Acid-sensing Ion Channels in Sensory Perception (2007)

Acid-activated currents blocked by amiloride have been reported for a long time in most neurons of the mammalian brain as well as in sensory neurons (1Krishtal O. Trends Neurosci. 2003; 26: 477-483Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar). A decade ago, Waldmann and colleagues (2Waldmann R. Champigny G. Bassilana F. Heurteaux C. Lazdunski M. Nature. 1997; 386: 173-177Crossref PubMed Scopus (1130) Google Scholar) were the first to clone the ion channels underlying these currents, which have been called acid-sensing ion channels (ASICs). 2The abbreviations used are: ASIC, acid-sensing ion channel; DRG, dorsal root ganglion; ENaC/DEG, epithelial amiloride-sensitive Na+ channels and degenerins; TRPV1, transient receptor potential vanilloid 1; CaMKII, calmodulin-dependent protein kinase II; NPAF, neuropeptide AF; NPFF, neuropeptide FF; NPSF, neuropeptide SF. 2The abbreviations used are: ASIC, acid-sensing ion channel; DRG, dorsal root ganglion; ENaC/DEG, epithelial amiloride-sensitive Na+ channels and degenerins; TRPV1, transient receptor potential vanilloid 1; CaMKII, calmodulin-dependent protein kinase II; NPAF, neuropeptide AF; NPFF, neuropeptide FF; NPSF, neuropeptide SF. ASICs are neuronal voltage-insensitive cationic channels activated by extracellular protons. They belong to the ENaC/DEG (epithelial amiloride-sensitive Na+ channel and degenerin) family of ion channels (3Kellenberger S. Schild L. Physiol. Rev. 2002; 82: 735-767Crossref PubMed Scopus (852) Google Scholar). ASICs share the same overall structure with other members of this family, which is characterized by two hydrophobic transmembrane regions flanking a large extracellular domain representing more than 50% of the protein and comprising many conserved cysteines (Fig. 1). Functional ASICs probably assemble as tetramers, as proposed for two other channels of the ENaC/DEG family, i.e. ENaC and FaNaC (the invertebrate FMRF-amide-activated Na+ channel). The ASIC family in mammals (ASICs have also been cloned from toadfish, lamprey, shark, and zebrafish) comprises four different genes encoding seven isoforms (4Wemmie J.A. Price M.P. Welsh M.J. Trends Neurosci. 2006; 29: 578-586Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 5Lingueglia E. Deval E. Lazdunski M. Peptides. 2006; 27: 1138-1152Crossref PubMed Scopus (83) Google Scholar) (Fig. 1). ASICs are widely expressed in neurons of both the central and the peripheral nervous system but have also been detected in non-neuronal tissues including testis (human ASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC3), and bone (ASIC1–3) (Table 1).TABLE IProperties of ASIC channels Open table in a new tab The only known activator of ASICs is extracellular proton. ASIC1b2 and ASIC2b are not activated by acidic pH on their own but are able to associate with other isoforms to modulate their properties (Table 1). ASIC4 has a particular status because it is not activated by proton and remains so far the least understood isoform. ASICs are voltage-independent, low conductance channels that mainly conduct Na+ (gNa ∼ 10–15 picosiemens). ASIC1a has the unique property among ASICs to be permeable to Ca2+ in its homomeric form, providing a novel pathway for Ca2+ entry into neurons. Extracellular Ca2+ also regulates these channels with a dual inhibitory and stimulatory effect. It has been proposed for ASIC3 that H+ ions would activate the channel by displacing Ca2+ from a high affinity binding site involved in the Ca2+ block and located on the extracellular side of the open pore (6Immke D.C. McCleskey E.W. Neuron. 2003; 37: 75-84Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). However, this model does not fully explain the activation of other ASICs by protons as shown for ASIC1a. The sensitivity to external protons, the activation and inactivation kinetics, and the pharmacology vary according to the ASIC subtypes and the subunit composition of the channel complex, with pH0.5 for activation ranging from 4.0 to 6.8 and activation thresholds as high as pH 7.2 (Table 1). Most ASICs are therefore activated by pH variations in the physiological range. Protons trigger a transient inward current that desensitizes rapidly (within seconds, Fig. 1). As a result, the properties of ASICs make these channels more suitable to sense dynamic pH fluctuations, but as discussed below they also have the capacity to respond to prolonged or slow acidification. Almost all ASIC isoforms are present in primary sensory neurons of the trigeminal, vagal, and dorsal root ganglia. ASIC1, ASIC2, and ASIC3 are significantly expressed in the small and medium nociceptive sensory neurons that are able to detect noxious chemical, thermal, and high threshold mechanical stimuli. ASIC2 and ASIC3 are also expressed in large neurons that mostly correspond to low threshold mechanoreceptors (see below). ASIC proteins have been detected in the soma and in the peripheral nerve endings of DRG neurons. The presence of certain ASICs (e.g. ASIC1a) on central projections in the dorsal horn of the spinal cord is less clear. Activation of ASICs by protons can depolarize the neurons and generate action potentials. A decrease in pH has been associated with non-adapting pain in human volunteers (7Steen K.H. Issberner U. Reeh P.W. Neurosci. Lett. 1995; 199: 29-32Crossref PubMed Scopus (104) Google Scholar), and the cutaneous acid-induced pain elicited by moderate pH (up to pH 6.0) appears to be largely mediated by ASICs (8Ugawa S. Ueda T. Ishida Y. Nishigaki M. Shibata Y. Shimada S. J. Clin. Invest. 2002; 110: 1185-1190Crossref PubMed Scopus (281) Google Scholar, 9Jones N.G. Slater R. Cadiou H. McNaughton P. McMahon S.B. J. Neurosci. 2004; 24: 10974-10979Crossref PubMed Scopus (205) Google Scholar). Pain associated with more acidic pH also involves the capsaicin receptor TRPV1, which participates in the DRG response to low range pH (below pH 6.0). ASICs have therefore been proposed to be involved in the perception of pain in conditions associated with tissue acidosis such as ischemia, inflammation, tumors, or lesions. All these situations are associated with prolonged acidification, raising the question of the activation of these channels by slow and/or prolonged acidosis. In fact, ASIC3-containing channels display in addition to the transient current a sustained component that does not inactivate while the pH remains acidic (Fig. 1). This sustained current involves different mechanisms depending on the extent of pH change. It results from the window of overlap between inactivation and activation of the transient current for small extracellular acidification (between pH 7.3 and 6.7) (10Yagi J. Wenk H.N. Naves L.A. McCleskey E.W. Circ. Res. 2006; 99: 501-509Crossref PubMed Scopus (194) Google Scholar) but seems to be independent of the peak current for more acidic pH. The fast reactivation of certain ASICs could also lead to their activation if oscillations of the extracellular pH occur (e.g. waves of acidification). ASIC3 thus appears as a good candidate for perception of non-adapting pain caused by acids and for modulation of nociceptive neuron excitability by low pH. In cardiac afferents, ASIC3 has been proposed to be the sensor of myocardial acidity that triggers angina during cardiac ischemia (11Sutherland S.P. Benson C.J. Adelman J.P. McCleskey E.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 711-716Crossref PubMed Scopus (328) Google Scholar). Interestingly, lactate and arachidonic acid, both released during ischemia, up-modulate ASIC1 and ASIC3. Data from the knock-out mouse support a role for ASIC3 but not ASIC1 in the sensing of tissue acidosis in muscle in models of secondary mechanical hyperalgesia induced by inflammation or by repeated acid injection into the muscle (12Sluka K.A. Price M.P. Breese N.M. Stucky C.L. Wemmie J.A. Welsh M.J. Pain. 2003; 106: 229-239Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar, 13Sluka K.A. Radhakrishnan R. Benson C.J. Eshcol J.O. Price M.P. Babinski K. Audette K.M. Yeomans D.C. Wilson S.P. Pain. 2007; 129: 102-112Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Chronic inflammation actually induces the expression of most ASICs at a transcriptional level (14Voilley N. Curr. Drug Targets Inflamm. Allergy. 2004; 3: 71-79Crossref PubMed Scopus (147) Google Scholar), and the ASIC3 current is potentiated by pro-inflammatory mediators such as serotonin, bradykinin, and arachidonic acid, suggesting a contribution of ASICs to the peripheral sensitization of nociceptors (Fig. 2). However, the available data obtained by gene inactivation and transgenic expression of a dominant-negative subunit in mice do not allow definite conclusions to be drawn concerning the precise roles of ASIC3 in acidic pain sensing and more generally in nociception (15Chen C.C. Zimmer A. Sun W.H. Hall J. Brownstein M.J. Zimmer A. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 8992-8997Crossref PubMed Scopus (260) Google Scholar, 16Price M.P. McIlwrath S.L. Xie J. Cheng C. Qiao J. Tarr D.E. Sluka K.A. Brennan T.J. Lewin G.R. Welsh M.J. Neuron. 2001; 32: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 17Mogil J.S. Breese N.M. Witty M.F. Ritchie J. Rainville M.L. Ase A. Abbadi N. Stucky C.L. Seguela P. J. Neurosci. 2005; 25: 9893-9901Crossref PubMed Scopus (109) Google Scholar). For instance, data in mice models suggest an increased sensitivity to some painful stimuli in the absence of ASIC3. It is interesting to note that the phenotypes observed might be influenced by specific local environments (e.g. expression of different ASIC-associated proteins), differences between the territories innervated (e.g. the ASIC3 protein is more expressed in muscle versus skin nociceptors in rat (18Molliver D.C. Immke D.C. Fierro L. Pare M. Rice F.L. McCleskey E.W. Mol. Pain. 2005; 1: 35Crossref PubMed Scopus (190) Google Scholar)), or species differences (e.g. the prevalence of ASIC-like currents is smaller in mouse versus rat skin nociceptors (19Leffler A. Monter B. Koltzenburg M. Neuroscience. 2006; 139: 699-709Crossref PubMed Scopus (105) Google Scholar)). A direct participation of central ASICs in pain processing could make the analysis even more complex. The expression of ASIC1a and ASIC2 in neurons of the spinal cord, where they are up-regulated by peripheral inflammation (20Wu L.J. Duan B. Mei Y.D. Gao J. Chen J.G. Zhuo M. Xu L. Wu M. Xu T.L. J. Biol. Chem. 2004; 279: 43716-43724Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar), may, for instance, contribute to the transmission and modulation of noxious information and participate in central sensitization associated with prolonged pain. Interestingly, this process shares significant similarities with hippocampal long term potentiation, which is impaired in ASIC1-inactivated mice (21Wemmie J.A. Chen J. Askwith C.C. Hruska-Hageman A.M. Price M.P. Nolan B.C. Yoder P.G. Lamani E. Hoshi T. Freeman Jr., J.H. Welsh M.J. Neuron. 2002; 34: 463-477Abstract Full Text Full Text PDF PubMed Scopus (549) Google Scholar). These mice also have defects in hippocampus-dependent spatial learning, cerebellum-dependent eye-blink conditioning, and amygdala-dependent fear conditioning (4Wemmie J.A. Price M.P. Welsh M.J. Trends Neurosci. 2006; 29: 578-586Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar). A large body of evidence suggests the presence of ASIC1a and probably ASIC2a in the synaptic membranes of central neurons (4Wemmie J.A. Price M.P. Welsh M.J. Trends Neurosci. 2006; 29: 578-586Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar). It has been proposed that synaptically released protons may activate ASICs (Fig. 2) although no direct evidence of a participation of these channels in synaptic transmission could be provided so far. This hypothesis is based on the low pH of synaptic vesicles and on the observation that exocytosed protons can modulate synaptic ion channels as shown for the presynaptic Ca2+ channel mediating vesicle release in the ribbon synapses of mammalian cone photoreceptors (22DeVries S.H. Neuron. 2001; 32: 1107-1117Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar). However, it remains to be established if the pH changes in the vicinity of synaptic cleft during chemical transmission in "classical" synapses are compatible with an activation of ASIC channels. Several members of the ENaC/DEG family of ion channels have been proposed to participate in mechanosensation, the most famous being the Caenorhabditis elegans degenerins (23Bounoutas A. Chalfie M. Pflugers Arch. 2007; DOI 10.1007/s00424-006-0187-xPubMed Google Scholar). ASIC2a and ASIC3 are expressed in mechanoreceptors, including specialized cutaneous mechanosensory structures like Meissner corpuscles, Merkel nerve endings, and palisades of lanceolate nerve endings surrounding the hair shaft (16Price M.P. McIlwrath S.L. Xie J. Cheng C. Qiao J. Tarr D.E. Sluka K.A. Brennan T.J. Lewin G.R. Welsh M.J. Neuron. 2001; 32: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 24Garcia-Anoveros J. Samad T.A. Zuvela-Jelaska L. Woolf C.J. Corey D.P. J. Neurosci. 2001; 21: 2678-2686Crossref PubMed Google Scholar, 25Price M.P. Lewin G.R. McIlwrath S.L. Cheng C. Xie J. Heppenstall P.A. Stucky C.L. Mannsfeldt A.G. Brennan T.J. Drummond H.A. Qiao J. Benson C.J. Tarr D.E. Hrstka R.F. Yang B. Williamson R.A. Welsh M.J. Nature. 2000; 407: 1007-1011Crossref PubMed Scopus (421) Google Scholar). Mice with targeted deletion of ASIC2 and ASIC3 were reported to display subtle alterations in both normal (ASIC2 and -3) and painful (ASIC3) cutaneous mechanical sensitivity (16Price M.P. McIlwrath S.L. Xie J. Cheng C. Qiao J. Tarr D.E. Sluka K.A. Brennan T.J. Lewin G.R. Welsh M.J. Neuron. 2001; 32: 1071-1083Abstract Full Text Full Text PDF PubMed Scopus (506) Google Scholar, 25Price M.P. Lewin G.R. McIlwrath S.L. Cheng C. Xie J. Heppenstall P.A. Stucky C.L. Mannsfeldt A.G. Brennan T.J. Drummond H.A. Qiao J. Benson C.J. Tarr D.E. Hrstka R.F. Yang B. Williamson R.A. Welsh M.J. Nature. 2000; 407: 1007-1011Crossref PubMed Scopus (421) Google Scholar), although knock-out mice for ASIC1 did not. Some sensory modalities are increased whereas other are decreased, depending on the type of mechanoreceptors and on the isoform of ASIC involved. ASIC1, ASIC2, and ASIC3 also contribute to visceral mechanosensation (26Page A.J. Brierley S.M. Martin C.M. Price M.P. Symonds E. Butler R. Wemmie J.A. Blackshaw L.A. Gut. 2005; 54: 1408-1415Crossref PubMed Scopus (235) Google Scholar, 27Jones III, R.C. Xu L. Gebhart G.F. J. Neurosci. 2005; 25: 10981-10989Crossref PubMed Scopus (362) Google Scholar), and the consequences of ASIC disruption are, in general, greater for visceral mechanoreceptor function than for cutaneous mechanoreceptors. ASIC1a contributes negatively in all classes of visceral afferents. Disruption of ASIC2 has a mixed effect whereas ASIC3 knockout mice have a markedly decreased mechanosensitivity in almost all classes of visceral afferents, indicating a clear positive effect (26Page A.J. Brierley S.M. Martin C.M. Price M.P. Symonds E. Butler R. Wemmie J.A. Blackshaw L.A. Gut. 2005; 54: 1408-1415Crossref PubMed Scopus (235) Google Scholar). Recently, a protein indispensable for the function of a subset of cutaneous mechanoreceptors in mouse, the stomatin-like protein 3 (SLP3), has been shown to associate in vitro with ASIC2a, ASIC2b, and ASIC3 and to inhibit the endogenous proton-gated currents in HEK-293 cells and in sensory neurons (28Wetzel C. Hu J. Riethmacher D. Benckendorff A. Harder L. Eilers A. Moshourab R. Kozlenkov A. Labuz D. Caspani O. Erdmann B. Machelska H. Heppenstall P.A. Lewin G.R. Nature. 2007; 445: 206-209Crossref PubMed Scopus (182) Google Scholar). All these data strongly suggest a participation of ASICs in mechanotransduction. However, a role as direct peripheral mechanoreceptors is not clear regarding the lack of evidence for mechanical gating of these channels (29Roza C. Puel J.L. Kress M. Baron A. Diochot S. Lazdunski M. Waldmann R. J. Physiol. (Lond.). 2004; 558: 659-669Crossref Scopus (104) Google Scholar, 30Drew L.J. Rohrer D.K. Price M.P. Blaver K.E. Cockayne D.A. Cesare P. Wood J.N. J. Physiol. (Lond.). 2004; 556: 691-710Crossref Scopus (215) Google Scholar). ASICs are expressed in rat and mouse taste receptor cells, and ASIC2 has been proposed to be a mammalian sour taste receptor (31Shimada S. Ueda T. Ishida Y. Yamamoto T. Ugawa S. Arch. Histol. Cytol. 2006; 69: 227-231Crossref PubMed Scopus (33) Google Scholar). However, taste cells from ASIC2 knock-out mice respond normally to acid stimuli (32Richter T.A. Dvoryanchikov G.A. Roper S.D. Chaudhari N. J. Neurosci. 2004; 24: 4088-4091Crossref PubMed Scopus (68) Google Scholar), and these mice show a normal behavioral response to acid taste stimuli. ASICs are therefore probably not acting as general mammalian sour receptors. Almost all ASICs have also been detected in rodent retina (33Lilley S. LeTissier P. Robbins J. J. Neurosci. 2004; 24: 1013-1022Crossref PubMed Scopus (63) Google Scholar, 34Ettaiche M. Guy N. Hofman P. Lazdunski M. Waldmann R. J. Neurosci. 2004; 24: 1005-1012Crossref PubMed Scopus (98) Google Scholar, 35Ettaiche M. Deval E. Cougnon M. Lazdunski M. Voilley N. J. Neurosci. 2006; 26: 5800-5809Crossref PubMed Scopus (69) Google Scholar, 36Brockway L.M. Zhou Z.H. Bubien J.K. Jovov B. Benos D.J. Keyser K.T. Am. J. Physiol. 2002; 283: C126-C134Crossref PubMed Scopus (76) Google Scholar). pH fluctuations play an important role in the retina, where acidic transients are involved in the fine-tuning of visual perception. ASIC2, which is present both in neurons and photoreceptors, is a negative modulator of rod phototransduction (34Ettaiche M. Guy N. Hofman P. Lazdunski M. Waldmann R. J. Neurosci. 2004; 24: 1005-1012Crossref PubMed Scopus (98) Google Scholar), whereas ASIC1a is a positive modulator of cone phototransduction and adaptation (35Ettaiche M. Deval E. Cougnon M. Lazdunski M. Voilley N. J. Neurosci. 2006; 26: 5800-5809Crossref PubMed Scopus (69) Google Scholar). Inactivation of the ASIC2 gene in mouse also sensitizes the retina toward light-induced degeneration (34Ettaiche M. Guy N. Hofman P. Lazdunski M. Waldmann R. J. Neurosci. 2004; 24: 1005-1012Crossref PubMed Scopus (98) Google Scholar). ASIC1, ASIC2, and ASIC3 are also expressed in the mouse inner ear (37Hildebrand M.S. de Silva M.G. Klockars T. Rose E. Price M. Smith R.J. McGuirt W.T. Christopoulos H. Petit C. Dahl H.H. Hear Res. 2004; 190: 149-160Crossref PubMed Scopus (62) Google Scholar, S. Chen S. Chen P. Price M.P. J. Neurosci. 2004; 24: PubMed Scopus Google Scholar). ASIC2 is mainly expressed in neurons in the ASIC2 knock-out mice show no significant (29Roza C. Puel J.L. Kress M. Baron A. Diochot S. Lazdunski M. Waldmann R. J. Physiol. (Lond.). 2004; 558: 659-669Crossref Scopus (104) Google Scholar, S. Chen S. Chen P. Price M.P. J. Neurosci. 2004; 24: PubMed Scopus Google Scholar), but ASIC2 contributes to S. Chen S. Chen P. Price M.P. J. Neurosci. 2004; 24: PubMed Scopus Google Scholar). ASIC3 knock-out mice have normal at of but in the range at (37Hildebrand M.S. de Silva M.G. Klockars T. Rose E. Price M. Smith R.J. McGuirt W.T. Christopoulos H. Petit C. Dahl H.H. Hear Res. 2004; 190: 149-160Crossref PubMed Scopus (62) Google Scholar). The of associated proteins to the the and the function of ASICs has in (Fig. 2). ASICs a binding at their for ASIC1, and and type for and with with with ASICs in the nervous system and with ASIC1 and ASIC2 A. J. Corey D.P. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. Wemmie J.A. Price M.P. Welsh M.J. J. 2002; PubMed Scopus Google Scholar). participates in the protein kinase of ASIC2a and ASIC3 its with the ASIC2b in vitro E. M. Baron A. E. Lazdunski M. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). N. Deval E. L. Lazdunski M. E. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar), E. C. M. M. Lazdunski M. E. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus (33) Google Scholar), and A.M. Benson C.J. Price M.P. Welsh M.J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar) associate with ASIC3 and modulate the current in expression by the proteins but or the expression of the channel important of its However, the effect of on the current probably a direct of the channel E. C. M. M. Lazdunski M. E. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Most of these proteins are present in DRG neurons and display some of with suggesting an in ASICs also to The is expressed in sensory neurons and brain and with the of ASIC1a to the expression of the channel its properties E. F. K. Wood J.N. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The protein is also expressed in sensory neurons and has been shown to associate with ASIC2a, and ASIC3 in vitro and to ASIC3 current and the of of the ASIC2a, and channels M.P. R.J. Eshcol J.O. Wemmie J.A. Benson C.J. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus (105) Google Scholar). As a protein indispensable for the function of a subset of cutaneous mechanoreceptors in mouse, in vitro with ASIC2a, ASIC2b, and ASIC3 (28Wetzel C. Hu J. Riethmacher D. Benckendorff A. Harder L. Eilers A. Moshourab R. Kozlenkov A. Labuz D. Caspani O. Erdmann B. Machelska H. Heppenstall P.A. Lewin G.R. Nature. 2007; 445: 206-209Crossref PubMed Scopus (182) Google Scholar). between and ASIC1a has been in which is by ischemia and to an of the ASIC1a current by J. Duan B. Xu L. Xu T.L. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). The activation of ASIC1a during the acidosis has been proposed to contribute to neuronal associated with brain ischemia M. J. Wemmie J.A. Price M.P. Welsh M.J. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). between ASIC3 and has also been in epithelial cells K. E. Chen L. Smith Benos D.J. S. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar), suggesting a between these channels. The physiological of most of these remains to be and lead to a of the currents for threshold by the peak and/or inactivation of ASIC1 and ASIC3 but not ASIC2a E. Deval E. Lazdunski M. Peptides. 2006; 27: 1138-1152Crossref PubMed Scopus (83) Google Scholar, C.C. Cheng C. M. Benson C. Price M.P. Welsh M.J. Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google Scholar). The effect seems to be direct on the ASIC3 is the to the response of DRG neurons J. Price M.P. Wemmie J.A. Askwith C.C. Welsh M.J. J. 2003; PubMed Scopus Google Scholar). is not present in but NPFF, NPAF, and are largely expressed in the central nervous system with a high level in the spinal cord where the expression is during has also been detected in small and DRG neurons. The modulation of ASICs by endogenous has therefore been proposed to play a role in the response to noxious acidosis. However, the modulation of ASICs addition at pH i.e. the channel is C.C. Cheng C. M. Benson C. Price M.P. Welsh M.J. Neuron. 2000; 26: Full Text Full Text PDF PubMed Scopus Google Scholar), raising these could ASICs in ASICs are blocked by amiloride and its and at A effect of amiloride has also been on the sustained component of ASIC3 (10Yagi J. Wenk H.N. Naves L.A. McCleskey E.W. Circ. Res. 2006; 99: 501-509Crossref PubMed Scopus (194) Google Scholar). ASICs are by of (14Voilley N. Curr. Drug Targets Inflamm. Allergy. 2004; 3: 71-79Crossref PubMed Scopus (147) Google Scholar). that and block ASICs in vitro and in have been S. M. Baron A. P. Lazdunski M. 2007; PubMed Scopus Google Scholar). The the ASIC1a homomeric channel whereas the homomeric ASIC3 as well as ASIC3-containing channels also with but does not inhibit the channel and its H. S. J. Physiol. 2006; PubMed Scopus Google Scholar). A small of ASIC currents between and on ASICs in DRG Interestingly, this has an effect in models of and pain G.R. Breese N.M. P. Pain. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), the positive role of ASICs in pain associated with these their a decade ago, ASICs have been shown to participate in a of different sensory Activation of ASIC3 in sensory neurons by the extracellular acidification induced in conditions such as ischemia, inflammation, tumors, or has been proposed to contribute to the of pain. TRPV1, important cationic channel in DRG is activated by pH and overlap of expression with ASIC3 among suggesting roles for these channels in nociception to acidosis. ASIC1 and ASIC2 may also contribute to pain processing in central neurons of the spinal cord, in a role at the The participation of ASICs in nociception probably more than and ASICs also participates in the mechanosensory but the remains largely ASICs on their own are not activated by mechanical but it has been based on available data for degenerins in C. that ASIC2 and ASIC3 could be able to mechanical the of or Interestingly, the contribution to might be independent of pH This the question of the of other stimuli than protons for these channels as ASIC4 for is not to pH. ASICs are present in the retina, taste cells, and inner They are important of the visual and have more subtle roles in taste and M. Lazdunski and A. E. J. M. and N. Voilley for support and and F. for with the