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Acid-sensing (proton-gated) ion channels (ASICs) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Acid-sensing ion channels (ASICs, nomenclature as agreed by NC-IUPHAR [32]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF-amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and 'orphan' channels that include BLINaC [41] and INaC [42] that have also been named BASICs, for bile acid-activated ion channels [53]. ASIC subunits contain two TM domains and assemble as homo- or hetero-trimers [5,28,31] to form proton-gated, voltage-insensitive, Na+ permeable, channels (reviewed in [30,52]). Splice variants of ASIC1 [provisionally termed ASIC1a (ASIC, ASICα, BNaC2α) [50], ASIC1b (ASICβ, BNaC2β) [12] and ASIC1b2 (ASICβ2) [45]; note that ASIC1a is also permeable to Ca2+] and ASIC2 [provisionally termed ASIC2a (MDEG1, BNaC1α, BNC1α) [27,40,51] and ASIC2b (MDEG2, BNaC1β) [35]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+-gated currents. A third member, ASIC3 (DRASIC, TNaC1) [49], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton-gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 [1,22,29,34]. ASIC channels are primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC1-3), photoreceptors and retinal cells (ASIC1-3), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and -3), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1-3), immune cells (ASIC1,-3 and -4) and bone (ASIC1-3). A neurotransmitter-like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception [23,33,58], responses to focal ischemia [54] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [26], as well as seizures [59] and pain [10,17-18,20]. Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH- sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones [3,8,25,35].
Channels and Subunits
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ASIC1
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ASIC2
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ASIC3
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Further reading
* Key recommended reading is highlighted with an asterisk
* Baron A, Lingueglia E. (2015) Pharmacology of acid-sensing ion channels - Physiological and therapeutical perspectives. Neuropharmacology, 94: 19-35. [PMID:25613302]
* Boscardin E, Alijevic O, Hummler E, Frateschi S, Kellenberger S. (2016) The function and regulation of acid-sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br. J. Pharmacol., 173 (18): 2671-701. [PMID:27278329]
Chen X, Orser BA, MacDonald JF. (2010) Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders. Eur. J. Pharmacol., 648 (1-3): 15-23. [PMID:20854810]
Deval E, Gasull X, Noël J, Salinas M, Baron A, Diochot S, Lingueglia E. (2010) Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol. Ther., 128 (3): 549-58. [PMID:20807551]
Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M. (2007) Peptides inhibitors of acid-sensing ion channels. Toxicon, 49 (2): 271-84. [PMID:17113616]
Dubé GR, Elagoz A, Mangat H. (2009) Acid sensing ion channels and acid nociception. Curr. Pharm. Des., 15 (15): 1750-66. [PMID:19442188]
Gründer S, Chen X. (2010) Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int J Physiol Pathophysiol Pharmacol, 2 (2): 73-94. [PMID:21383888]
* Gründer S, Pusch M. (2015) Biophysical properties of acid-sensing ion channels (ASICs). Neuropharmacology, 94: 9-18. [PMID:25585135]
* Kellenberger S, Schild L. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol. Rev., 67 (1): 1-35. [PMID:25287517]
Kress M, Waldmann R. (2006) Acid Sensing Ionic Channels. In The Nociceptive Membrane Edited by Oh E (Elsevier) 241-276. [ISBN:9780121533571]
Krishtal O. (2003) The ASICs: signaling molecules? Modulators?. Trends Neurosci., 26 (9): 477-83. [PMID:12948658]
Lingueglia E. (2007) Acid-sensing ion channels in sensory perception. J. Biol. Chem., 282 (24): 17325-9. [PMID:17430882]
Lingueglia E, Deval E, Lazdunski M. (2006) FMRFamide-gated sodium channel and ASIC channels: a new class of ionotropic receptors for FMRFamide and related peptides. Peptides, 27 (5): 1138-52. [PMID:16516345]
Noël J, Salinas M, Baron A, Diochot S, Deval E, Lingueglia E. (2010) Current perspectives on acid-sensing ion channels: new advances and therapeutic implications. Expert Rev Clin Pharmacol, 3 (3): 331-46. [PMID:22111614]
* Osmakov DI, Andreev YA, Kozlov SA. (2014) Acid-sensing ion channels and their modulators. Biochemistry Mosc., 79 (13): 1528-45. [PMID:25749163]
Reeh PW, Kress M. (2001) Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol, 1 (1): 45-51. [PMID:11712534]
Sluka KA, Winter OC, Wemmie JA. (2009) Acid-sensing ion channels: A new target for pain and CNS diseases. Curr Opin Drug Discov Devel, 12 (5): 693-704. [PMID:19736627]
Voilley N. (2004) Acid-sensing ion channels (ASICs): new targets for the analgesic effects of non-steroid anti-inflammatory drugs (NSAIDs). Curr Drug Targets Inflamm Allergy, 3 (1): 71-9. [PMID:15032643]
Waldmann R. (2001) Proton-gated cation channels--neuronal acid sensors in the central and peripheral nervous system. Adv. Exp. Med. Biol., 502: 293-304. [PMID:11950145]
Waldmann R, Lazdunski M. (1998) H(+)-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol., 8 (3): 418-24. [PMID:9687356]
Wemmie JA, Price MP, Welsh MJ. (2006) Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci., 29 (10): 578-86. [PMID:16891000]
Xiong ZG, Chu XP, Simon RP. (2007) Acid sensing ion channels--novel therapeutic targets for ischemic brain injury. Front. Biosci., 12: 1376-86. [PMID:17127388]
Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP. (2008) Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol, 8 (1): 25-32. [PMID:17945532]
Xu TL, Duan B. (2009) Calcium-permeable acid-sensing ion channel in nociceptive plasticity: a new target for pain control. Prog. Neurobiol., 87 (3): 171-80. [PMID:19388206]
Xu TL, Xiong ZG. (2007) Dynamic regulation of acid-sensing ion channels by extracellular and intracellular modulators. Curr. Med. Chem., 14 (16): 1753-63. [PMID:17627513]
References
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15. Chu XP, Wemmie JA, Wang WZ, Zhu XM, Saugstad JA, Price MP, Simon RP, Xiong ZG. (2004) Subunit-dependent high-affinity zinc inhibition of acid-sensing ion channels. J. Neurosci., 24 (40): 8678-89. [PMID:15470133]
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20. Diochot S, Baron A, Salinas M, Douguet D, Scarzello S, Dabert-Gay AS, Debayle D, Friend V, Alloui A, Lazdunski M et al.. (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature, 490 (7421): 552-5. [PMID:23034652]
21. Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M. (2007) Peptides inhibitors of acid-sensing ion channels. Toxicon, 49 (2): 271-84. [PMID:17113616]
22. Donier E, Rugiero F, Jacob C, Wood JN. (2008) Regulation of ASIC activity by ASIC4--new insights into ASIC channel function revealed by a yeast two-hybrid assay. Eur. J. Neurosci., 28 (1): 74-86. [PMID:18662336]
23. Du J, Reznikov LR, Price MP, Zha XM, Lu Y, Moninger TO, Wemmie JA, Welsh MJ. (2014) Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc. Natl. Acad. Sci. U.S.A., 111 (24): 8961-6. [PMID:24889629]
24. Dubé GR, Lehto SG, Breese NM, Baker SJ, Wang X, Matulenko MA, Honoré P, Stewart AO, Moreland RB, Brioni JD. (2005) Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain, 117 (1-2): 88-96. [PMID:16061325]
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26. Friese MA, Craner MJ, Etzensperger R, Vergo S, Wemmie JA, Welsh MJ, Vincent A, Fugger L. (2007) Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nat. Med., 13 (12): 1483-9. [PMID:17994101]
27. García-Añoveros J, Derfler B, Neville-Golden J, Hyman BT, Corey DP. (1997) BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proc. Natl. Acad. Sci. U.S.A., 94 (4): 1459-64. [PMID:9037075]
28. Gonzales EB, Kawate T, Gouaux E. (2009) Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature, 460 (7255): 599-604. [PMID:19641589]
29. Gründer S, Geissler HS, Bässler EL, Ruppersberg JP. (2000) A new member of acid-sensing ion channels from pituitary gland. Neuroreport, 11 (8): 1607-11. [PMID:10852210]
30. Gründer S, Pusch M. (2015) Biophysical properties of acid-sensing ion channels (ASICs). Neuropharmacology, 94: 9-18. [PMID:25585135]
31. Jasti J, Furukawa H, Gonzales EB, Gouaux E. (2007) Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature, 449 (7160): 316-23. [PMID:17882215]
32. Kellenberger S, Schild L. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol. Rev., 67 (1): 1-35. [PMID:25287517]
33. Kreple CJ, Lu Y, Taugher RJ, Schwager-Gutman AL, Du J, Stump M, Wang Y, Ghobbeh A, Fan R, Cosme CV et al.. (2014) Acid-sensing ion channels contribute to synaptic transmission and inhibit cocaine-evoked plasticity. Nat. Neurosci., 17 (8): 1083-91. [PMID:24952644]
34. Lin SH, Chien YC, Chiang WW, Liu YZ, Lien CC, Chen CC. (2015) Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety. Eur. J. Neurosci., 41 (12): 1553-68. [PMID:25828470]
35. Lingueglia E, de Weille JR, Bassilana F, Heurteaux C, Sakai H, Waldmann R, Lazdunski M. (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J. Biol. Chem., 272 (47): 29778-83. [PMID:9368048]
36. Mamet J, Baron A, Lazdunski M, Voilley N. (2002) Proinflammatory mediators, stimulators of sensory neuron excitability via the expression of acid-sensing ion channels. J. Neurosci., 22 (24): 10662-70. [PMID:12486159]
37. Marra S, Ferru-Clément R, Breuil V, Delaunay A, Christin M, Friend V, Sebille S, Cognard C, Ferreira T, Roux C et al.. (2016) Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids. EMBO J., 35 (4): 414-28. [PMID:26772186]
38. Peigneur S, Béress L, Möller C, Marí F, Forssmann WG, Tytgat J. (2012) A natural point mutation changes both target selectivity and mechanism of action of sea anemone toxins. FASEB J., 26 (12): 5141-51. [PMID:22972919]
39. Pidoplichko VI, Dani JA. (2006) Acid-sensitive ionic channels in midbrain dopamine neurons are sensitive to ammonium, which may contribute to hyperammonemia damage. Proc. Natl. Acad. Sci. U.S.A., 103 (30): 11376-80. [PMID:16847263]
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43. Sherwood TW, Lee KG, Gormley MG, Askwith CC. (2011) Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J. Neurosci., 31 (26): 9723-34. [PMID:21715637]
44. Smith ES, Cadiou H, McNaughton PA. (2007) Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience, 145 (2): 686-98. [PMID:17258862]
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NC-IUPHAR subcommittee and family contributors
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Stephan Kellenberger
Laurent Schild |
How to cite this family page
Database page citation:
Stephan Kellenberger, Laurent Schild. Acid-sensing (proton-gated) ion channels (ASICs). Accessed on 24/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=118.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Peters JA, Kelly E, Marrion NV, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Ligand-gated ion channels. Br J Pharmacol. 174 Suppl 1: S130-S159.
Psalmotoxin 1 (PcTx1) inhibits ASIC1a by increasing the affinity to H+ and promoting channel desensitization [13,25]. PcTx1 has little effect on ASIC2a, ASIC3 or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 but does inhibit ASIC1a expressed as a heteromultimer with ASIC2b [43]. ASIC1-containing homo- and heteromers are inhibited by Mambalgins, toxins contained in the black mamba venom, which induce in ASIC1a an acidic shift of the pH dependence of activation [20]. APETx2 most potently blocks homomeric ASIC3 channels, but also ASIC2b+ASIC3, ASIC1b+ASIC3, and ASIC1a+ASIC3 heteromeric channels with IC50 values of 117 nM, 900 nM and 2 µM, respectively. APETx2 has no effect on ASIC1a, ASIC1b, ASIC2a, or ASIC2a+ASIC3 [19,21]. APETx2 inhibits however also voltage-gated Na+ channels [9,38]. IC50 values for A-317567 are inferred from blockade of ASIC channels native to dorsal root ganglion neurones [24]. The pEC50 values for proton activation of ASIC channels are influenced by numerous factors including extracellular di- and poly-valent ions, Zn2+, protein kinase C and serine proteases (reviewed in [32,52]). Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC50 values for H+-activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences [4,16,49]. The transient ASIC current component is Na+-selective (PNa/PK of about 10) [49,55] whereas the sustained current component that is observed with ASIC3 and some ASIC heteromers is non-selective between Na+ and K+ [16]. The reducing agents dithiothreitol (DTT) and glutathione (GSH) increase ASIC1a currents expressed in CHO cells and ASIC-like currents in sensory ganglia and central neurons [2,14] whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [57]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [48]. Non-steroidal anti-inflammatory drugs (NSAIDs) are direct inhibitors of ASIC currents (reviewed in [6]). Extracellular Zn2+ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [7]. However, removal of contaminating Zn2+ by chelation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a+ASIC2 channels by Zn2+ indicating complex biphasic actions of the divalent [15]. Nitric oxide potentiates submaximal currents activated by H+ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [11]. Ammonium ions activate ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia [39]. The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide FMRFamide and related substances, such as neuropeptides FF and SF, is reviewed in detail in [46]. Inflammatory conditions and particular pro-inflammatory mediators such as arachidonic acid induce overexpression of ASIC-encoding genes and enhance ASIC currents [18,36,44]. The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid [18]. ASIC3 is partially activated by the lipids lysophosphatidylcholine (LPC) and arachidonic acid [37]. Mit-Toxin, which is contained in the venom of the Texas coral snake, activates several ASIC subtypes [10]. Selective activation of ASIC3 by GMQ at a site separate from the proton binding site is potentiated by mild acidosis and reduced extracellular Ca2+ [56].