Acid-sensing ion channels in pain and disease

Why do neurons sense extracellular acid? In large part, this question has driven increasing investigation on acid-sensing ion channels (ASICs) in the CNS and the peripheral nervous system for the past two decades. Significant progress has been made in understanding the structure and function of ASICs at the molecular level. Studies aimed at clarifying their physiological importance have suggested roles for ASICs in pain, neurological and psychiatric disease. This Review highlights recent findings linking these channels to physiology and disease. In addition, it discusses some of the implications for therapy and points out questions that remain unanswered.

[1]  Xiaoxiang Zheng,et al.  Puerarin inhibits acid-sensing ion channels and protects against neuron death induced by acidosis. , 2010, Planta medica.

[2]  P M Pattany,et al.  Proton MR spectroscopy of the brain in 14 patients with Parkinson disease. , 1995, AJNR. American journal of neuroradiology.

[3]  Stefan Gründer,et al.  Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. , 2010, International journal of physiology, pathophysiology and pharmacology.

[4]  L. Fugger,et al.  Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system , 2007, Nature Medicine.

[5]  Yen-Chu Lin,et al.  Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons , 2010, Neuroscience Research.

[6]  D. Benos,et al.  Participation of the Chaperone Hsc70 in the Trafficking and Functional Expression of ASIC2 in Glioma Cells* , 2007, Journal of Biological Chemistry.

[7]  D. Benos,et al.  Knockdown of ASIC1 and Epithelial Sodium Channel Subunits Inhibits Glioblastoma Whole Cell Current and Cell Migration* , 2009, The Journal of Biological Chemistry.

[8]  August G. Wang,et al.  A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene , 2011, European Journal of Human Genetics.

[9]  M. Welsh,et al.  Oxidant regulated inter-subunit disulfide bond formation between ASIC1a subunits , 2009, Proceedings of the National Academy of Sciences.

[10]  H. Feng,et al.  Role of Acid-Sensing Ion Channel 1a in the Secondary Damage of Traumatic Spinal Cord Injury , 2011, Annals of surgery.

[11]  S. Gründer,et al.  Permeating protons contribute to tachyphylaxis of the acid‐sensing ion channel (ASIC) 1a , 2007, The Journal of physiology.

[12]  L. Bianchi.  Mechanotransduction: Touch and Feel at the Molecular Level as Modeled in Caenorhabditis elegans , 2007, Molecular Neurobiology.

[13]  J. Joyner,et al.  Identification of Protein Domains That Control Proton and Calcium Sensitivity of ASIC1a* , 2009, The Journal of Biological Chemistry.

[14]  E. J. van den Oord,et al.  Lack of association between the amiloride-sensitive cation channel 2 (ACCN2) gene and anxiety spectrum disorders , 2008, Psychiatric genetics.

[15]  E. Hall,et al.  Pathobiology of dynorphins in trauma and disease. , 2005, Frontiers in bioscience : a journal and virtual library.

[16]  Tian-Le Xu,et al.  Serotonin Facilitates Peripheral Pain Sensitivity in a Manner That Depends on the Nonproton Ligand Sensing Domain of ASIC3 Channel , 2013, The Journal of Neuroscience.

[17]  Miguel Salinas,et al.  Acid-sensing ion channels (ASICs): pharmacology and implication in pain. , 2010, Pharmacology & therapeutics.

[18]  P. Little,et al.  Ethylisopropylamiloride-sensitive pH control mechanisms modulate vascular smooth muscle cell growth. , 1991, The American journal of physiology.

[19]  A. M. Wunsch,et al.  Expressing acid-sensing ion channel 3 in the brain alters acid-evoked currents and impairs fear conditioning , 2011, Genes, brain, and behavior.

[20]  Yuan-hui Fu,et al.  ASIC1a polymorphism is associated with temporal lobe epilepsy , 2011, Epilepsy Research.

[21]  M. Lazdunski,et al.  A proton-gated cation channel involved in acid-sensing , 1997, Nature.

[22]  Tian-Le Xu,et al.  Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death , 2005, Neuron.

[23]  Fang Yu,et al.  A Nonproton Ligand Sensor in the Acid-Sensing Ion Channel , 2010, Neuron.

[24]  M. Welsh,et al.  Neuropeptide FF and FMRFamide Potentiate Acid-Evoked Currents from Sensory Neurons and Proton-Gated DEG/ENaC Channels , 2000, Neuron.

[25]  Mei-Yi Zhang,et al.  Amiloride is neuroprotective in an MPTP model of Parkinson's disease , 2008, Neurobiology of Disease.

[26]  P. McNaughton,et al.  Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action , 2007, Neuroscience.

[27]  M. Welsh,et al.  Neuroprotection in Ischemia Blocking Calcium-Permeable Acid-Sensing Ion Channels , 2004, Cell.

[28]  W. Pulsinelli,et al.  Dynamics of interstitial and intracellular pH in evolving brain infarct. , 1991, The American journal of physiology.

[29]  J. Wemmie,et al.  Acid-sensing ion channels: A new target for pain and CNS diseases. , 2009, Current opinion in drug discovery & development.

[30]  Jun-Hyeong Cho,et al.  Presynaptic release probability is increased in hippocampal neurons from ASIC1 knockout mice. , 2008, Journal of neurophysiology.

[31]  S. McMahon,et al.  Acid-Induced Pain and Its Modulation in Humans , 2004, The Journal of Neuroscience.

[32]  Matthew A. Howard,et al.  The Amygdala Is a Chemosensor that Detects Carbon Dioxide and Acidosis to Elicit Fear Behavior , 2009, Cell.

[33]  Tian-Le Xu,et al.  Neurobiology of Disease Extracellular Spermine Exacerbates Ischemic Neuronal Injury through Sensitization of Asic1a Channels to Extracellular Acidosis , 2022 .

[34]  J. Rosenbaum,et al.  Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions. , 2001, American journal of medical genetics.

[35]  Olga V. Demler,et al.  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. , 2005, Archives of general psychiatry.

[36]  Jodi L. McBride,et al.  Restoring Acid-Sensing Ion Channel-1a in the Amygdala of Knock-Out Mice Rescues Fear Memory But Not Unconditioned Fear Responses , 2008, The Journal of Neuroscience.

[37]  C. Askwith,et al.  Dynorphin Opioid Peptides Enhance Acid-Sensing Ion Channel 1a Activity and Acidosis-Induced Neuronal Death , 2009, The Journal of Neuroscience.

[38]  M. Lazdunski,et al.  The Acid-sensitive Ionic Channel Subunit ASIC and the Mammalian Degenerin MDEG Form a Heteromultimeric H+-gated Na+ Channel with Novel Properties* , 1997, The Journal of Biological Chemistry.

[39]  E. Mccleskey,et al.  Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons , 2001, Nature Neuroscience.

[40]  E. Mccleskey,et al.  Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. , 1999, Circulation research.

[41]  J. Wemmie,et al.  Acid‐sensing ion channel 1: A novel therapeutic target for migraine with aura , 2012, Annals of neurology.

[42]  A. Staruschenko,et al.  Subunit‐dependent cadmium and nickel inhibition of acid‐sensing ion channels , 2007, Developmental neurobiology.

[43]  M. Lazdunski,et al.  Protein Kinase C Stimulates the Acid-sensing Ion Channel ASIC2a via the PDZ Domain-containing Protein PICK1* , 2002, The Journal of Biological Chemistry.

[44]  M. Esiri,et al.  Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. , 2011, Brain : a journal of neurology.

[45]  M. Lazdunski,et al.  H+-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels , 1998, Current Opinion in Neurobiology.

[46]  George P Patrinos,et al.  Evidence for association of an ACCN1 gene variant with response to lithium treatment in Sardinian patients with bipolar disorder. , 2011, Pharmacogenomics.

[47]  R. R. Sonnenschein,et al.  PH of cerebral cortex during induced convulsions. , 1955, Journal of neurophysiology.

[48]  M. Lazdunski,et al.  The Mammalian Degenerin MDEG, an Amiloride-sensitive Cation Channel Activated by Mutations Causing Neurodegeneration in Caenorhabditis elegans(*) , 1996, The Journal of Biological Chemistry.

[49]  T. Brennan,et al.  The mammalian sodium channel BNC1 is required for normal touch sensation , 2000, Nature.

[50]  D. Benos,et al.  Acid-sensing Ion Channels in Malignant Gliomas* , 2003, The Journal of Biological Chemistry.

[51]  P. N’Gouemo,et al.  Amiloride delays the onset of pilocarpine-induced seizures in rats , 2008, Brain Research.

[52]  D. Vohora,et al.  Anticonvulsant effect of amiloride in pentetrazole-induced status epilepticus in mice. , 2006, Pharmacological reports : PR.

[53]  D. Benos,et al.  Glioma-specific Cation Conductance Regulates Migration and Cell Cycle Progression* , 2011, The Journal of Biological Chemistry.

[54]  C. M. Adams,et al.  Paradoxical Stimulation of a DEG/ENaC Channel by Amiloride* , 1999, The Journal of Biological Chemistry.

[55]  Sampsa Vanhatalo,et al.  Five percent CO2 is a potent, fast‐acting inhalation anticonvulsant , 2011, Epilepsia.

[56]  Z. Xiong,et al.  Physiological and pathological functions of acid-sensing ion channels in the central nervous system. , 2012, Current drug targets.

[57]  F. Porreca,et al.  Dural afferents express acid-sensing ion channels: A role for decreased meningeal pH in migraine headache , 2011, PAIN®.

[58]  R. Fitzsimonds,et al.  Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system , 2003, The Journal of physiology.

[59]  M. Lazdunski,et al.  Nonsteroid Anti-Inflammatory Drugs Inhibit Both the Activity and the Inflammation-Induced Expression of Acid-Sensing Ion Channels in Nociceptors , 2001, The Journal of Neuroscience.

[60]  D. Geschwind,et al.  High density SNP association study of a major autism linkage region on chromosome 17. , 2007, Human molecular genetics.

[61]  K. Essin,et al.  Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons , 2002, Neuroscience.

[62]  G. Jenkins,et al.  A Genomewide Association Study of Citalopram Response in Major Depressive Disorder , 2010, Biological Psychiatry.

[63]  Eric Gouaux,et al.  Pore architecture and ion sites in acid sensing ion channels and P2X receptors , 2009, Nature.

[64]  J. Wemmie.  Neurobiology of panic and pH chemosensation in the brain , 2011, Dialogues in clinical neuroscience.

[65]  Michael D. Ehlers,et al.  Structural and functional organization of the synapse , 2008 .

[66]  Douglas R. Langbehn,et al.  Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior , 2009, The Journal of Neuroscience.

[67]  D. Gruol,et al.  Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons , 1980, Brain Research.

[68]  F. Abboud,et al.  The Ion Channel ASIC2 Is Required for Baroreceptor and Autonomic Control of the Circulation , 2009, Neuron.

[69]  M. Avoli,et al.  Regional and Subunit-Specific Downregulation of Acid-Sensing Ion Channels in the Pilocarpine Model of Epilepsy , 2001, Neurobiology of Disease.

[70]  P. Ahring,et al.  pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits* , 2004, Journal of Biological Chemistry.

[71]  X. Gasull,et al.  Human ASIC3 channel dynamically adapts its activity to sense the extracellular pH in both acidic and alkaline directions , 2012, Proceedings of the National Academy of Sciences.

[72]  Tian-Le Xu,et al.  ASIC3 Channels Integrate Agmatine and Multiple Inflammatory Signals through the Nonproton Ligand Sensing Domain , 2010, Molecular pain.

[73]  F. Abboud,et al.  Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  M. Lazdunski,et al.  Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing , 2004, The Journal of physiology.

[75]  Eric Gouaux,et al.  Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. , 2007, Nature.

[76]  Tian-Le Xu,et al.  Upregulation of Acid-Sensing Ion Channel ASIC1a in Spinal Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity , 2007, The Journal of Neuroscience.

[77]  J. Anineneville-Golden.  BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels , 1997 .

[78]  Xiang-ming Zha.  Acid-sensing ion channels: trafficking and synaptic function , 2013, Molecular Brain.

[79]  Tian-Le Xu,et al.  Calcium-permeable Acid-sensing Ion Channel Is a Molecular Target of the Neurotoxic Metal Ion Lead* , 2006, Journal of Biological Chemistry.

[80]  A. Burlingame,et al.  A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain , 2011, Nature.

[81]  M. Lazdunski,et al.  ASIC3, a sensor of acidic and primary inflammatory pain , 2008, The EMBO journal.

[82]  R. Simon,et al.  Modulation of Acid-sensing Ion Channel Currents, Acid-induced Increase of Intracellular Ca2+, and Acidosis-mediated Neuronal Injury by Intracellular pH* , 2006, Journal of Biological Chemistry.

[83]  Tian-Le Xu,et al.  Molecular Mechanism of Constitutive Endocytosis of Acid-Sensing Ion Channel 1a and Its Protective Function in Acidosis-Induced Neuronal Death , 2013, The Journal of Neuroscience.

[84]  M. Welsh,et al.  Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[85]  D. Benos,et al.  Amiloride Docking to Acid-sensing Ion Channel-1* , 2010, The Journal of Biological Chemistry.

[86]  M. Welsh,et al.  Cloning and Expression of a Novel Human Brain Na Channel (*) , 1996, The Journal of Biological Chemistry.

[87]  C. Askwith,et al.  Structure and activity of the acid-sensing ion channels. , 2012, American journal of physiology. Cell physiology.

[88]  John A. Wemmie,et al.  Acid-Sensing Ion Channel 1 Is Localized in Brain Regions with High Synaptic Density and Contributes to Fear Conditioning , 2003, The Journal of Neuroscience.

[89]  M. Lazdunski,et al.  A Modulatory Subunit of Acid Sensing Ion Channels in Brain and Dorsal Root Ganglion Cells* , 1997, The Journal of Biological Chemistry.

[90]  Su-Youne Chang,et al.  Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. , 2008, Current opinion in pharmacology.

[91]  M. Lazdunski,et al.  Asic3 is a neuronal mechanosensor for pressure-induced vasodilation that protects against pressure ulcers , 2012, Nature Medicine.

[92]  Alain Lecoq,et al.  Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels* , 2000, The Journal of Biological Chemistry.

[93]  M. Howard,et al.  Seizure termination by acidosis depends on ASIC1a , 2008, Nature Neuroscience.

[94]  J. A. Dani,et al.  Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[95]  J. Wemmie,et al.  ASIC1 and ASIC3 play different roles in the development of Hyperalgesia after inflammatory muscle injury. , 2010, Journal of Pain.

[96]  T. Brennan,et al.  Simultaneous Disruption of Mouse ASIC1a, ASIC2 and ASIC3 Genes Enhances Cutaneous Mechanosensitivity , 2012, PloS one.

[97]  Yen-Chu Lin,et al.  Acid-Sensing Ion Channel-1a Is Not Required for Normal Hippocampal LTP and Spatial Memory , 2013, Journal of Neuroscience.

[98]  M. Welsh,et al.  ASIC2 Subunits Target Acid-Sensing Ion Channels to the Synapse via an Association with PSD-95 , 2009, The Journal of Neuroscience.

[99]  Elaine Holmes,et al.  Metabolic characterization of the R6/2 transgenic mouse model of Huntington's disease by high-resolution MAS 1H NMR spectroscopy. , 2006, Journal of proteome research.

[100]  D. Cox,et al.  Association between the ACCN1 Gene and Multiple Sclerosis in Central East Sardinia , 2007, PloS one.

[101]  B R Rosen,et al.  1H NMR spectroscopy studies of Huntington's disease , 1998, Neurology.

[102]  S. Shimada,et al.  Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. , 2002, The Journal of clinical investigation.

[103]  O. Krishtal,et al.  A receptor for protons in the nerve cell membrane , 1980, Neuroscience.

[104]  Tian-Le Xu,et al.  PI3-kinase/Akt Pathway-Regulated Membrane Insertion of Acid-Sensing Ion Channel 1a Underlies BDNF-Induced Pain Hypersensitivity , 2012, The Journal of Neuroscience.

[105]  H. Kalbacher,et al.  The Tarantula Toxin Psalmotoxin 1 Inhibits Acid-sensing Ion Channel (ASIC) 1a by Increasing Its Apparent H+ Affinity , 2005, The Journal of general physiology.

[106]  P. Séguéla,et al.  Mammalian ASIC2a and ASIC3 Subunits Co-assemble into Heteromeric Proton-gated Channels Sensitive to Gd3+ * , 2000, The Journal of Biological Chemistry.

[107]  S. Kellenberger,et al.  Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons. , 2004, American journal of physiology. Cell physiology.

[108]  C. Papasian,et al.  Modulation of acid-sensing ion channels: molecular mechanisms and therapeutic potential. , 2011, International journal of physiology, pathophysiology and pharmacology.

[109]  M. Welsh,et al.  Acid-Sensing Ion Channels (ASICs) and pH in Synapse Physiology , 2008 .

[110]  Penny A. MacDonald,et al.  Parkin-mediated monoubiquitination of the PDZ protein PICK1 regulates the activity of acid-sensing ion channels. , 2007, Molecular biology of the cell.

[111]  S. Gründer,et al.  Alternative Splicing and Interaction with Di- and Polyvalent Cations Control the Dynamic Range of Acid-sensing Ion Channel 1 (ASIC1)* , 2002, The Journal of Biological Chemistry.

[112]  Y. Yu,et al.  Modulation of acid-sensing ion channels by Cu2+ in cultured hypothalamic neurons of the rat , 2007, Neuroscience.

[113]  Hye-Young Heo,et al.  Detecting activity-evoked pH changes in human brain , 2012, Proceedings of the National Academy of Sciences.

[114]  T. Brennan,et al.  The ion channel ASIC1 contributes to visceral but not cutaneous mechanoreceptor function. , 2004, Gastroenterology.

[115]  Linfu Zhou,et al.  Ginsenoside-Rd attenuates TRPM7 and ASIC1a but promotes ASIC2a expression in rats after focal cerebral ischemia , 2012, Neurological Sciences.

[116]  John A Wemmie,et al.  Overexpression of acid-sensing ion channel 1a in transgenic mice increases acquired fear-related behavior. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[117]  S. McMahon,et al.  Modulation of Acid-Sensing Ion Channel Activity by Nitric Oxide , 2007, The Journal of Neuroscience.

[118]  R. Dempsey,et al.  Blockade of Ornithine Decarboxylase Enzyme Protects against Ischemic Brain Damage , 1994, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[119]  G. Dubé,et al.  Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels , 2005, Pain.

[120]  M. Min,et al.  Mice lacking Asic3 show reduced anxiety‐like behavior on the elevated plus maze and reduced aggression , 2010, Genes, brain, and behavior.

[121]  M. Brownstein,et al.  A role for ASIC3 in the modulation of high-intensity pain stimuli , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[122]  J. Sheu,et al.  Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats , 2009, Journal of Biomedical Science.

[123]  D. Benos,et al.  Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1. , 2004, American journal of physiology. Cell physiology.

[124]  A. Eschalier,et al.  A tarantula peptide against pain via ASIC1a channels and opioid mechanisms , 2007, Nature Neuroscience.

[125]  D. Zorov,et al.  Role of acidosis, NMDA receptors, and acid-sensitive ion channel 1a (ASIC1a) in neuronal death induced by ischemia , 2008, Biochemistry (Moscow).

[126]  Tian-Le Xu,et al.  Proton production, regulation and pathophysiological roles in the mammalian brain , 2012, Neuroscience Bulletin.

[127]  D. Benos,et al.  Surface Expression of ASIC2 Inhibits the Amiloride-sensitive Current and Migration of Glioma Cells* , 2006, Journal of Biological Chemistry.

[128]  M. Zhuo,et al.  Characterization of Acid-sensing Ion Channels in Dorsal Horn Neurons of Rat Spinal Cord* , 2004, Journal of Biological Chemistry.

[129]  M. Lazdunski,et al.  A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid‐sensitive channel in sensory neurons , 2004, The EMBO journal.

[130]  K. Sawicka,et al.  Amiloride enhances the anticonvulsant action of various antiepileptic drugs in the mouse maximal electroshock seizure model , 2008, Journal of Neural Transmission.

[131]  John A. Wemmie,et al.  The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory , 2002, Neuron.

[132]  M. Welsh,et al.  Acid-sensing Ion Channel 2 (ASIC2) Modulates ASIC1 H+-activated Currents in Hippocampal Neurons* , 2004, Journal of Biological Chemistry.

[133]  R. Simon,et al.  Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. , 2006, Brain : a journal of neurology.

[134]  Miao Yi-feng,et al.  Neuroprotective effect of sophocarpine against transient focal cerebral ischemia via down-regulation of the acid-sensing ion channel 1 in rats , 2011, Brain Research.

[135]  C. Askwith,et al.  Heteromeric Acid-Sensing Ion Channels (ASICs) Composed of ASIC2b and ASIC1a Display Novel Channel Properties and Contribute to Acidosis-Induced Neuronal Death , 2011, The Journal of Neuroscience.

[136]  M. Rudolph,et al.  Structure of the Acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1 , 2012, Nature Communications.

[137]  D. Attwell,et al.  Modulation of ASIC channels in rat cerebellar purkinje neurons by ischaemia‐related signals , 2002, The Journal of physiology.

[138]  T. Knöpfel,et al.  Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. , 2008, Human molecular genetics.

[139]  M. Jenkinson,et al.  Targeting ASIC1 in primary progressive multiple sclerosis: evidence of neuroprotection with amiloride. , 2013, Brain : a journal of neurology.

[140]  Michelle K. Knowles,et al.  Sensing Muscle Ischemia: Coincident Detection of Acid and ATP via Interplay of Two Ion Channels , 2010, Neuron.

[141]  M. Welsh,et al.  Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines , 2006, Proceedings of the National Academy of Sciences.

[142]  J. Wemmie,et al.  Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels , 2004, The Journal of Neuroscience.

[143]  S. Shimada,et al.  Nafamostat mesilate reversibly blocks acid-sensing ion channel currents. , 2007, Biochemical and biophysical research communications.

[144]  S. Gründer,et al.  Identification of the Ca 2 (cid:1) Blocking Site of Acid-sensing Ion Channel (ASIC) 1: Implications for Channel Gating , 2004 .

[145]  John A. Wemmie,et al.  Targeting ASIC1a Reduces Innate Fear and Alters Neuronal Activity in the Fear Circuit , 2007, Biological Psychiatry.

[146]  John A. Wemmie,et al.  Acid-sensing ion channels: advances, questions and therapeutic opportunities , 2006, Trends in Neurosciences.