning platforms is the Interprofessional Education Collaborative (IPEC) competencies. A project was designed to integrate the nationally defined IPEC competencies throughout an asynchronous, online baccalaureate nursing completion programme. A programme-wide review led to targeted revision of course and unit-level objectives, learning experiences, and assessments based on the IPEC framework. As a result of this effort, the programme curriculum now provides interprofessional learning activities across all courses. This report provides a method for using the IPEC competencies to incorporate IPE within various asynchronous learning assessments, assuring students learn about, with, and from other professions.

Asynchronous Parallelization of a CFD Solver

OpenAIRE

Abdi, Daniel S.; Bitsuamlak, Girma T.

2015-01-01

The article of record as published may be found at http://dx.doi.org/10.1155/2015/295393 A Navier-Stokes equations solver is parallelized to run on a cluster of computers using the domain decomposition method. Two approaches of communication and computation are investigated, namely, synchronous and asynchronous methods. Asynchronous communication between subdomains is not commonly used inCFDcodes; however, it has a potential to alleviate scaling bottlenecks incurred due to process...

Asynchronous networks: modularization of dynamics theorem

Science.gov (United States)

Bick, Christian; Field, Michael

2017-02-01

Building on the first part of this paper, we develop the theory of functional asynchronous networks. We show that a large class of functional asynchronous networks can be (uniquely) represented as feedforward networks connecting events or dynamical modules. For these networks we can give a complete description of the network function in terms of the function of the events comprising the network: the modularization of dynamics theorem. We give examples to illustrate the main results.

Neofusicoccum parvum Colonization of the Grapevine Woody Stem Triggers Asynchronous Host Responses at the Site of Infection and in the Leaves

Directory of Open Access Journals (Sweden)

Mélanie Massonnet

2017-06-01

Full Text Available Grapevine trunk diseases cause important economic losses in vineyards worldwide. Neofusicoccum parvum, one of the most aggressive causal agents of the trunk disease Botryosphaeria dieback, colonizes cells and tissues of the grapevine wood, leading to the formation of an internal canker. Symptoms then extend to distal shoots, with wilting of leaves and bud mortality. Our aim was to characterize the transcriptional dynamics of grapevine genes in the woody stem and in the leaves during Neofusicoccum parvum colonization. Genome-wide transcriptional profiling at seven distinct time points (0, 3, and 24 hours; 2, 6, 8, and 12 weeks showed that both stems and leaves undergo extensive transcriptomic reprogramming in response to infection of the stem. While most intense transcriptional responses were detected in the stems at 24 hours, strong responses were not detected in the leaves until the next sampling point at 2 weeks post-inoculation. Network co-expression analysis identified modules of co-expressed genes common to both organs and showed most of these genes were asynchronously modulated. The temporal shift between stem vs. leaf responses affected transcriptional modulation of genes involved in both signal perception and transduction, as well as downstream biological processes, including oxidative stress, cell wall rearrangement and cell death. Promoter analysis of the genes asynchronously modulated in stem and leaves during N. parvum colonization suggests that the temporal shift of transcriptional reprogramming between the two organs might be due to asynchronous co-regulation by common transcriptional regulators. Topology analysis of stem and leaf co-expression networks pointed to specific transcription factor-encoding genes, including WRKY and MYB, which may be associated with the observed transcriptional responses in the two organs.

Human Digital Meissner Corpuscles Display Immunoreactivity for the Multifunctional Ion Channels Trpc6 and Trpv4.

Science.gov (United States)

Alonso-González, Paula; Cabo, Roberto; San José, Isabel; Gago, Angel; Suazo, Iván C; García-Suárez, Olivia; Cobo, Juan; Vega, José A

2017-06-01

Ion channels are at the basis of the sensory processes including mechanosensing. Some members of the transient receptor potential (TRP) ion channel superfamily have been proposed as mechanosensors, but their putative role in mechanotransduction is controversial. Among them there are TRP canonical 6 (TRPC6) and TRP vanilloid 4 (TRPV4) ion channels, which are known to cooperate in mechanical hyperalgesia. Here, we investigated the occurrence, distribution, and possible colocalization of TRPC6 and TRPV4 in human digital Meissner sensory corpuscles using immunohistochemistry and double immunofluorescence (associate with markers for specific corpuscular constituents). TRPC6 immunoreactivity was restricted to the axon of Meissner corpuscles, whereas TRPV4 was detected in the axon but also in the lamellar cells. Moreover, axonal colocalization of TRPV4 and TRPC6 was found in the digital Meissner corpuscles. Present results demonstrate for the first time the occurrence and colocalization of two ion channels candidates to mechanosensors in human cutaneous mechanoreceptors. The functional significance of these ion channels in that place remains to be clarified, but should be related to different properties of mechanosensitivity. Anat Rec, 300:1022-1031, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Asynchronous SAR ADC

NARCIS (Netherlands)

2011-01-01

An asynchronous analog to digital convertor for converting an analog input signal into a digital output is presented. According to an embodiment, the analog to digital convertor comprises a clock input operable to receive an external clock signal having a clock period, a comparator operable to

The Phase-1 Upgrade of the 
ATLAS Level-1 Endcap Muon Trigger

CERN Document Server

Akatsuka, Shunichi; The ATLAS collaboration

2018-01-01

Talk slides for RealTime 2018, 9th -15th June 2018 @ Williamsburg, Virginia, USA. Time slot 20 min. (probably 15 min. presentation + 5 min. discussion). This talk is on Phase-1 Upgrade of the Level-1 Endcap Muon trigger. The first part of this presentation describes the overview of the ATLAS trigger system, muon trigger in Run 2 and the Phase-1 Upgrade, and the strategy of phase-1 upgrade. Then in the following few pages, the physics algorithm of the Run 3 muon trigger and its performance is described. The main focus of this talk is on the implementation of the trigger logic to the FPGA. The key component of the trigger part implementation is described, using a schematic diagram and a simulation output screenshot.

Dynamic Performances of Asynchronous Machines | Ubeku ...

African Journals Online (AJOL)

The per-phase parameters of a 1.5 hp, 380 V, 50 Hz, 4 poles, 3 phase asynchronous machine used in the simulation were computed with reading obtained from a dc, no-load and blocked rotor tests carried out on the machine in the laboratory. The results obtained from the computer simulations confirmed the capabilities ...

Simulating fail-stop in asynchronous distributed systems

Science.gov (United States)

Sabel, Laura; Marzullo, Keith

1994-01-01

The fail-stop failure model appears frequently in the distributed systems literature. However, in an asynchronous distributed system, the fail-stop model cannot be implemented. In particular, it is impossible to reliably detect crash failures in an asynchronous system. In this paper, we show that it is possible to specify and implement a failure model that is indistinguishable from the fail-stop model from the point of view of any process within an asynchronous system. We give necessary conditions for a failure model to be indistinguishable from the fail-stop model, and derive lower bounds on the amount of process replication needed to implement such a failure model. We present a simple one-round protocol for implementing one such failure model, which we call simulated fail-stop.

Asynchronous decentralized method for interconnected electricity markets

International Nuclear Information System (INIS)

Huang, Anni; Joo, Sung-Kwan; Song, Kyung-Bin; Kim, Jin-Ho; Lee, Kisung

2008-01-01

This paper presents an asynchronous decentralized method to solve the optimization problem of interconnected electricity markets. The proposed method decomposes the optimization problem of combined electricity markets into individual optimization problems. The impact of neighboring markets' information is included in the objective function of the individual market optimization problem by the standard Lagrangian relaxation method. Most decentralized optimization methods use synchronous models of communication to exchange updated market information among markets during the iterative process. In this paper, however, the solutions of the individual optimization problems are coordinated through an asynchronous communication model until they converge to the global optimal solution of combined markets. Numerical examples are presented to demonstrate the advantages of the proposed asynchronous method over the existing synchronous methods. (author)

Optimization of parameters of special asynchronous electric drives

Science.gov (United States)

Karandey, V. Yu; Popov, B. K.; Popova, O. B.; Afanasyev, V. L.

2018-03-01

The article considers the solution of the problem of parameters optimization of special asynchronous electric drives. The solution of the problem will allow one to project and create special asynchronous electric drives for various industries. The created types of electric drives will have optimum mass-dimensional and power parameters. It will allow one to realize and fulfill the set characteristics of management of technological processes with optimum level of expenses of electric energy, time of completing the process or other set parameters. The received decision allows one not only to solve a certain optimizing problem, but also to construct dependences between the optimized parameters of special asynchronous electric drives, for example, with the change of power, current in a winding of the stator or rotor, induction in a gap or steel of magnetic conductors and other parameters. On the constructed dependences, it is possible to choose necessary optimum values of parameters of special asynchronous electric drives and their components without carrying out repeated calculations.

The ATLAS Level-1 Topological Trigger performance in Run 2

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00120419; The ATLAS collaboration

2017-01-01

The Level-1 trigger is the first event rate reducing step in the ATLAS detector trigger system, with an output rate of up to 100 kHz and decision latency smaller than 2.5 μs. During the LHC shutdown after Run 1, the Level-1 trigger system was upgraded at hardware, firmware and software levels. In particular, a new electronics sub-system was introduced in the real-time data processing path: the Level-1 Topological trigger system. It consists of a single electronics shelf equipped with two Level-1 Topological processor blades. They receive real-time information from the Level-1 calorimeter and muon triggers, which is processed to measure angles between trigger objects, invariant masses or other kinematic variables. Complementary to other requirements, these measurements are taken into account in the final Level-1 trigger decision. The system was installed and commissioning started in 2015 and continued during 2016. As part of the commissioning, the decisions from individual algorithms were simulated and compar...

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.

Multiparty Asynchronous Session Types

DEFF Research Database (Denmark)

Honda, Kohei; Yoshida, Nobuko; Carbone, Marco

2016-01-01

. This work extends the foregoing theories of binary session types to multiparty, asynchronous sessions, which often arise in practical communication-centered applications. Presented as a typed calculus for mobile processes, the theory introduces a new notion of types in which interactions involving multiple......Communication is a central elements in software development. As a potential typed foundation for structured communication-centered programming, session types have been studied over the past decade for a wide range of process calculi and programming languages, focusing on binary (two-party) sessions...... peers are directly abstracted as a global scenario. Global types retain the friendly type syntax of binary session types while specifying dependencies and capturing complex causal chains of multiparty asynchronous interactions. A global type plays the role of a shared agreement among communication peers...

Data analysis at Level-1 Trigger level

CERN Document Server

Wittmann, Johannes; Aradi, Gregor; Bergauer, Herbert; Jeitler, Manfred; Wulz, Claudia; Apanasevich, Leonard; Winer, Brian; Puigh, Darren Michael

2017-01-01

With ever increasing luminosity at the LHC, optimum online data selection is getting more and more important. While in the case of some experiments (LHCb and ALICE) this task is being completely transferred to computer farms, the others - ATLAS and CMS - will not be able to do this in the medium-term future for technological, detector-related reasons. Therefore, these experiments pursue the complementary approach of migrating more and more of the offline and High-Level Trigger intelligence into the trigger electronics. This paper illustrates how the Level-1 Trigger of the CMS experiment and in particular its concluding stage, the Global Trigger, take up this challenge.

Interpolation algorithm for asynchronous ADC-data

Directory of Open Access Journals (Sweden)

S. Bramburger

2017-09-01

Full Text Available This paper presents a modified interpolation algorithm for signals with variable data rate from asynchronous ADCs. The Adaptive weights Conjugate gradient Toeplitz matrix (ACT algorithm is extended to operate with a continuous data stream. An additional preprocessing of data with constant and linear sections and a weighted overlap of step-by-step into spectral domain transformed signals improve the reconstruction of the asycnhronous ADC signal. The interpolation method can be used if asynchronous ADC data is fed into synchronous digital signal processing.

Beam Test of the ATLAS Level-1 Calorimeter Trigger System

CERN Document Server

Garvey, J; Mahout, G; Moye, T H; Staley, R J; Thomas, J P; Typaldos, D; Watkins, P M; Watson, A; Achenbach, R; Föhlisch, F; Geweniger, C; Hanke, P; Kluge, E E; Mahboubi, K; Meier, K; Meshkov, P; Rühr, F; Schmitt, K; Schultz-Coulon, H C; Ay, C; Bauss, B; Belkin, A; Rieke, S; Schäfer, U; Tapprogge, T; Trefzger, T; Weber, GA; Eisenhandler, E F; Landon, M; Apostologlou, P; Barnett, B M; Brawn, I P; Davis, A O; Edwards, J; Gee, C N P; Gillman, A R; Mirea, A; Perera, V J O; Qian, W; Sankey, D P C; Bohm, C; Hellman, S; Hidvegi, A; Silverstein, S

2005-01-01

The Level-1 Calorimter Trigger consists of a Preprocessor (PP), a Cluster Processor (CP), and a Jet/Energy-sum Processor (JEP). The CP and JEP receive digitised trigger-tower data from the Preprocessor and produce Region-of-Interest (RoIs) and trigger multiplicities. The latter are sent in real time to the Central Trigger Processor (CTP) where the Level-1 decision is made. On receipt of a Level-1 Accept, Readout Driver Modules (RODs), provide intermediate results to the data acquisition (DAQ) system for monitoring and diagnostic purpose. RoI information is sent to the RoI builder (RoIB) to help reduce the amount of data required for the Level-2 Trigger The Level-1 Calorimeter Trigger System at the test beam consisted of 1 Preprocessor module, 1 Cluster Processor Module, 1 Jet/Energy Module and 2 Common Merger Modules. Calorimeter energies were sucessfully handled thourghout the chain and trigger object sent to the CTP. Level-1 Accepts were sucessfully produced and used to drive the readout path. Online diagno...

The LHCb vertex locator and level-1 trigger

CERN Document Server

Dijkstra, H

2000-01-01

LHCb will study CP violation and other rare phenomena in B-decays with a forward detector at the LHC. One of the challenges is to design a fast and efficient trigger. The design of the silicon Vertex Locator (VELO) has been driven by the requirements of one of the most selective triggers of the experiment. The VELO trigger is designed to work at an input rate of 1 MHz. The requirements and implementation of the VELO and the associated trigger are summarised, followed by a description of an upgrade which improves the trigger performance significantly. (3 refs).

Synchronous and Asynchronous ATM Multiplexor Properties Comparsion

OpenAIRE

Jan Zabka

2006-01-01

The article is aimed to ATM multiplexor computer model utilisation. Based on simulation runs we try to review aspects of use a synchronous and asynchronous ATM multiplexors. ATM multiplexor is the input queuing model with three inputs. Synchronous multiplexor works without an input priority. Multiplexor inputs are served periodically. Asynchronous multiplexor model supports several queuing and priority mechanisms. CLR and CTD are basic performance parameters. Input cell flows are genera...

Asynchronous communication in real space process algebra

OpenAIRE

Baeten, JCM Jos; Bergstra, JA Jan

1990-01-01

A version of classical real space process algebra is given in which messages travel with constant speed through a three-dimensional medium. It follows that communication is asynchronous and has a broadcasting character. A state operator is used to describe asynchronous message transfer and a priority mechanism allows to express the broadcasting mechanism. As an application, a protocol is specified in which the receiver moves with respect to the sender.

Asynchronous Learning Sources in a High-Tech Organization

Science.gov (United States)

Bouhnik, Dan; Giat, Yahel; Sanderovitch, Yafit

2009-01-01

Purpose: The purpose of this study is to characterize learning from asynchronous sources among research and development (R&D) personnel. It aims to examine four aspects of asynchronous source learning: employee preferences regarding self-learning; extent of source usage; employee satisfaction with these sources and the effect of the sources on the…

TCDQ-TCT retraction and losses during asynchronous beam dump

CERN Document Server

Bracco, Chiara; Quaranta, Elena; CERN. Geneva. ATS Department

2016-01-01

The protection provided by the TCDQs in case of asynchronous beam dump depends strongly on their correct setup. They have to respect the strict hierarchy of the full collimation system and shield the tertiary collimators in the experimental regions. This MD aimed at performing asynchronous beam dump tests with different configurations, in order to assess the minimum allowed retraction between TCTs and TCDQs and, as a consequence, on the The protection provided by the TCDQs in case of asynchronous beam dump depends strongly on their correct setup. They have to respect the strict hierarchy of the full collimation system and shield the tertiary collimators in the experimental regions. This MD aimed at performing asynchronous beam dump tests with different configurations, in order to assess the minimum allowed retraction between TCTs and TCDQs and, as a consequence, on the β* reach.

Argo: A Time-Elastic Time-Division-Multiplexed NOC using Asynchronous Routers

DEFF Research Database (Denmark)

Kasapaki, Evangelia; Sparsø, Jens

2014-01-01

are either synchronous or mesochronous. We use asynchronous routers to achieve a simpler, smaller, and more robust, self-timed design. Our design exploits the fact that pipelined asynchronous circuits also behave as ripple FIFOs. Thus, it avoids the need for explicit synchronization FIFOs between the routers......In this paper we explore the use of asynchronous routers in a time-division-multiplexed (TDM) network-on-chip (NOC), Argo, that is being developed for a multi-processor platform for hard real-time systems. TDM inherently requires a common time reference, and existing TDM-based NOC designs...... delays derived from a 65nm CMOS implementation, a worstcase analysis shows that a typical design can tolerate a skew of 1-5 cycles (depending on FIFO depths and NI clock frequency). Simulation results of a 2 x 2 NOC confirm this....

TRPV4 related skeletal dysplasias: a phenotypic spectrum highlighted byclinical, radiographic, and molecular studies in 21 new families

Directory of Open Access Journals (Sweden)

Sillence David

2011-06-01

Full Text Available Abstract Background The TRPV4 gene encodes a calcium-permeable ion-channel that is widely expressed, responds to many different stimuli and participates in an extraordinarily wide range of physiologic processes. Autosomal dominant brachyolmia, spondylometaphyseal dysplasia Kozlowski type (SMDK and metatropic dysplasia (MD are currently considered three distinct skeletal dysplasias with some shared clinical features, including short stature, platyspondyly, and progressive scoliosis. Recently, TRPV4 mutations have been found in patients diagnosed with these skeletal phenotypes. Methods and Results We critically analysed the clinical and radiographic data on 26 subjects from 21 families, all of whom had a clinical diagnosis of one of the conditions described above: 15 with MD; 9 with SMDK; and 2 with brachyolmia. We sequenced TRPV4 and identified 9 different mutations in 22 patients, 4 previously described, and 5 novel. There were 4 mutation-negative cases: one with MD and one with SMDK, both displaying atypical clinical and radiographic features for these diagnoses; and two with brachyolmia, who had isolated spine changes and no metaphyseal involvement. Conclusions Our data suggest the TRPV4 skeletal dysplasias represent a continuum of severity with areas of phenotypic overlap, even within the same family. We propose that AD brachyolmia lies at the mildest end of this spectrum and, since all cases described with this diagnosis and TRPV4 mutations display metaphyseal changes, we suggest that it is not a distinct entity but represents the mildest phenotypic expression of SMDK.

Basic Algorithms for the Asynchronous Reconfigurable Mesh

Directory of Open Access Journals (Sweden)

Yosi Ben-Asher

2002-01-01

Full Text Available Many constant time algorithms for various problems have been developed for the reconfigurable mesh (RM in the past decade. All these algorithms are designed to work with synchronous execution, with no regard for the fact that large size RMs will probably be asynchronous. A similar observation about the PRAM model motivated many researchers to develop algorithms and complexity measures for the asynchronous PRAM (APRAM. In this work, we show how to define the asynchronous reconfigurable mesh (ARM and how to measure the complexity of asynchronous algorithms executed on it. We show that connecting all processors in a row of an n×n ARM (the analog of barrier synchronization in the APRAM model can be solved with complexity Θ(nlog⁡n. Intuitively, this is average work time for solving such a problem. Next, we describe general a technique for simulating T -step synchronous RM algorithms on the ARM with complexity of Θ(T⋅n2log⁡n. Finally, we consider the simulation of the classical synchronous algorithm for counting the number of non-zero bits in an n bits vector using (k

Strict optical orthogonal codes for purely asynchronous code-division multiple-access applications

Science.gov (United States)

Zhang, Jian-Guo

1996-12-01

Strict optical orthogonal codes are presented for purely asynchronous optical code-division multiple-access (CDMA) applications. The proposed code can strictly guarantee the peaks of its cross-correlation functions and the sidelobes of any of its autocorrelation functions to have a value of 1 in purely asynchronous data communications. The basic theory of the proposed codes is given. An experiment on optical CDMA systems is also demonstrated to verify the characteristics of the proposed code.

Operation of the Upgraded ATLAS Level-1 Central Trigger System

CERN Document Server

Glatzer, Julian Maximilian Volker; The ATLAS collaboration

2015-01-01

The ATLAS Level-1 Central Trigger (L1CT) system is a central part of ATLAS data-taking and has undergone a major upgrade for Run 2 of the LHC, in order to cope with the expected increase of instantaneous luminosity of a factor of 2 with respect to Run 1. The upgraded hardware offers more flexibility in the trigger decisions due to the double amount of trigger inputs and usable trigger channels. It also provides an interface to the new topological trigger system. Operationally - particularly useful for commissioning, calibration and test runs - it allows concurrent running of up to 3 different sub-detector combinations. In this contribution, we give an overview of the operational software framework of the L1CT system with particular emphasis of the configuration, controls and monitoring aspects. The software framework allows a consistent configuration with respect to the ATLAS experiment and the LHC machine, upstream and downstream trigger processors, and the data acquisition. Trigger and dead-time rates are m...

ATLAS LAr Calorimeter Trigger Electronics Phase-1 Upgrade

CERN Document Server

Aad, Georges; The ATLAS collaboration

2017-01-01

The upgrade of the Large Hadron Collider (LHC) scheduled for a shut-down period of 2019-2020, referred to as the Phase-I upgrade, will increase the instantaneous luminosity to about three times the design value. Since the current ATLAS trigger system does not allow sufficient increase of the trigger rate, an improvement of the trigger system is required. The Liquid Argon (LAr) Calorimeter read-out will therefore be modified to use digital trigger signals with a higher spatial granularity in order to improve the identification efficiencies of electrons, photons, tau, jets and missing energy, at high background rejection rates at the Level-1 trigger. The new trigger signals will be arranged in 34000 so-called Super Cells which achieves 5-10 times better granularity than the trigger towers currently used and allows an improved background rejection. The readout of the trigger signals will process the signal of the Super Cells at every LHC bunch-crossing at 12-bit precision and a frequency of 40 MHz. The data will...

Reactive Hippocampal Astrocytes Display an Increased Expression of Trpv4 Channels After Cerebral Hypoxia/Ischemia

Czech Academy of Sciences Publication Activity Database

Butenko, Olena; Džamba, Dávid; Prajerová, Iva; Benešová, Jana; Honsa, Pavel; Benfenati, V.; Ferroni, S.; Anděrová, Miroslava

2011-01-01

Roč. 59, Supplement 1 (2011), S126-S127 ISSN 0894-1491. [European meeting on Glia l Cells in Health and Disease /10./. 13.09.2011-17.09.2011, Prague] Institutional research plan: CEZ:AV0Z50390703; CEZ:AV0Z50520701 Keywords : TRPV4 * astrocytes * cerebral hypoxia/ischemia Subject RIV: FH - Neurology

Pharmacists' perception of synchronous versus asynchronous distance learning for continuing education programs.

Science.gov (United States)

Buxton, Eric C

2014-02-12

To evaluate and compare pharmacists' satisfaction with the content and learning environment of a continuing education program series offered as either synchronous or asynchronous webinars. An 8-lecture series of online presentations on the topic of new drug therapies was offered to pharmacists in synchronous and asynchronous webinar formats. Participants completed a 50-question online survey at the end of the program series to evaluate their perceptions of the distance learning experience. Eighty-two participants completed the survey instrument (41 participants from the live webinar series and 41 participants from the asynchronous webinar series.) Responses indicated that while both groups were satisfied with the program content, the asynchronous group showed greater satisfaction with many aspects of the learning environment. The synchronous and asynchronous webinar participants responded positively regarding the quality of the programming and the method of delivery, but asynchronous participants rated their experience more positively overall.

The new UA1 calorimeter trigger

International Nuclear Information System (INIS)

Eisenhandler, E.

1988-01-01

The new UA1 first-level calorimeter trigger processor is described, with emphasis on the fast two-dimensional electromagnetic cluster-finding that is its most novel feature. This processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. (author)

Designing Asynchronous Circuits for Low Power: An IFIR Filter

DEFF Research Database (Denmark)

Nielsen, Lars Skovby; Sparsø, Jens

1999-01-01

This paper addresses the design of asynchronous circuits for low power through an example: a filter bank for a digital hearing aid. The asynchronous design re-implements an existing synchronous circuit which is used in a commercial product. For comparison, both designs have been fabricated...

FPGA BASED ASYNCHRONOUS PIPELINED MB-OFDM UWB TRANSMITTER BACKEND MODULES

Directory of Open Access Journals (Sweden)

M. Santhi

2010-03-01

Full Text Available In this paper, a novel scheme is proposed which comprises the advantages of asynchronous pipelining techniques and the advantages of FPGAs for implementing a 200Mbps MB-OFDM UWB transmitter digital backend modules. In asynchronous pipelined system, registers are used as in synchronous system. But they are controlled by handshaking signals. Since FPGAs are rich in registers, design and implementation of asynchronous pipelined MBOFDM UWB transmitter on FPGA using four-phase bundled-data protocol is considered in this paper. Novel ideas have also been proposed for designing asynchronous OFDM using Modified Radix-24 SDF and asynchronous interleaver using two RAM banks. Implementation has been performed on ALTERA STRATIX II EP2S60F1020C4 FPGA and it is operating at a speed of 350MHz. It is assured that the proposed MB-OFDM UWB system can be made to work on STRATIX III device with the operating frequency of 528MHz in compliance to the ECMA-368 standard. The proposed scheme is also applicable for FPGA from other vendors and ASIC.

L1 track finding for a time multiplexed trigger

Energy Technology Data Exchange (ETDEWEB)

Cieri, D., E-mail: davide.cieri@bristol.ac.uk [University of Bristol, Bristol (United Kingdom); Rutherford Appleton Laboratory, Didcot (United Kingdom); Brooke, J.; Grimes, M. [University of Bristol, Bristol (United Kingdom); Newbold, D. [University of Bristol, Bristol (United Kingdom); Rutherford Appleton Laboratory, Didcot (United Kingdom); Harder, K.; Shepherd-Themistocleous, C.; Tomalin, I. [Rutherford Appleton Laboratory, Didcot (United Kingdom); Vichoudis, P. [CERN, Geneva (Switzerland); Reid, I. [Brunel University, London (United Kingdom); Iles, G.; Hall, G.; James, T.; Pesaresi, M.; Rose, A.; Tapper, A.; Uchida, K. [Imperial College, London (United Kingdom)

2016-07-11

At the HL-LHC, proton bunches will cross each other every 25 ns, producing an average of 140 pp-collisions per bunch crossing. To operate in such an environment, the CMS experiment will need a L1 hardware trigger able to identify interesting events within a latency of 12.5 μs. The future L1 trigger will make use also of data coming from the silicon tracker to control the trigger rate. The architecture that will be used in future to process tracker data is still under discussion. One interesting proposal makes use of the Time Multiplexed Trigger concept, already implemented in the CMS calorimeter trigger for the Phase I trigger upgrade. The proposed track finding algorithm is based on the Hough Transform method. The algorithm has been tested using simulated pp-collision data. Results show a very good tracking efficiency. The algorithm will be demonstrated in hardware in the coming months using the MP7, which is a μTCA board with a powerful FPGA capable of handling data rates approaching 1 Tb/s.

L1 Track Finding for a Time Multiplexed Trigger

CERN Document Server

AUTHOR|(CDS)2090481; Grimes, M.; Newbold, D.; Harder, K.; Shepherd-Themistocleous, C.; Tomalin, I.; Vichoudis, P.; Reid, I.; Iles, G.; Hall, G.; James, T.; Pesaresi, M.; Rose, A.; Tapper, A.; Uchida, K.

2016-01-01

At the HL-LHC, proton bunches will cross each other every 25 ns, producing an average of 140 p p-collisions per bunch crossing. To operate in such an environment, the CMS experiment will need a L1 hardware trigger able to identify interesting events within a latency of 12.5 us. The future L1 trigger will make use also of data coming from the silicon tracker to control the trigger rate. The architecture that will be used in future to process tracker data is still under discussion. One interesting proposal makes use of the Time Multiplexed Trigger concept, already implemented in the CMS calorimeter trigger for the Phase I trigger upgrade. The proposed track finding algorithm is based on the Hough Transform method. The algorithm has been tested using simulated pp-collision data. Results show a very good tracking efficiency. The algorithm will be demonstrated in hardware in the coming months using the MP7, which is a uTCA board with a powerful FPGA capable of handling data rates approaching 1 Tb/s.

Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method.

OpenAIRE

Simonin Céline; Awale Mahendra; Brand Michael; van Deursen Ruud; Schwartz Julian; Fine Michael; Kovacs Gergely; Häfliger Pascal; Gyimesi Gergely; Sithampari Abilashan; Charles Roch-Philippe; Hediger Matthias A; Reymond Jean-Louis

2015-01-01

Herein we report the discovery of the first potent and selective inhibitor of TRPV6 a calcium channel overexpressed in breast and prostate cancer and its use to test the effect of blocking TRPV6 mediated Ca(2+) influx on cell growth. The inhibitor was discovered through a computational method xLOS a 3D shape and pharmacophore similarity algorithm a type of ligand based virtual screening (LBVS) method described briefly here. Starting with a single weakly active seed molecule two successive rou...

Integrating Asynchronous Digital Design Into the Computer Engineering Curriculum

Science.gov (United States)

Smith, S. C.; Al-Assadi, W. K.; Di, J.

2010-01-01

As demand increases for circuits with higher performance, higher complexity, and decreased feature size, asynchronous (clockless) paradigms will become more widely used in the semiconductor industry, as evidenced by the International Technology Roadmap for Semiconductors' (ITRS) prediction of a likely shift from synchronous to asynchronous design…

Exploring Asynchronous and Synchronous Tool Use in Online Courses

Science.gov (United States)

Oztok, Murat; Zingaro, Daniel; Brett, Clare; Hewitt, Jim

2013-01-01

While the independent contributions of synchronous and asynchronous interaction in online learning are clear, comparatively less is known about the pedagogical consequences of using both modes in the same environment. In this study, we examine relationships between students' use of asynchronous discussion forums and synchronous private messages…

An Overview of the Asynchronous Digital Systems – Part 3

Directory of Open Access Journals (Sweden)

Mihai Timis

2008-01-01

Full Text Available Implementation methods for the digital asynchronous systems use different predefined models like self timed circuits, speed independent circuits, delay insensitive circuits, handshake protocol implementation in asynchronous systems,C Muller circuits.

An Overview of the Asynchronous Digital Systems – Part 2

Directory of Open Access Journals (Sweden)

Mihai Timis

2008-01-01

Full Text Available Implementation methods for the digital asynchronous systems use different predefined models like self timed circuits, speed independent circuits, delay insensitive circuits, handshake protocol implementation in asynchronous systems,C Muller circuits.

An oral TRPV1 antagonist attenuates laser radiant-heat-evoked potentials and pain ratings from UV(B)-inflamed and normal skin.

Science.gov (United States)

Schaffler, Klaus; Reeh, Peter; Duan, W Rachel; Best, Andrea E; Othman, Ahmed A; Faltynek, Connie R; Locke, Charles; Nothaft, Wolfram

2013-02-01

Laser (radiant-heat) evoked potentials (LEPs) from vertex-EEG peak-to-peak (PtP) amplitude were used to determine acute antinociceptive/antihyperalgesic efficacy of ABT-102, a novel TRPV1 antagonist efficacious in preclinical pain models, compared with active controls and placebo in normal and UV(B)-inflamed skin. This was a randomized, placebo- and active-controlled, double-blind, intra-individual, crossover trial. Twenty-four healthy subjects received six sequences of single doses of ABT-102 (0.5, 2, 6 mg), etoricoxib 90 mg, tramadol 100 mg and placebo. Painful stimuli were induced by CO(2) -laser on normal and UV(B) -inflamed skin. LEPs and visual analogue scale (VAS-pain) ratings were taken at baseline and hourly up to 8 h post-dose from both skin types. Compared with placebo, significant mean decreases in the primary variable of LEP PtP-amplitude from UV(B)-inflamed skin were observed with ABT-102 6 mg (P < 0.001), ABT-102 2 mg (P = 0.002), tramadol 100 mg (P < 0.001), and etoricoxib 90 mg (P = 0.001) over the 8 h period; ABT-102 0.5 mg was similar to placebo. ABT-102 6 mg was superior to active controls over the 8 h period (P < 0.05) whereas ABT-102 2 mg was comparable. Improvements in VAS scores compared with placebo were observed with ABT-102 6 mg (P < 0.001) and ABT-102 2 mg (P = 0.002). ABT-102 average plasma concentrations were 1.3, 4.4 and 9.4 ng ml(-1) for the 0.5, 2 and 6 mg doses, respectively. There were no clinically significant safety findings. TRPV-1 antagonism appears promising in the management of clinical pain, but requires further investigation. © 2012 Abbott. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

The ATLAS Level-1 Muon to Central Trigger Processor Interface

CERN Document Server

Berge, D; Farthouat, P; Haas, S; Klofver, P; Krasznahorkay, A; Messina, A; Pauly, T; Schuler, G; Spiwoks, R; Wengler, T; PH-EP

2007-01-01

The Muon to Central Trigger Processor Interface (MUCTPI) is part of the ATLAS Level-1 trigger system and connects the output of muon trigger system to the Central Trigger Processor (CTP). At every bunch crossing (BC), the MUCTPI receives information on muon candidates from each of the 208 muon trigger sectors and calculates the total multiplicity for each of six transverse momentum (pT) thresholds. This multiplicity value is then sent to the CTP, where it is used together with the input from the Calorimeter trigger to make the final Level-1 Accept (L1A) decision. In addition the MUCTPI provides summary information to the Level-2 trigger and to the data acquisition (DAQ) system for events selected at Level-1. This information is used to define the regions of interest (RoIs) that drive the Level-2 muontrigger processing. The MUCTPI system consists of a 9U VME chassis with a dedicated active backplane and 18 custom designed modules. The design of the modules is based on state-of-the-art FPGA devices and special ...

The CMS Level-1 Calorimeter Trigger for LHC Run II

CERN Document Server

Zabi, Alexandre; Cadamuro, Luca; Davignon, Olivier; Romanteau, Thierry; Strebler, Thomas; Cepeda, Maria Luisa; Sauvan, Jean-baptiste; Wardle, Nicholas; Aggleton, Robin Cameron; Ball, Fionn Amhairghen; Brooke, James John; Newbold, David; Paramesvaran, Sudarshan; Smith, D; Taylor, Joseph Ross; Fountas, Konstantinos; Baber, Mark David John; Bundock, Aaron; Breeze, Shane Davy; Citron, Matthew; Elwood, Adam Christopher; Hall, Geoffrey; Iles, Gregory Michiel; Laner Ogilvy, Christian; Penning, Bjorn; Rose, A; Shtipliyski, Antoni; Tapper, Alexander; Durkin, Timothy John; Harder, Kristian; Harper, Sam; Shepherd-Themistocleous, Claire; Thea, Alessandro; Williams, Thomas Stephen; Dasu, Sridhara Rao; Dodd, Laura Margaret; Klabbers, Pamela Renee; Levine, Aaron; Ojalvo, Isabel Rose; Ruggles, Tyler Henry; Smith, Nicholas Charles; Smith, Wesley; Svetek, Ales; Forbes, R; Tikalsky, Jesra Lilah; Vicente, Marcelo

2017-01-01

Results from the completed Phase 1 Upgrade of the Compact Muon Solenoid (CMS) Level-1 Calorimeter Trigger are presented. The upgrade was completed in two stages, with the first running in 2015 for proton and Heavy Ion collisions and the final stage for 2016 data taking. The Level-1 trigger has been fully commissioned and has been used by CMS to collect over 43 fb-1 of data since the start of the Large Hadron Collider (LHC) Run II. The new trigger has been designed to improve the performance at high luminosity and large number of simultaneous inelastic collisions per crossing (pile-up). For this purpose it uses a novel design, the Time Multiplexed Trigger (TMT), which enables the data from an event to be processed by a single trigger processor at full granularity over several bunch crossings. The TMT design is a modular design based on the uTCA standard. The trigger processors are instrumented with Xilinx Virtex-7 690 FPGAs and 10 Gbps optical links. The TMT architecture is flexible and the number of trigger p...

Router Designs for an Asynchronous Time-Division-Multiplexed Network-on-Chip

DEFF Research Database (Denmark)

Kasapaki, Evangelia; Sparsø, Jens; Sørensen, Rasmus Bo

2013-01-01

In this paper we explore the design of an asynchronous router for a time-division-multiplexed (TDM) network-on-chip (NOC) that is being developed for a multi-processor platform for hard real-time systems. TDM inherently requires a common time reference, and existing TDM-based NOC designs are either....... This adds hardware complexity and increases area and power consumption. We propose to use asynchronous routers in order to achieve a simpler, more robust and globally-asynchronous NOC, and this represents an unexplored point in the design space. The paper presents a range of alternative router designs. All...... routers have been synthesized for a 65nm CMOS technology, and the paper reports post-layout figures for area, speed and energy and compares the asynchronous designs with an existing mesochronous clocked router. The results show that an asynchronous router is 2 times smaller, marginally slower...

The ALICE High Level Trigger: status and plans

CERN Document Server

Krzewicki, Mikolaj; Gorbunov, Sergey; Breitner, Timo; Lehrbach, Johannes; Lindenstruth, Volker; Berzano, Dario

2015-01-01

The ALICE High Level Trigger (HLT) is an online reconstruction, triggering and data compression system used in the ALICE experiment at CERN. Unique among the LHC experiments, it extensively uses modern coprocessor technologies like general purpose graphic processing units (GPGPU) and field programmable gate arrays (FPGA) in the data flow. Realtime data compression is performed using a cluster finder algorithm implemented on FPGA boards. These data, instead of raw clusters, are used in the subsequent processing and storage, resulting in a compression factor of around 4. Track finding is performed using a cellular automaton and a Kalman filter algorithm on GPGPU hardware, where both CUDA and OpenCL technologies can be used interchangeably. The ALICE upgrade requires further development of online concepts to include detector calibration and stronger data compression. The current HLT farm will be used as a test bed for online calibration and both synchronous and asynchronous processing frameworks already before t...

The Topological Processor for the future ATLAS Level-1 Trigger

CERN Document Server

Kahra, C; The ATLAS collaboration

2014-01-01

ATLAS is an experiment on the Large Hadron Collider (LHC), located at the European Organization for Nuclear Research (CERN) in Switzerland. By 2015 the LHC instantaneous luminosity will be increased from $10^{34}$ up to $3\\cdot 10^{34} \\mathrm{cm}^{-2} \\mathrm{s}^{-1}$. This places stringent operational and physical requirements on the ATLAS Trigger in order to reduce the 40MHz collision rate to a manageable event storage rate of 1kHz while at the same time, selecting those events that contain interesting physics events. The Level-1 Trigger is the first rate-reducing step in the ATLAS Trigger, with an output rate of 100kHz and decision latency of less than $2.5 \\mu \\mathrm{s}$. It is composed of the Calorimeter Trigger, the Muon Trigger and the Central Trigger Processor (CTP). In 2014, there will be a new electronics module: the Topological Processor (L1Topo). The L1Topo will make it possible, for the first time, to use detailed information from subdetectors in a single Level-1 module. This allows the determi...

TRIGGER

CERN Multimedia

W. Smith

2012-01-01

  Level-1 Trigger The Level-1 Trigger group is ready to deploy improvements to the L1 Trigger algorithms for 2012. These include new high-PT patterns for the RPC endcap, an improved CSC PT assignment, a new PT-matching algorithm for the Global Muon Trigger, and new calibrations for ECAL, HCAL, and the Regional Calorimeter Trigger. These should improve the efficiency, rate, and stability of the L1 Trigger. The L1 Trigger group also is migrating the online systems to SLC5. To make the data transfer from the Global Calorimeter Trigger to the Global Trigger more reliable and also to allow checking the data integrity online, a new optical link system has been developed by the GCT and GT groups and successfully tested at the CMS electronics integration facility in building 904. This new system is now undergoing further tests at Point 5 before being deployed for data-taking this year. New L1 trigger menus have recently been studied and proposed by Emmanuelle Perez and the L1 Detector Performance Group...

Evaluation of discrete modeling efficiency of asynchronous electric machines

OpenAIRE

Byczkowska-Lipińska, Liliana; Stakhiv, Petro; Hoholyuk, Oksana; Vasylchyshyn, Ivanna

2011-01-01

In the paper the problem of effective mathematical macromodels in the form of state variables intended for asynchronous motor transient analysis is considered. Their comparing with traditional mathematical models of asynchronous motors including models built into MATLAB/Simulink software was carried out and analysis of their efficiency was conducted.

Two Studies Examining Argumentation in Asynchronous Computer Mediated Communication

Science.gov (United States)

Joiner, Richard; Jones, Sarah; Doherty, John

2008-01-01

Asynchronous computer mediated communication (CMC) would seem to be an ideal medium for supporting development in student argumentation. This paper investigates this assumption through two studies. The first study compared asynchronous CMC with face-to-face discussions. The transactional and strategic level of the argumentation (i.e. measures of…

MODELING AND INVESTIGATION OF ASYNCHRONOUS TWO-MACHINE SYSTEM MODES

Directory of Open Access Journals (Sweden)

V. S. Safaryan

2014-01-01

Full Text Available The paper considers stationary and transient processes of an asynchronous two-machine system. A mathematical model for investigation of stationary and transient modes, static characteristics and research results of dynamic process pertaining to starting-up the asynchronous two-machine system has been given in paper.

CHARACTERISTIC OF MECHANISMS OF ANTIULCEROGENIC ACTION OF AGENTS OF VANILLOID RECEPTORS (TRPV1 ON THE MODEL OF GASTROPATHY INDUCED BY ACETYLSALICYLIC ACID

Directory of Open Access Journals (Sweden)

F. V. Hladkykh

2017-01-01

Full Text Available One of the main problems of the use of acetylsalicylic acid (ASA is its withdrawal or initial “non-prescription” resulted from the prior developed or potential side effects in the gastrointestinal tract. In this case, the reasons for the abolition of ASA are not only serious complications in the form of gastrointestinal bleeding or perforations, butalso dyspeptic phenomena that are accompanied by the ongoing development of aspirin-induced gastroenteropathy. The aim of the study. To characterize the mechanisms of antiulcerogenic action of agonist TRPV1 (transient receptor potential vanilloid 1 vanillin (100 mg/kg on the model of subchronic ASA-induced gastropathy in rats. Materials and methods. The study was performed on 35 mature male rats. Gastropathy induced by ASA was simulated by a fiveday intragastric (i.g. introduction via the orogastric probe of an ASA suspension of 150 mg/kg/ day during 5 days. Omeprazole (50 mg/kg, i.g. and vanillin (100 mg/kg, i.g. were administered in the form of suspensions 60 minutes prior to the use of ASA. The concentration of malonic dialdehyde, and the activity of catalase were determined in the homogenates of gastric mucosa. The prooxidant/antioxidant ratio (ProAntidex was calculated dased on the ratio of catalase activity (mcat/kg and the concentration of malondialdehyde (MDA concentration (umol/kg. The content of NO metabolites in the stomach tissues was determined by the method of Miranda K.M. et al. Results and discussion. Preventive prophylactic use of vanillin (100 mg/kg leads to the decrease in the intensity of processes of lipid peroxidation in the gastric mucosa caused by the action of ASA (150 mg/kg. This was indicated by a statistically significant (p≤0.05 decrease of 26.4% in MDA content and an increase in catalase activity by 29.0% relatively to those animalswith ASA-induced gastropathy without correction. Also, the use of vanillin resulted in a statistically significant (p≤0.05 increase in

PsychVACS: a system for asynchronous telepsychiatry.

Science.gov (United States)

Odor, Alberto; Yellowlees, Peter; Hilty, Donald; Parish, Michelle Burke; Nafiz, Najia; Iosif, Ana-Maria

2011-05-01

To describe the technical development of an asynchronous telepsychiatry application, the Psychiatric Video Archiving and Communication System. A client-server application was developed in Visual Basic.Net with Microsoft(®) SQL database as the backend. It includes the capability of storing video-recorded psychiatric interviews and manages the workflow of the system with automated messaging. Psychiatric Video Archiving and Communication System has been used to conduct the first ever series of asynchronous telepsychiatry consultations worldwide. A review of the software application and the process as part of this project has led to a number of improvements that are being implemented in the next version, which is being written in Java. This is the first description of the use of video recorded data in an asynchronous telemedicine application. Primary care providers and consulting psychiatrists have found it easy to work with and a valuable resource to increase the availability of psychiatric consultation in remote rural locations.

ASCERTAINMENT OF THE EQUIVALENT CIRCUIT PARAMETERS OF THE ASYNCHRONOUS MACHINE

Directory of Open Access Journals (Sweden)

V. S. Safaryan

2015-01-01

Full Text Available The article considers experimental and analytical determination of the asynchronous machine equivalent-circuit parameters with application of the reference data. Transient processes investigation of the asynchronous machines necessitates the equivalent circuit parameters (resistance impedance, inductances and coefficient of the stator-rotor contours mutual inductance that help form the transitory-process mathematical simulation model. The reference books do not provide those parameters; they instead give the rated ones (active power, voltage, slide, coefficient of performance and capacity coefficient as well as the ratio of starting and nominal currents and torques. The noted studies on the asynchronous machine equivalent-circuits parametrization fail to solve the problems ad finem or solve them with admissions. The paper presents experimental and analytical determinations of the asynchronous machine equivalent-circuit parameters: the experimental one based on the results of two measurements and the analytical one where the problem boils down to solving a system of nonlineal algebraic equations. The authors investigate the equivalent asynchronous machine input-resistance properties and adduce the dependence curvatures of the input-resistances on the slide. They present a symbolic model for analytical parameterization of the asynchronous machine equivalent-circuit that represents a system of nonlineal equations and requires one of the rotor-parameters arbitrary assignment. The article demonstrates that for the asynchronous machine equivalent-circuit experimental parameterization the measures are to be conducted of the stator-circuit voltage, current and active power with two different slides and arbitrary assignment of one of the rotor parameters. The paper substantiates the fact that additional measurement does not discard the rotor-parameter choice arbitrariness. The authors establish that in motoring mode there is a critical slide by which the

Effect of asynchronous updating on the stability of cellular automata

International Nuclear Information System (INIS)

Baetens, J.M.; Van der Weeën, P.; De Baets, B.

2012-01-01

Highlights: ► An upper bound on the Lyapunov exponent of asynchronously updated CA is established. ► The employed update method has repercussions on the stability of CAs. ► A decision on the employed update method should be taken with care. ► Substantial discrepancies arise between synchronously and asynchronously updated CA. ► Discrepancies between different asynchronous update schemes are less pronounced. - Abstract: Although cellular automata (CAs) were conceptualized as utter discrete mathematical models in which the states of all their spatial entities are updated simultaneously at every consecutive time step, i.e. synchronously, various CA-based models that rely on so-called asynchronous update methods have been constructed in order to overcome the limitations that are tied up with the classical way of evolving CAs. So far, only a few researchers have addressed the consequences of this way of updating on the evolved spatio-temporal patterns, and the reachable stationary states. In this paper, we exploit Lyapunov exponents to determine to what extent the stability of the rules within a family of totalistic CAs is affected by the underlying update method. For that purpose, we derive an upper bound on the maximum Lyapunov exponent of asynchronously iterated CAs, and show its validity, after which we present a comparative study between the Lyapunov exponents obtained for five different update methods, namely one synchronous method and four well-established asynchronous methods. It is found that the stability of CAs is seriously affected if one of the latter methods is employed, whereas the discrepancies arising between the different asynchronous methods are far less pronounced and, finally, we discuss the repercussions of our findings on the development of CA-based models.

Level-1 $\\tau$ trigger performance in 2017 data

CERN Document Server

CMS Collaboration

2018-01-01

In 2017, the LHC achieved an instantaneous luminosity of 2.06x10$^{34}$cm$^{-2}$s$^{-1}$, and a peak average pile-up of more than 50. This document describes the performance of the CMS Level-1 calorimeter trigger for $\\tau$ leptons using 40.9 fb$^{-1}$ of 2017 data. Details of the Level-1 trigger algorithms can be found in CMS-DP-2015-009. The previous Level-1 $\\tau$ performance report can be found in CMS-DP-2017-022.

Towards a Level-1 Tracking Trigger for the ATLAS Experiment

CERN Document Server

De Santo, A; The ATLAS collaboration

2016-01-01

In preparation for the high-luminosity phase of the Large Hadron Collider, ATLAS is planning a trigger upgrade that will enable the experiment to use tracking information already at the first trigger level. This will provide enhanced background rejection power at trigger level while preserving much needed flexibility for the trigger system. The status and current plans for the new ATLAS Level-1 tracking trigger are presented.

Detection of Failure in Asynchronous Motor Using Soft Computing Method

Science.gov (United States)

Vinoth Kumar, K.; Sony, Kevin; Achenkunju John, Alan; Kuriakose, Anto; John, Ano P.

2018-04-01

This paper investigates the stator short winding failure of asynchronous motor also their effects on motor current spectrums. A fuzzy logic approach i.e., model based technique possibly will help to detect the asynchronous motor failure. Actually, fuzzy logic similar to humanoid intelligent methods besides expected linguistic empowering inferences through vague statistics. The dynamic model is technologically advanced for asynchronous motor by means of fuzzy logic classifier towards investigate the stator inter turn failure in addition open phase failure. A hardware implementation was carried out with LabVIEW for the online-monitoring of faults.

Treatment of trigeminal ganglion neurons in vitro with NGF, GDNF or BDNF: effects on neuronal survival, neurochemical properties and TRPV1-mediated neuropeptide secretion

Directory of Open Access Journals (Sweden)

Patwardhan Amol M

2005-01-01

Full Text Available Abstract Background Nerve growth factor (NGF, glial cell line-derived neurotrophic factor (GDNF and brain-derived neurotrophic factor (BDNF all play important roles in the development of the peripheral sensory nervous system. Additionally, these growth factors are proposed to modulate the properties of the sensory system in the adult under pathological conditions brought about by nerve injury or inflammation. We have examined the effects of NGF, GDNF and BDNF on adult rat trigeminal ganglion (TG neurons in culture to gain a better understanding of how these growth factors alter the cytochemical and functional phenotype of these neurons, with special attention to properties associated with nociception. Results Compared with no growth factor controls, GDNF, at 1 and 100 ng/ml, significantly increased by nearly 100% the number of neurons in culture at 5 days post-plating. A significant, positive, linear trend of increasing neuron number as a function of BDNF concentration was observed, also peaking at nearly 100%. NGF treatment was without effect. Chronic treatment with NGF and GDNF significantly and concentration-dependently increased 100 nM capsaicin (CAP-evoked calcitonin gene-related peptide (CGRP release, reaching approximately 300% at the highest concentration tested (100 ng/ml. Also, NGF and GDNF each augmented anandamide (AEA- and arachidonyl-2-chloroethylamide (ACEA-evoked CGRP release, while BDNF was without effect. Utilizing immunohistochemistry to account for the proportions of TRPV1- or CGRP-positive neurons under each growth factor treatment condition and then standardizing evoked CGRP release to these proportions, we observed that NGF was much more effective in enhancing CAP- and 50 mM K+-evoked CGRP release than was GDNF. Furthermore, NGF and GDNF each altered the concentration-response function for CAP- and AEA-evoked CGRP release, increasing the Emax without altering the EC50 for either compound. Conclusions Taken together, our

Functional transient receptor potential vanilloid 1 and transient receptor potential vanilloid 4 channels along different segments of the renal vasculature

DEFF Research Database (Denmark)

Chen, L; Kaßmann, M; Sendeski, M

2015-01-01

with functional TRPV1 having a narrow, discrete distribution in the resistance vasculature and TRPV4 having more universal, widespread distribution along different vascular segments. We suggest that TRPV1/4 channels are potent therapeutic targets for site-specific vasodilation in the kidney.......AIM: Transient receptor potential vanilloid 1 (TRPV1) and vanilloid 4 (TRPV4) cation channels have been recently identified to promote endothelium-dependent relaxation of mouse mesenteric arteries. However, the role of TRPV1 and TRPV4 in the renal vasculature is largely unknown. We hypothesized...... that TRPV1/4 plays a role in endothelium-dependent vasodilation of renal blood vessels. METHODS: We studied the distribution of functional TRPV1/4 along different segments of the renal vasculature. Mesenteric arteries were studied as control vessels. RESULTS: The TRPV1 agonist capsaicin relaxed mouse...

The UA1 trigger processor

International Nuclear Information System (INIS)

Grayer, G.H.

1981-01-01

Experiment UA1 is a large multi-purpose spectrometer at the CERN proton-antiproton collider, scheduled for late 1981. The principal trigger is formed on the basis of the energy deposition in calorimeters. A trigger decision taken in under 2.4 microseconds can avoid dead time losses due to the bunched nature of the beam. To achieve this we have built fast 8-bit charge to digital converters followed by two identical digital processors tailored to the experiment. The outputs of groups of the 2440 photomultipliers in the calorimeters are summed to form a total of 288 input channels to the ADCs. A look-up table in RAM is used to convert the digitised photomultiplier signals to energy in one processor, combinations of input channels, and also counts the number of clusters with electromagnetic or hadronic energy above pre-determined levels. Up to twelve combinations of these conditions, together with external information, may be combined in coincidence or in veto to form the final trigger. Provision has been made for testing using simulated data in an off-line mode, and sampling real data when on-line. (orig.)

Upgrade of the ATLAS Level-1 Calorimeter Trigger

CERN Document Server

Wessels, M; The ATLAS collaboration

2014-01-01

The Level-1 Calorimeter Trigger (L1Calo) of the ATLAS experiment has been operating well since the start of LHC data taking, and played a major role in the Higgs boson discovery. To face the new challenges posed by the upcoming increases of the LHC proton beam energy and luminosity, a series of upgrades is planned for L1Calo. The initial upgrade phase in 2013-14 includes substantial improvements to the analogue and digital signal processing to allow more sophisticated digital filters for energy and timing measurement, as well as compensate for pile-up and baseline shifting effects. Two existing digital algorithm processor subsystems will receive substantial hardware and firmware upgrades to increase the real-time data path bandwidth, allowing topological information to be transmitted and processed at Level-1. An entirely new subsystem, the Level-1 Topological Processor, will receive real-time data from both the upgraded L1Calo and Level-1 Muon Trigger to perform trigger algorithms based on entire event topolo...

The ATLAS Muon Trigger Performance : Run 1 and initial Run 2.

CERN Document Server

Kasahara, Kota; The ATLAS collaboration

2015-01-01

The ATLAS Muon Trigger Performance: Run 1 and Initial Run 2 Performance

Events with muons in the final state are an important signature for many physics topics at the Large Hadron Collider (LHC). An efficient trigger on muons and a detailed understanding of its performance are required. In 2012, the last year of Run 1, the instantaneous luminosity of the LHC reached 7.7x10^33 cm -2s-1 and the average number of events that occur in a same bunch crossing was 25. The ATLAS Muon trigger has successfully adapted to this changing environment by making use of isolation requirements, combined trigger signatures with electron and jet trigger objects, and by using so-called full-scan triggers, which make use of the full event information to search for di-lepton signatures, seeded by single lepton objects. A stable and highly efficient muon trigger was vital in the discovery of Higgs boson in 2012 and for many searches for new physics. 
The performance of muon triggers during the LHC Run 1 data-taking campaigns i...

Asynchronous Operators of Sequential Logic Venjunction & Sequention

CERN Document Server

Vasyukevich, Vadim

2011-01-01

This book is dedicated to new mathematical instruments assigned for logical modeling of the memory of digital devices. The case in point is logic-dynamical operation named venjunction and venjunctive function as well as sequention and sequentional function. Venjunction and sequention operate within the framework of sequential logic. In a form of the corresponding equations, they organically fit analytical expressions of Boolean algebra. Thus, a sort of symbiosis is formed using elements of asynchronous sequential logic on the one hand and combinational logic on the other hand. So, asynchronous

Simulation and Validation of the ATLAS Level-1 Topological Trigger

CERN Document Server

Bakker, Pepijn Johannes; The ATLAS collaboration

2017-01-01

The ATLAS experiment has recently commissioned a new component of its first-level trigger: the L1 topological trigger. This system, using state-of-the-art FPGA processors, makes it possible to reject events by applying topological requirements, such as kinematic criteria involving clusters, jets, muons, and total transverse energy. The data recorded using the L1Topological trigger demonstrates that this innovative trigger strategy allows for an improved rejection rate without efficiency loss. This improvement has been shown for several relevant physics processes leading to low-$p_T$ leptons, including $H\\to{}\\tau{}\\tau{}$ and $J/\\Psi\\to{}\\mu{}\\mu{}$. In addition, an accurate simulation of the L1Topological trigger is used to validate and optimize the performance of this trigger. To reach such an accuracy, this simulation must take into account the fact that the firmware algorithms are executed on a FPGA architecture, while the simulation is executed on a floating point architecture.

The UA1 upgrade calorimeter trigger processor

International Nuclear Information System (INIS)

Bains, N.; Baird, S.A.; Biddulph, P.

1990-01-01

The increased luminosity of the improved CERN Collider and the more subtle signals of second-generation collider physics demand increasingly sophisticated triggering. We have built a new first-level trigger processor designed to use the excellent granularity of the UA1 upgrade calorimeter. This device is entirely digital and handles events in 1.5 μs, thus introducing no deadtime. Its most novel feature is fast two-dimensional electromagnetic cluster-finding with the possibility of demanding an isolated shower of limited penetration. The processor allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. This hard-wired processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It was used extensively in the 1988 and 1989 runs of the CERN Collider. (author)

The UA1 upgrade calorimeter trigger processor

International Nuclear Information System (INIS)

Bains, M.; Charleton, D.; Ellis, N.; Garvey, J.; Gregory, J.; Jimack, M.P.; Jovanovic, P.; Kenyon, I.R.; Baird, S.A.; Campbell, D.; Cawthraw, M.; Coughlan, J.; Flynn, P.; Galagedera, S.; Grayer, G.; Halsall, R.; Shah, T.P.; Stephens, R.; Biddulph, P.; Eisenhandler, E.; Fensome, I.F.; Landon, M.; Robinson, D.; Oliver, J.; Sumorok, K.

1990-01-01

The increased luminosity of the improved CERN Collider and the more subtle signals of second-generation collider physics demand increasingly sophisticated triggering. We have built a new first-level trigger processor designed to use the excellent granularity of the UA1 upgrade calorimeter. This device is entirely digital and handles events in 1.5 μs, thus introducing no dead time. Its most novel feature is fast two-dimensional electromagnetic cluster-finding with the possibility of demanding an isolated shower of limited penetration. The processor allows multiple combinations of triggers on electromagnetic showers, hadronic jets and energy sums, including a total-energy veto of multiple interactions and a full vector sum of missing transverse energy. This hard-wired processor is about five times more powerful than its predecessor, and makes extensive use of pipelining techniques. It was used extensively in the 1988 and 1989 runs of the CERN Collider. (orig.)

Dexamethasone rapidly increases GABA release in the dorsal motor nucleus of the vagus via retrograde messenger-mediated enhancement of TRPV1 activity.

Directory of Open Access Journals (Sweden)

Andrei V Derbenev

Full Text Available Glucocorticoids influence vagal parasympathetic output to the viscera via mechanisms that include modulation of neural circuitry in the dorsal vagal complex, a principal autonomic regulatory center. Glucocorticoids can modulate synaptic neurotransmitter release elsewhere in the brain by inducing release of retrograde signalling molecules. We tested the hypothesis that the glucocorticoid agonist dexamethasone (DEX modulates GABA release in the rat dorsal motor nucleus of the vagus (DMV. Whole-cell patch-clamp recordings revealed that DEX (1-10 µM rapidly (i.e. within three minutes increased the frequency of tetrodotoxin-resistant, miniature IPSCs (mIPSCs in 67% of DMV neurons recorded in acutely prepared slices. Glutamate-mediated mEPSCs were also enhanced by DEX (10 µM, and blockade of ionotropic glutamate receptors reduced the DEX effect on mIPSC frequency. Antagonists of type I or II corticosteroid receptors blocked the effect of DEX on mIPSCs. The effect was mimicked by application of the membrane-impermeant BSA-conjugated DEX, and intracellular blockade of G protein function with GDP βS in the recorded cell prevented the effect of DEX. The enhancement of GABA release was blocked by the TRPV1 antagonists, 5'-iodoresiniferatoxin or capsazepine, but was not altered by the cannabinoid type 1 receptor antagonist AM251. The DEX effect was prevented by blocking fatty acid amide hydrolysis or by inhibiting anandamide transport, implicating involvement of the endocannabinoid system in the response. These findings indicate that DEX induces an enhancement of GABA release in the DMV, which is mediated by activation of TRPV1 receptors on afferent terminals. The effect is likely induced by anandamide or other 'endovanilloid', suggesting activation of a local retrograde signal originating from DMV neurons to enhance synaptic inhibition locally in response to glucocorticoids.

[A novel proposal explaining sleep disturbance of children in Japan--asynchronization].

Science.gov (United States)

Kohyama, Jun

2008-07-01

It has been reported that more than half of the children in Japan suffer from daytime sleepiness. In contrast, about one quarter of junior high-school students in Japan complain of insomnia. According to the International Classification of Sleep Disorders (Second edition), these children could be diagnosed as having behaviorally-induced insufficient sleep syndrome due to inadequate sleeping habits. Getting on adequate amount of sleep should solve such problems;however, such a therapeutic approach often fails. Although social factors are involved in these sleep disturbances, I feel that a novel notion - asynchronization - leads to an understanding of the pathophysiology of disturbances in these children. Further, it could contribute to resolve their problems. The essence of asynchronization is a disturbance of various aspects (e.g., cycle, amplitude, phase, and interrelationship) of the biological rhythms that normally exhibits circadian oscillation. The main cause of asynchronization is hypothesized to be the combination of light exposure during night and the lack of light exposure in the morning. Asynchronization results in the disturbance of variable systems. Thus, symptoms of asynchronization include disturbances of the autonomic nervous system (sleepiness, insomnia, disturbance of hormonal excretion, gastrointestinal problems, etc.) and higher brain function (disorientation, loss of sociality, loss of will or motivation, impaired alertness and performance, etc.). Neurological (attention deficit, aggression, impulsiveness, hyperactivity, etc.), psychiatric (depressive disorders, personality disorders, anxiety disorders, etc.) and somatic (tiredness, fatigue, etc.) disturbances could also be symptoms of asynchronization. At the initial phase of asynchronization, disturbances are functional and can be resolved relatively easily, such as by the establishment of a regular sleep-wakefulness cycle;however, without adequate intervention the disturbances could gradually

Development of the new trigger processor board for the ATLAS Level-1 endcap muon trigger for Run-3

CERN Document Server

AUTHOR|(INSPIRE)INSPIRE-00525035; The ATLAS collaboration

2017-01-01

The instantaneous luminosity of the LHC will be increased by up to a factor of three with respect to the original design value at Run-3 (starting 2021). The ATLAS Level-1 end-cap muon trigger in LHC Run-3 will identify muons by combining data from the Thin-Gap Chamber detector (TGC) and the New Small Wheel (NSW), which is a new detector and will be able to operate in a high background hit rate at Run-3, to suppress the Level-1 trigger rate. In order to handle data from both TGC and NSW, a new trigger processor board has been developed. The board has a modern FPGA to make use of Multi-Gigabit transceiver technology. The readout system for trigger data has also been designed with TCP/IP instead of a dedicated ASIC. This letter presents the electronics and its firmware of the ATLAS Level-1 end-cap muon trigger processor board for LHC Run-3.

Localized radio frequency communication using asynchronous transfer mode protocol

Science.gov (United States)

Witzke, Edward L.; Robertson, Perry J.; Pierson, Lyndon G.

2007-08-14

A localized wireless communication system for communication between a plurality of circuit boards, and between electronic components on the circuit boards. Transceivers are located on each circuit board and electronic component. The transceivers communicate with one another over spread spectrum radio frequencies. An asynchronous transfer mode protocol controls communication flow with asynchronous transfer mode switches located on the circuit boards.

Electrotechnics - AC motors. Asynchronous and brush-less motors - Lecture and exercises with solutions; Electrotechnique - Moteurs a courant alternatif. Moteurs asynchrones et brushless - Cours et problemes resolus