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Romain Guinamard - One of the best experts on this subject based on the ideXlab platform.
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trpm4 non selective Cation Channel variants in long qt syndrome
BMC Medical Genetics, 2017Co-Authors: Thomas Hof, Romain Guinamard, Hui Liu, Laurent Salle, Jeanjacques Schott, Corinne Ducreux, Gilles Millat, Philippe Chevalier, Vincent Probst, Patrice BouvagnetAbstract:Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4). Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current. This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4−/− mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.
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trpm4 in cardiac electrical activity
Cardiovascular Research, 2015Co-Authors: Romain Guinamard, Thomas Hof, Hui Liu, Patrice Bouvagnet, Christophe Simard, Laurent SalleAbstract:TRPM4 forms a Non-Selective Cation Channel activated by internal Ca(2+). Its functional expression was demonstrated in cardiomyocytes of several mammalian species including humans, but the Channel is also present in many other tissues. The recent characterization of the TRPM4 inhibitor 9-phenanthrol, and the availability of transgenic mice have helped to clarify the role of TRPM4 in cardiac electrical activity, including diastolic depolarization from the sino-atrial node cells in mouse, rat, and rabbit, as well as action potential duration in mouse cardiomyocytes. In rat and mouse, pharmacological inhibition of TRPM4 prevents cardiac ischaemia-reperfusion injuries and decreases the occurrence of arrhythmias. Several studies have identified TRPM4 mutations in patients with inherited cardiac diseases including conduction blocks and Brugada syndrome. This review identifies TRPM4 as a significant actor in cardiac electrophysiology.
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the trpm4 non selective Cation Channel contributes to the mammalian atrial action potential
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Christophe Simard, Thomas Hof, Zakia Keddache, Pierre Launay, Romain GuinamardAbstract:The TRPM4 calcium-activated Non-Selective monovalent Cation Channel has been reported in mammalian atrial cardiomyocytes, but its impliCation in this tissue remains unknown. We used a combination of pharmacological tools and disruption of the Trpm4 gene in mice to investigate the Channel impliCation in atrial action potential (AP). To search for TRPM4 activity, single Channel currents were recorded on freshly isolated atrial cardiomyocytes using the patch-clamp technique. To investigate TRPM4 impliCation in AP, the transmembrane potential was recorded on the multicellular preparation using intracellular microelectrodes after isolating the mouse atrium, under electrical stimulation (rate=5Hz). Isolated atrial cardiomyocytes from the Trpm4(+/+) mouse expressed a typical TRPM4 current while cardiomyocytes from Trpm4(-/-) mouse did not. The Trpm4(+/+) mouse atrium exhibited AP durations at 50, 70 and 90% repolarization of 8.9±0.5ms, 16.0±1.0ms, and 30.2±1.6ms, respectively. The Non-Selective Cation Channel inhibitor flufenamic acid (10(-6) and 10(-5)mol·L(-1)) produced a concentration-dependent decrease in AP duration. Similarly, the TRPM4-inhibitor 9-phenanthrol reversibly reduced the duration of AP with an EC50 at 21×10(-6)mol·L(-1), which is similar to that reported for TRPM4 current inhibition in HEK-293 cells. 9-Phenanthrol had no effect on other AP parameters. The effect of 9-phenanthrol is markedly reduced in the mouse ventricle, which displays only weak expression of the Channel. Moreover, atria from Trpm4(-/-) mice exhibited an AP that was 20% shorter than that of atria from littermate control mice, and the effect of 9-phenanthrol on AP was abolished in the Trpm4(-/-) mice. Our results showed that TRPM4 is implicated in the waveform of the atrial action potential. It is thus a potential target for pharmacological approaches against atrial arrhythmias.
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a calcium permeable non selective Cation Channel in the thick ascending limb apical membrane of the mouse kidney
Biochimica et Biophysica Acta, 2012Co-Authors: Romain Guinamard, Marc Paulais, Stephane Lourdel, Jacques TeulonAbstract:Abstract Non-Selective Cation Channels have been described in the basolateral membrane of the renal tubule, but little is known about functional Channels on the apical side. Apical membranes of microdissected fragments of mouse cortical thick ascending limbs were searched for ion Channels using the cell-free configuration of the patch-clamp technique. A Cation Channel with a linear current–voltage relationship (19 pS) that was permeable both to monovalent Cations [PNH4(1.7) > PNa (1.0) = PK (1.0)] and to Ca2+ (PCa/PNa ≈ 0.3) was detected. Unlike the basolateral TRPM4 Ca2+-impermeable Non-Selective Cation Channel, this Non-Selective Cation Channel was insensitive to internal Ca2+, pH and ATP. The Channel was already active after patch excision, and its activity increased after reduced pressure was applied via the pipette. External gadolinium (10− 5 M) decreased the Channel-open probability by 70% in outside-out patches, whereas external amiloride (10− 4 M) had no effect. Internal flufenamic acid (10− 4 M) inhibited the Channel in inside-out patches. Its properties suggest that the current might be supported by the TRPM7 protein that is expressed in the loop of Henle. The conduction properties of the Channel suggest that it could be involved in Ca2+ signaling.
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functional characterization of a ca2 activated non selective Cation Channel in human atrial cardiomyocytes
The Journal of Physiology, 2004Co-Authors: Romain Guinamard, Aurelien Chatelier, Marie Demion, Daniel Potreau, Sylvie Patri, Mohammad Rahmati, Patrick BoisAbstract:Cardiac arrhythmias, which occur in a wide variety of conditions where intracellular calcium is increased, have been attributed to the activation of a transient inward current (Iti). Iti is the result of three different [Ca]i-sensitive currents: the Na+–Ca2+ exchange current, a Ca2+-activated chloride current and a Ca2+-activated Non-Selective Cationic current. Using the cell-free configuration of the patch-clamp technique, we have characterized the properties of a Ca2+-activated Non-Selective Cation Channel (NSCCa) in freshly dissociated human atrial cardiomyocytes. In excised inside-out patches, the Channel presented a linear I–V relationship with a conductance of 19 ± 0.4 pS. It discriminated poorly among monovalent Cations (Na+ and K+) and was slightly permeable to Ca2+ ions. The Channel's open probability was increased by depolarization and a rise in internal calcium, for which the Kd for [Ca2+]i was 20.8 μm. Channel activity was reduced in the presence of 0.5 mm ATP or 10 μm glibenclamide on the cytoplasmic side to 22.1 ± 16.8 and 28.5 ± 8.6%, respectively, of control. It was also inhibited by 0.1 mm flufenamic acid. The Channel shares several properties with TRPM4b and TRPM5, two members of the ‘TRP melastatin’ subfamily. In conclusion, the NSCCa Channel is a serious candidate to support the delayed after-depolarizations observed in [Ca2+] overload and thus may be implicated in the genesis of arrhythmias.
Makoto Tominaga - One of the best experts on this subject based on the ideXlab platform.
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transient receptor potential vanilloid 4 mediates sour taste sensing via type iii taste cell differentiation
Scientific Reports, 2019Co-Authors: Kenjiro Matsumoto, Akihiro Ohishi, Ken Iwatsuki, Kaho Yamazaki, Satoko Takayanagi, Masahiro Tsuji, Eitaro Aihara, Daichi Utsumi, Takuya Tsukahara, Makoto TominagaAbstract:Taste buds are comprised of taste cells, which are classified into types I to IV. Transient receptor potential (TRP) Channels play a significant role in taste perception. TRP vanilloid 4 (TRPV4) is a Non-Selective Cation Channel that responds to mechanical, thermal, and chemical stimuli. The present study aimed to define the function and expression of TRPV4 in taste buds using Trpv4-deficient mice. In circumvallate papillae, TRPV4 colocalized with a type IV cell and epithelial cell marker but not type I, II, or III markers. Behavioural studies showed that Trpv4 deficiency reduced sensitivity to sourness but not to sweet, umami, salty, and bitter tastes. Trpv4 deficiency significantly reduced the expression of type III cells compared with that in wild type (WT) mice in vivo and in taste bud organoid experiments. Trpv4 deficiency also significantly reduced Ki67-positive cells and β-catenin expression compared with those in WT circumvallate papillae. Together, the present results suggest that TRPV4 contributes to sour taste sensing by regulating type III taste cell differentiation in mice.
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identifiCation of significant amino acids in multiple transmembrane domains of human transient receptor potential ankyrin 1 trpa1 for activation by eudesmol an oxygenized sesquiterpene in hop essential oil
Journal of Biological Chemistry, 2015Co-Authors: Kazuaki Ohara, Mikio Katayama, Takafumi Fukuda, Hiroyuki Okada, Sayoko Kitao, Yuko Ishida, Kyoko Kato, Chika Takahashi, Kunitoshi Uchida, Makoto TominagaAbstract:Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable Non-Selective Cation Channel that is activated by various noxious or irritant substances in nature, including spicy compounds. Many TRPA1 chemical activators have been reported; however, only limited information is available regarding the amino acid residues that contribute to the activation by non-electrophilic activators, whereas activation mechanisms by electrophilic ligands have been well characterized. We used intracellular Ca2+ measurements and whole-cell patch clamp recordings to show that eudesmol, an oxygenated sesquiterpene present at high concentrations in the essential oil of hop cultivar Hallertau Hersbrucker, could activate human TRPA1. Gradual activation of inward currents with outward rectifiCation by eudesmol was observed in human embryonic kidney-derived 293 cells expressing human TRPA1. This activation was completely blocked by a TRPA1-specific inhibitor, HC03–0031. We identified three critical amino acid residues in human TRPA1 in putative transmembrane domains 3, 4, and 5, namely threonine at 813, tyrosine at 840, and serine at 873, for activation by β-eudesmol in a systematic mutational study. Our results revealed a new TRPA1 activator in hop essential oil and provide a novel insight into mechanisms of human TRPA1 activation by non-electrophilic chemicals.
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a 3 5 nm structure of rat trpv4 Cation Channel revealed by zernike phase contrast cryoelectron microscopy
Journal of Biological Chemistry, 2010Co-Authors: Hideki Shigematsu, Makoto Tominaga, Takaaki Sokabe, Radostin Danev, Kuniaki NagayamaAbstract:The transient receptor potential vanilloid 4 (TRPV4) is a Non-Selective Cation Channel responsive to various stimuli including cell swelling, warm temperatures (27–35 °C), and chemical compounds such as phorbol ester derivatives. Here we report the three-dimensional structure of full-length rat TRPV4 purified from baculovirus-infected Sf9 cells. Hexahistidine-tagged rat TRPV4 (His-rTRPV4) was solubilized with detergent and purified through affinity chromatography and size-exclusion chromatography. Chemical cross-linking analysis revealed that detergent-solubilized His-rTRPV4 was a tetramer. The 3.5-nm structure of rat TRPV4 was determined by cryoelectron microscopy using single-particle reconstruction from Zernike phase-contrast images. The overall structure comprises two distinct regions; a larger dense component, likely corresponding to the cytoplasmic N- and C-terminal regions, and a smaller component corresponding to the transmembrane region.
Pedro Grandes - One of the best experts on this subject based on the ideXlab platform.
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visualization by high resolution immunoelectron microscopy of the transient receptor potential vanilloid 1 at inhibitory synapses of the mouse dentate gyrus
PLOS ONE, 2015Co-Authors: Mirenjosune Canduela, Juan Mendizabalzubiaga, Nagore Puente, Leire Reguero, Izaskun Elezgarai, Almudena Ramosuriarte, Inmaculada Gerrikagoitia, Pedro GrandesAbstract:We have recently shown that the transient receptor potential vanilloid type 1 (TRPV1), a Non-Selective Cation Channel in the peripheral and central nervous system, is localized at postsynaptic sites of the excitatory perforant path synapses in the hippocampal dentate molecular layer (ML). In the present work, we have studied the distribution of TRPV1 at inhibitory synapses in the ML. With this aim, a preembedding immunogold method for high resolution electron microscopy was applied to mouse hippocampus. About 30% of the inhibitory synapses in the ML are TRPV1 immunopositive, which is mostly localized perisynaptically (∼60% of total immunoparticles) at postsynaptic dendritic membranes receiving symmetric synapses in the inner 1/3 of the layer. This TRPV1 pattern distribution is not observed in the ML of TRPV1 knock-out mice. These findings extend the knowledge of the subcellular localization of TRPV1 to inhibitory synapses of the dentate molecular layer where the Channel, in addition to excitatory synapses, is present.
Michael F Jackson - One of the best experts on this subject based on the ideXlab platform.
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trpm2 a candidate therapeutic target for treating neurological diseases
Acta Pharmacologica Sinica, 2018Co-Authors: Jillian C Belrose, Michael F JacksonAbstract:Transient receptor potential melastatin 2 (TRPM2) is a calcium (Ca2+)-permeable Non-Selective Cation Channel belonging to the TRP ion Channel family. Oxidative stress-induced TRPM2 activation provokes aberrant intracellular Ca2+ accumulation and cell death in a variety of cell types, including neurons. Aberrant TRPM2 function has been implicated in several neurological disorders including ischemia/stroke, Alzheimer's disease, neuropathic pain, Parkinson's disease and bipolar disorder. In addition to research identifying a role for TRPM2 in disease, progress has been made in the identifiCation of physiological functions of TRPM2 in the brain, including recent evidence that TRPM2 is necessary for the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression, an important form of synaptic plasticity at glutamate synapses. Here, we summarize recent evidence on the role of TRPM2 in the central nervous system (CNS) in health and disease and discuss the potential therapeutic impliCations of targeting TRPM2. Collectively, these studies suggest that TRPM2 represents a prospective novel therapeutic target for neurological disorders.
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loss of glutathione homeostasis associated with neuronal senescence facilitates trpm2 Channel activation in cultured hippocampal pyramidal neurons
Molecular Brain, 2012Co-Authors: Jillian C Belrose, Yufeng Xie, Lynn J Gierszewski, John F Macdonald, Michael F JacksonAbstract:Background Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable Non-Selective Cation Channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 Channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 Channel activity in long-term cultures of hippocampal neurons.
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dependence of nmda gsk 3β mediated metaplasticity on trpm2 Channels at hippocampal ca3 ca1 synapses
Molecular Brain, 2011Co-Authors: Yufeng Xie, Yasuo Mori, Jillian C Belrose, John F Macdonald, Gang Lei, Michael Tymianski, Michael F JacksonAbstract:Transient receptor potential melastatin 2 (TRPM2) is a calcium permeable Non-Selective Cation Channel that functions as a sensor of cellular redox status. Highly expressed within the CNS, we have previously demonstrated the functional expression of these Channels in CA1 pyramidal neurons of the hippocampus. Although implicated in oxidative stress-induced neuronal cell death, and potentially in neurodegenerative disease, the physiological role of TRPM2 in the central nervous system is unknown. Interestingly, we have shown that the activation of these Channels may be sensitized by co-incident NMDA receptor activation, suggesting a potential contribution of TRPM2 to synaptic transmission. Using hippocampal cultures and slices from TRPM2 null mice we demonstrate that the loss of these Channels selectively impairs NMDAR-dependent long-term depression (LTD) while sparing long-term potentiation. Impaired LTD resulted from an inhibition of GSK-3β, through increased phosphorylation, and a reduction in the expression of PSD95 and AMPARs. Notably, LTD could be rescued in TRPM2 null mice by recruitment of GSK-3β signaling following dopamine D2 receptor stimulation. We propose that TRPM2 Channels play a key role in hippocampal synaptic plasticity.
Thomas Hof - One of the best experts on this subject based on the ideXlab platform.
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trpm4 non selective Cation Channel variants in long qt syndrome
BMC Medical Genetics, 2017Co-Authors: Thomas Hof, Romain Guinamard, Hui Liu, Laurent Salle, Jeanjacques Schott, Corinne Ducreux, Gilles Millat, Philippe Chevalier, Vincent Probst, Patrice BouvagnetAbstract:Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes. A cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4). Four TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current. This study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4−/− mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.
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trpm4 in cardiac electrical activity
Cardiovascular Research, 2015Co-Authors: Romain Guinamard, Thomas Hof, Hui Liu, Patrice Bouvagnet, Christophe Simard, Laurent SalleAbstract:TRPM4 forms a Non-Selective Cation Channel activated by internal Ca(2+). Its functional expression was demonstrated in cardiomyocytes of several mammalian species including humans, but the Channel is also present in many other tissues. The recent characterization of the TRPM4 inhibitor 9-phenanthrol, and the availability of transgenic mice have helped to clarify the role of TRPM4 in cardiac electrical activity, including diastolic depolarization from the sino-atrial node cells in mouse, rat, and rabbit, as well as action potential duration in mouse cardiomyocytes. In rat and mouse, pharmacological inhibition of TRPM4 prevents cardiac ischaemia-reperfusion injuries and decreases the occurrence of arrhythmias. Several studies have identified TRPM4 mutations in patients with inherited cardiac diseases including conduction blocks and Brugada syndrome. This review identifies TRPM4 as a significant actor in cardiac electrophysiology.
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the trpm4 non selective Cation Channel contributes to the mammalian atrial action potential
Journal of Molecular and Cellular Cardiology, 2013Co-Authors: Christophe Simard, Thomas Hof, Zakia Keddache, Pierre Launay, Romain GuinamardAbstract:The TRPM4 calcium-activated Non-Selective monovalent Cation Channel has been reported in mammalian atrial cardiomyocytes, but its impliCation in this tissue remains unknown. We used a combination of pharmacological tools and disruption of the Trpm4 gene in mice to investigate the Channel impliCation in atrial action potential (AP). To search for TRPM4 activity, single Channel currents were recorded on freshly isolated atrial cardiomyocytes using the patch-clamp technique. To investigate TRPM4 impliCation in AP, the transmembrane potential was recorded on the multicellular preparation using intracellular microelectrodes after isolating the mouse atrium, under electrical stimulation (rate=5Hz). Isolated atrial cardiomyocytes from the Trpm4(+/+) mouse expressed a typical TRPM4 current while cardiomyocytes from Trpm4(-/-) mouse did not. The Trpm4(+/+) mouse atrium exhibited AP durations at 50, 70 and 90% repolarization of 8.9±0.5ms, 16.0±1.0ms, and 30.2±1.6ms, respectively. The Non-Selective Cation Channel inhibitor flufenamic acid (10(-6) and 10(-5)mol·L(-1)) produced a concentration-dependent decrease in AP duration. Similarly, the TRPM4-inhibitor 9-phenanthrol reversibly reduced the duration of AP with an EC50 at 21×10(-6)mol·L(-1), which is similar to that reported for TRPM4 current inhibition in HEK-293 cells. 9-Phenanthrol had no effect on other AP parameters. The effect of 9-phenanthrol is markedly reduced in the mouse ventricle, which displays only weak expression of the Channel. Moreover, atria from Trpm4(-/-) mice exhibited an AP that was 20% shorter than that of atria from littermate control mice, and the effect of 9-phenanthrol on AP was abolished in the Trpm4(-/-) mice. Our results showed that TRPM4 is implicated in the waveform of the atrial action potential. It is thus a potential target for pharmacological approaches against atrial arrhythmias.
