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Bernd Nilius - One of the best experts on this subject based on the ideXlab platform.
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molecular functions of anoctamin 6 tmem16f a chloride Channel Cation Channel or phospholipid scramblase
Pflügers Archiv: European Journal of Physiology, 2014Co-Authors: Karl Kunzelmann, Bernd Nilius, Grzegorz Owsianik, Rainer Schreiber, Jiraporn Ousingsawat, Lalida Sirianant, Podchanart Wanitchakool, Edouard M Bevers, Johan W M HeemskerkAbstract:Anoctamin 6 (Ano6; TMEM16F gene) is a ubiquitous protein; the expression of which is defective in patients with Scott syndrome, an inherited bleeding disorder based on defective scrambling of plasma membrane phospholipids. For Ano6, quite diverse functions have been described: (1) it can form an outwardly rectifying, Ca2+-dependent and a volume-regulated Cl− Channel; (2) it was claimed to be a Ca2+-regulated nonselective Cation Channel permeable for Ca2+; (3) it was shown to be essential for Ca2+-mediated scrambling of membrane phospholipids; and (4) it can regulate cell blebbing and microparticle shedding. Deficiency of Ano6 in blood cells from Scott patients or Ano6 null mice appears to affect all of these cell responses. Furthermore, Ano6 deficiency in mice impairs the mineralization of osteoblasts, resulting in reduced skeletal development. These diverse results have been obtained under different experimental conditions, which may explain some of the contradictions. This review therefore aims to summarize the currently available information on the diverse roles of Ano6 and tries to clear up some of the existing controversies.
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agonist induced changes in ca2 permeation through the nociceptor Cation Channel trpa1
Biophysical Journal, 2010Co-Authors: Yuji Karashima, Karel Talavera, Annelies Janssens, Jean Prenen, Thomas Voets, Bernd NiliusAbstract:The Ca2+-permeable Cation Channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca2+ ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated Channel to Cations of different size, we estimated a pore diameter of ∼11 A. Combined patch-clamp and Fura-2 fluorescence recordings revealed that with 2 mM extracellular Ca2+, and at a membrane potential of −80 mV, ∼17% of the inward TRPA1 current is carried by Ca2+. Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 A and an increase in divalent Cation selectivity and fractional Ca2+ current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca2+ current also prevented mustard-oil-induced increases in Ca2+ permeation. It is interesting that fractional Ca2+ currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca2+ in the pore hinders monovalent Cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca2+ influx.
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increased ige dependent mast cell activation and anaphylactic responses in mice lacking the calcium activated nonselective Cation Channel trpm4
Nature Immunology, 2007Co-Authors: Rudi Vennekens, Jenny Olausson, Marcel Meissner, Wilhelm Bloch, Ilka Mathar, Stephan E Philipp, Frank Schmitz, Petra Weissgerber, Bernd NiliusAbstract:Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective Cation Channel TRPM4
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the ca2 activated Cation Channel trpm4 is regulated by phosphatidylinositol 4 5 biphosphate
The EMBO Journal, 2006Co-Authors: Bernd Nilius, Annelies Janssens, Rudi Vennekens, Jean Prenen, Grzegorz Owsianik, Frank Mahieu, Thomas VoetsAbstract:Transient receptor potential (TRP) Channel, melastatin subfamily (TRPM)4 is a Ca2+-activated monovalent Cation Channel that depolarizes the plasma membrane and thereby modulates Ca2+ influx through Ca2+-permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca2+ ([Ca2+]i). Here we show that phosphatidylinositol 4,5-biphosphate (PIP2) counteracts desensitization to [Ca2+]i in inside-out patches and rundown of TRPM4 currents in whole-cell patch-clamp experiments. PIP2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the Channel's Ca2+ sensitivity 100-fold. Conversely, activation of the phospholipase C (PLC)-coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP2 potently inhibited currents through TRPM4. Neutralization of basic residues in a C-terminal pleckstrin homology (PH) domain accelerated TRPM4 current desensitization and strongly attenuated the effect of PIP2, whereas mutations to the C-terminal TRP box and TRP domain had no effect on the PIP2 sensitivity. Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity.
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The Selectivity Filter of the Cation Channel TRPM4
The Journal of biological chemistry, 2005Co-Authors: Bernd Nilius, Annelies Janssens, Jean Prenen, Chunbo Wang, Grzegorz Owsianik, Michael X Zhu, Thomas VoetsAbstract:Abstract Transient receptor potential Channel melastatin subfamily (TRPM) 4 and its close homologue, TRPM5, are the only two members of the large transient receptor potential superfamily of Cation Channels that are impermeable to Ca2+. In this study, we located the TRPM4 selectivity filter and investigated possible structural elements that render it Ca2+-impermeable. Based on homology with known Cation Channel pores, we identified an acidic stretch of six amino acids in the loop between transmembrane helices TM5 and TM6 (981EDMDVA986) as a potential selectivity filter. Substitution of this six-amino acid stretch with the selectivity filter of TRPV6 (TIIDGP) resulted in a functional Channel that combined the gating hallmarks of TRPM4 (activation by Ca2+, voltage dependence) with TRPV6-like sensitivity to block by extracellular Ca2+ and Mg2+ as well as Ca2+ permeation. Neutralization of Glu981 resulted in a Channel with normal permeability properties but a strongly reduced sensitivity to block by intracellular spermine. Neutralization of Asp982 yielded a functional Channel that exhibited extremely fast desensitization (τ < 5 s), possibly indicating destabilization of the pore. Neutralization of Asp984 resulted in a non-functional Channel with a dominant negative phenotype when coexpressed with wild type TRPM4. Combined neutralization of all three acidic residues resulted in a functional Channel whose voltage dependence was shifted toward very positive potentials. Substitution of Gln977 by a glutamate, the corresponding residue in divalent Cation-permeable TRPM Channels, altered the monovalent Cation permeability sequence and resulted in a pore with moderate Ca2+ permeability. Our findings delineate the selectivity filter of TRPM Channels and provide the first insight into the molecular basis of monovalent Cation selectivity.
Thomas Voets - One of the best experts on this subject based on the ideXlab platform.
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agonist induced changes in ca2 permeation through the nociceptor Cation Channel trpa1
Biophysical Journal, 2010Co-Authors: Yuji Karashima, Karel Talavera, Annelies Janssens, Jean Prenen, Thomas Voets, Bernd NiliusAbstract:The Ca2+-permeable Cation Channel TRPA1 acts as an ionotropic receptor for various pungent compounds and as a noxious cold sensor in sensory neurons. It is unclear what proportion of the TRPA1-mediated current is carried by Ca2+ ions and how the permeation pathway changes during stimulation. Here, based on the relative permeability of the nonstimulated Channel to Cations of different size, we estimated a pore diameter of ∼11 A. Combined patch-clamp and Fura-2 fluorescence recordings revealed that with 2 mM extracellular Ca2+, and at a membrane potential of −80 mV, ∼17% of the inward TRPA1 current is carried by Ca2+. Stimulation with mustard oil evoked an apparent dilatation of the pore of 3 A and an increase in divalent Cation selectivity and fractional Ca2+ current. Mutations in the putative pore that reduced the divalent permeability and fractional Ca2+ current also prevented mustard-oil-induced increases in Ca2+ permeation. It is interesting that fractional Ca2+ currents for wild-type and mutant TRPA1 were consistently higher than values predicted based on biionic reversal potentials using the Goldman-Hodgkin-Katz equation, suggesting that binding of Ca2+ in the pore hinders monovalent Cation permeation. We conclude that the pore of TRPA1 is dynamic and supports a surprisingly large Ca2+ influx.
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the ca2 activated Cation Channel trpm4 is regulated by phosphatidylinositol 4 5 biphosphate
The EMBO Journal, 2006Co-Authors: Bernd Nilius, Annelies Janssens, Rudi Vennekens, Jean Prenen, Grzegorz Owsianik, Frank Mahieu, Thomas VoetsAbstract:Transient receptor potential (TRP) Channel, melastatin subfamily (TRPM)4 is a Ca2+-activated monovalent Cation Channel that depolarizes the plasma membrane and thereby modulates Ca2+ influx through Ca2+-permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca2+ ([Ca2+]i). Here we show that phosphatidylinositol 4,5-biphosphate (PIP2) counteracts desensitization to [Ca2+]i in inside-out patches and rundown of TRPM4 currents in whole-cell patch-clamp experiments. PIP2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the Channel's Ca2+ sensitivity 100-fold. Conversely, activation of the phospholipase C (PLC)-coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP2 potently inhibited currents through TRPM4. Neutralization of basic residues in a C-terminal pleckstrin homology (PH) domain accelerated TRPM4 current desensitization and strongly attenuated the effect of PIP2, whereas mutations to the C-terminal TRP box and TRP domain had no effect on the PIP2 sensitivity. Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity.
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The Selectivity Filter of the Cation Channel TRPM4
The Journal of biological chemistry, 2005Co-Authors: Bernd Nilius, Annelies Janssens, Jean Prenen, Chunbo Wang, Grzegorz Owsianik, Michael X Zhu, Thomas VoetsAbstract:Abstract Transient receptor potential Channel melastatin subfamily (TRPM) 4 and its close homologue, TRPM5, are the only two members of the large transient receptor potential superfamily of Cation Channels that are impermeable to Ca2+. In this study, we located the TRPM4 selectivity filter and investigated possible structural elements that render it Ca2+-impermeable. Based on homology with known Cation Channel pores, we identified an acidic stretch of six amino acids in the loop between transmembrane helices TM5 and TM6 (981EDMDVA986) as a potential selectivity filter. Substitution of this six-amino acid stretch with the selectivity filter of TRPV6 (TIIDGP) resulted in a functional Channel that combined the gating hallmarks of TRPM4 (activation by Ca2+, voltage dependence) with TRPV6-like sensitivity to block by extracellular Ca2+ and Mg2+ as well as Ca2+ permeation. Neutralization of Glu981 resulted in a Channel with normal permeability properties but a strongly reduced sensitivity to block by intracellular spermine. Neutralization of Asp982 yielded a functional Channel that exhibited extremely fast desensitization (τ < 5 s), possibly indicating destabilization of the pore. Neutralization of Asp984 resulted in a non-functional Channel with a dominant negative phenotype when coexpressed with wild type TRPM4. Combined neutralization of all three acidic residues resulted in a functional Channel whose voltage dependence was shifted toward very positive potentials. Substitution of Gln977 by a glutamate, the corresponding residue in divalent Cation-permeable TRPM Channels, altered the monovalent Cation permeability sequence and resulted in a pore with moderate Ca2+ permeability. Our findings delineate the selectivity filter of TRPM Channels and provide the first insight into the molecular basis of monovalent Cation selectivity.
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regulation of the ca2 sensitivity of the nonselective Cation Channel trpm4
Journal of Biological Chemistry, 2005Co-Authors: Bernd Nilius, Annelies Janssens, Jean Prenen, Thomas Voets, Jisen Tang, Chunbo Wang, Grzegorz Owsianik, Michael X ZhuAbstract:Abstract TRPM4, a Ca2+-activated Cation Channel of the transient receptor potential superfamily, undergoes a fast desensitization to Ca2+. The mechanisms underlying the alterations in Ca2+ sensitivity are unknown. Here we show that cytoplasmic ATP reversed Ca2+ sensitivity after desensitization, whereas mutations to putative ATP binding sites resulted in faster and more complete desensitization. Phorbol ester-induced activation of protein kinase C (PKC) increased the Ca2+ sensitivity of wild-type TRPM4 but not of two mutants mutated at putative PKC phosphorylation sites. Overexpression of a calmodulin mutant unable to bind Ca2+ dramatically reduced TRPM4 activation. We identified five Ca2+-calmodulin binding sites in TRPM4 and showed that deletion of any of the three C-terminal sites strongly impaired current activation by reducing Ca2+ sensitivity and shifting the voltage dependence of activation to very positive potentials. Thus, the Ca2+ sensitivity of TRPM4 is regulated by ATP, PKC-dependent phosphorylation, and calmodulin binding at the C terminus.
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intracellular nucleotides and polyamines inhibit the ca2 activated Cation Channel trpm4b
Pflügers Archiv: European Journal of Physiology, 2004Co-Authors: Bernd Nilius, Jean Prenen, Thomas Voets, Guy DroogmansAbstract:TRPM4b (in contrast to the short splice variant TRPM4a) is a Ca2+-activated but Ca2+-impermeable Cation Channel. We have studied TRPM4 currents in inside-out patches. Supramicromolar Ca2+ concentrations applied at the inner side, [Ca2+]i, activated TRPM4 with an EC50 value of 0.37 mM, a value that is much higher than that of whole-cell currents. Current amplitudes decreased above 1 mM [Ca2+]i, (IC50 9.3 mM). Sr2+ but not Ba2+could partially substitute for Ca2+. ATP, ADP, AMP and AMP-PNP all quickly and reversibly inhibited TRPM4 with IC50 values between 2 and 19 μM (at +100 mV). Adenosine also blocked TRPM4 at 630 μM. The block at high ATP concentrations was incomplete and was not affected by the presence of free Mg2+. ADP induced the most sensitive block with an IC50 of 2.2 μM. For inhibition of TRPM4 by free ATP4−, an IC50 value of 1.7±0.3 μM was calculated. GTP, UTP and CTP at concentrations up to 1 mM did not induce a similar block. Spermine blocked TRPM4 currents with an IC50 of 61 μM. In conclusion, TRPM4 is a Channel that can be effectively modulated by intracellular nucleotides and polyamines.
Barry V L Potter - One of the best experts on this subject based on the ideXlab platform.
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synthesis of terminal ribose analogues of adenosine 5 diphosphate ribose as probes for the transient receptor potential Cation Channel trpm2
Journal of Organic Chemistry, 2019Co-Authors: Ondřej Baszczyňski, Joanna M Watt, Monika D Rozewitz, Andreas H Guse, Ralf Fliegert, Barry V L PotterAbstract:TRPM2 (transient receptor potential Cation Channel, subfamily M, member 2) is a nonselective Cation Channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9 H) domain activates the Channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail, we designed synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydroxyl group from the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1″-β- O-methyl-2″,3″- O-isopropylidene derivative was evaluated. Removal of either C1″ or C3″ hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifiCations and blocking all three hydroxyl groups resulted in TRPM2 antagonists. Our results demonstrate the critical role of these hydroxyl groups in Channel activation.
Youxing Jiang - One of the best experts on this subject based on the ideXlab platform.
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structures of the calcium activated non selective Cation Channel trpm4
Nature, 2017Co-Authors: Weizhong Zeng, Qingfeng Chen, Youxing JiangAbstract:Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective Cation Channel, in the apo and ATP-bound states.
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Structures of the calcium-activated, non-selective Cation Channel TRPM4
Nature, 2017Co-Authors: Jiangtao Guo, Weizhong Zeng, Qingfeng Chen, Ji She, Xiao-chen Bai, Youxing JiangAbstract:Melastatin-related transient receptor potential (TRPM) ion Channels are the largest group of the TRP superfamily and, as such, are widespread throughout the body with diverse physiological roles including heat and taste sensation and regulating ion homeostasis. For example, TRPM4 is a Ca^2+-activated non-selective Channel expressed in many of the central organs including the brain and heart, and is involved in the cardiac rhythm, breath pacemaking and insulin secretion. In this issue of Nature , two groups report the structure of TRPM4 by electron cryo-microscopy. Wei Lü and colleagues solved the structure of human TRPM4, which shows an umbrella-like structure, bound to Ca(ɪɪ) and decavanadate. Youxing Jiang and colleagues report the structure of mouse TRPM4 with and without ATP, which inhibits Channel activity. These studies provide the first structural insights into the TRPM family. Electron cryo-microscopy structures of mouse TRPM4, a calcium-activated, non-selective Cation Channel, in the apo and ATP-bound states. TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P_2) -modulated, non-selective Cation Channel that belongs to the family of melastatin-related transient receptor potential (TRPM) Channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 Channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the Channel; ATP binds at the nucleotide-binding domain and inhibits Channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent Cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1–S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca^2+- and PtdIns(4,5)P_2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.
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structures of the calcium activated non selective Cation Channel trpm4
Nature, 2017Co-Authors: Jiangtao Guo, Weizhong Zeng, Qingfeng Chen, Ji She, Xiao-chen Bai, Youxing JiangAbstract:TRPM4 is a calcium-activated, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) -modulated, non-selective Cation Channel that belongs to the family of melastatin-related transient receptor potential (TRPM) Channels. Here we present the electron cryo-microscopy structures of the mouse TRPM4 Channel with and without ATP. TRPM4 consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the Channel; ATP binds at the nucleotide-binding domain and inhibits Channel activity. TRPM4 has an exceptionally wide filter but is only permeable to monovalent Cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca2+- and PtdIns(4,5)P2-binding sites. These structures provide an essential starting point for elucidating the complex gating mechanisms of TRPM4 and reveal the molecular architecture of the TRPM family.
Rudi Vennekens - One of the best experts on this subject based on the ideXlab platform.
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increase in cytosolic ca2 produced by hypoxia and other depolarizing stimuli activates a non selective Cation Channel in chemoreceptor cells of rat carotid body
The Journal of Physiology, 2014Co-Authors: Rudi Vennekens, Dawon Kang, Jiaju Wang, James O Hogan, Marc Freichel, Carl WhiteAbstract:Key points Hypoxia is thought to depolarize glomus cells by inhibiting the outward K+ current, which sets in motion a cascade of ionic events that lead to transmitter secretion, increased afferent carotid sinus nerve activity and increased ventilation. Our study of Na+-permeable Channels in glomus cells has revealed that hypoxia not only inhibits TASK background K+ Channels but also indirectly activates a non-selective Cation Channel with a single Channel conductance of 20 pS. Under physiological conditions, the reversal potential of the Cation Channel is ∼ –28 mV, indicating that Na+ influx is also involved in hypoxia-induced excitation of glomus cells. Activation of the 20 pS Cation Channel is present when the O2 content is 5% or less, indicating that Na+ influx occurs during moderate to severe hypoxia ( 5% O2). The 20 pS Cation Channel is directly activated by a rise in intracellular Ca2+. Thus, factors that elevate intracellular Ca2+ such as hypoxia, extracellular acidosis and high external KCl all activate the Cation Channel. A feed-forward mechanism may be present in which an initial depolarization-induced rise in intracellular Ca2+ opens the Na+-permeable Cation Channel, and the Na+ influx causes additional depolarization and influx of Ca2+ into glomus cells. Abstract The current model of O2 sensing by carotid body chemoreceptor (glomus) cells is that hypoxia inhibits the outward K+ current and causes cell depolarization, Ca2+ influx via voltage-dependent Ca2+ Channels and a rise in intracellular [Ca2+] ([Ca2+]i). Here we show that hypoxia (<5% O2), in addition to inhibiting the two-pore domain K+ Channels TASK-1/3 (TASK), indirectly activates an ∼20 pS Channel in isolated glomus cells. The 20 pS Channel was permeable to K+, Na+ and Cs+ but not to Cl− or Ca2+. The 20 pS Channel was not sensitive to voltage. Inhibition of TASK by external acid, depolarization of glomus cells with high external KCl (20 mm) or opening of the Ca2+ Channel with FPL64176 activated the 20 pS Channel when 1 mm Ca2+ was present in the external solution. Ca2+ (10 μm) applied to the cytosolic side of inside-out patches activated the 20 pS Channel. The threshold [Ca2+]i for activation of the 20 pS Channel in cell-attached patches was ∼200 nm. The reversal potential of the 20 pS Channel was estimated to be −28 mV. Our results reveal a sequential mechanism in which hypoxia (<5% O2) first inhibits the K+ conductance and then activates a Na+-permeable, non-selective Cation Channel via depolarization-induced rise in [Ca2+]i. Our results suggest that inhibition of K+ efflux and stimulation of Na+ influx both contribute to the depolarization of glomus cells during moderate to severe hypoxia.
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TRPM4 Cation Channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis
Nature Medicine, 2012Co-Authors: Benjamin Schattling, Veit Flockerzi, Karin Steinbach, Edda Thies, Martin Kruse, Aurélie Menigoz, Friederike Ufer, Wolfgang Brück, Olaf Pongs, Rudi VennekensAbstract:Axonal and neuronal damage are commonly seen in patients with multiple sclerosis. Manuel A. Friese and his colleagues now report that the Cation Channel transient receptor potential melastatin 4 (TRPM4) is upregulated in multiple sclerosis lesions in patients and contributes to disease in vivo . Genetic deletion or pharmacological inhibition of TRPM4 in a mouse model of multiple sclerosis reduces clinical scores and is neuroprotective, suggesting this may represent a novel therapeutic target. In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) Cation Channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the antidiabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4 ^−/− mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro . Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.
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increased ige dependent mast cell activation and anaphylactic responses in mice lacking the calcium activated nonselective Cation Channel trpm4
Nature Immunology, 2007Co-Authors: Rudi Vennekens, Jenny Olausson, Marcel Meissner, Wilhelm Bloch, Ilka Mathar, Stephan E Philipp, Frank Schmitz, Petra Weissgerber, Bernd NiliusAbstract:Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective Cation Channel TRPM4
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the ca2 activated Cation Channel trpm4 is regulated by phosphatidylinositol 4 5 biphosphate
The EMBO Journal, 2006Co-Authors: Bernd Nilius, Annelies Janssens, Rudi Vennekens, Jean Prenen, Grzegorz Owsianik, Frank Mahieu, Thomas VoetsAbstract:Transient receptor potential (TRP) Channel, melastatin subfamily (TRPM)4 is a Ca2+-activated monovalent Cation Channel that depolarizes the plasma membrane and thereby modulates Ca2+ influx through Ca2+-permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca2+ ([Ca2+]i). Here we show that phosphatidylinositol 4,5-biphosphate (PIP2) counteracts desensitization to [Ca2+]i in inside-out patches and rundown of TRPM4 currents in whole-cell patch-clamp experiments. PIP2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the Channel's Ca2+ sensitivity 100-fold. Conversely, activation of the phospholipase C (PLC)-coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP2 potently inhibited currents through TRPM4. Neutralization of basic residues in a C-terminal pleckstrin homology (PH) domain accelerated TRPM4 current desensitization and strongly attenuated the effect of PIP2, whereas mutations to the C-terminal TRP box and TRP domain had no effect on the PIP2 sensitivity. Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity.
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voltage dependence of the ca2 activated Cation Channel trpm4
Journal of Biological Chemistry, 2003Co-Authors: Bernd Nilius, Rudi Vennekens, Ulrich Wissenbach, Marc Freichel, Jean Prenen, Guy Droogmans, Thomas Voets, Veit FlockerziAbstract:Abstract TRPM4 is a Ca2+-activated but Ca2+-impermeable Cation Channel. An increase of [Ca2+]i induces activation and subsequent reduction of currents through TRPM4 Channels. This inactivation is strikingly decreased in cell-free patches. In whole cell and cell-free configuration, currents through TRPM4 deactivate rapidly at negative potentials. At positive potentials, currents are much larger and activate slowly. This voltage-dependent behavior induces a striking outward rectifiCation of the steady state currents. The instantaneous current-voltage relationship, derived from the amplitude of tail currents following a prepulse to positive potentials, is linear. Currents show a Boltzmann type of activation; the fraction of open Channels increases at positive potentials and is low at negative potentials. Voltage dependence is not due to block by divalent Cations or to voltage-dependent binding of intracellular Ca2+ to an activator site, indicating that TRPM4 is a transient receptor potential Channel with an intrinsic voltage-sensing mechanism. Voltage dependence of TRPM4 may be functionally important, especially in excitable tissues generating plateau-like or bursting action potentials.