Acid-sensing (proton-gated) ion channels (ASICs)

Overview: Acid-sensing ion channels (ASICs, provisional nomenclature; see Wemmie et al., 2006; Lingueglia, 2007) 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 (Sakai et al., 1999) and INaC (Schaefer et al., 2000). ASIC subunits contain two putative TM domains and assemble as homo- or hetero-trimers (Jasti et al., 2007; Gonzales et al., 2009) to form proton-gated, voltage-insensitive, Na⁺-permeable, channels. Splice variants of ASIC1 [provisionally termed ASIC1a (ASIC, ASICα, BNaC2α) (Waldmann et al., 1997a), ASIC1b (ASICβ, BNaC2β) (Chen et al., 1998) and ASIC1b2 (ASICβ2) (Ugawa et al., 2001); note that ASIC1a is also permeable to Ca²⁺] and ASIC2 [provisionally termed ASIC2a (MDEG1, BNaC1α, BNC1a) (Price et al., 1996; Waldmann et al., 1996; Garcia-Anoveros et al., 1997) and ASIC2b (MDEG2, BNaC1β); (Lingueglia et al., 1997)] 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) (Waldmann et al., 1997b), 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 down-regulate the expression of ASIC1a and ASIC3 (Akopian et al., 2000; Grunder et al., 2000; Donier et al., 2008). 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), vascular smooth muscle cells (ASIC1–3), immune cells (ASIC1, −3 and −4) and bone (ASIC1–3). The activation of ASIC1a within the central nervous system contributes to neuronal injury caused by focal ischemia (Xiong et al., 2007) and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis (Friese et al., 2007). However, activation of ASIC1a can terminate seizures (Ziemann et al., 2008). Further proposed roles for centrally and peripherally located ASICs are reviewed in Wemmie et al. (2006) and Lingueglia (2007). The relationship of the cloned ASICs to endogenously expressed proton-gated ion channels is becoming established (Escoubas et al., 2000; Sutherland et al., 2001; Wemmie et al., 2002; 2003; 2006; Diochot et al., 2004; 2007; Lingueglia et al., 2006; Lingueglia 2007; Hattori et al., 2009). Heterologously expressed heteromultimers form ion channels with altered kinetics, ion selectivity, pH-sensitivity and sensitivity to blockers that resemble some of the native proton-activated currents recorded from neurones (Lingueglia et al., 1997; Babinski et al., 2000; Escoubas et al., 2000; Baron et al., 2008).

Nomenclature	ASIC1	ASIC2	ASIC3
Other names	ASIC; BNaC2	BNC1; BNaC1; MDEG	DRASIC, TNaC1
Ensembl ID	ENSG00000110881	ENSG00000108684	ENSG00000213199
Endogenous activators	Extracellular H+ (ASIC1a, pEC50∼ 6.2–6.8; ASIC1b, pEC50∼ 5.1–6.2)	Extracellular H+ (pEC50∼ 4.1–5.0)	Extracellular H+ (transient component pEC50∼ 6.2–6.7) (sustained component pEC50∼ 3.5–4.3)
Blockers (IC50)	ASIC1a: psalmotoxin 1 (PcTx1) (0.9 nM), Zn2+ (∼7 nM), A-317567 (∼2 µM), Pb2+ (∼4 µM), Ni2+ (∼0.6 mM), amiloride (10 µM), EIPA, benzamil (10 µM), ibuprofen/flurbiprofen (350 µM) ASIC1b: amiloride (21–23 µM), Pb2+ (∼1.5 µM)	Amiloride (28 µM), A-317567 (∼30 µM), Cd2+ (∼1 mM)	APETx2 (63 nM) (transient component only), amiloride (16–63 µM) (transient component only – sustained component enhanced by 200 µM amiloride at pH 4), A-317567 (∼10 µM), aspirin/diclofenac (92 µM – sustained component), salicylic acid (260 µM – sustained component), Gd3+ (40 µM)
Functional characteristics	ASIC1a: γ∼ 14 pS; PNa/PK= 5–13, PNa/PCa= 2.5; rapid activation rate (5.8–13.7 ms), rapid inactivation rate (1.2–4 s) at pH 6.0, slow recovery (5.3–13 s) at pH 7.4 ASIC1b: γ∼ 19 pS; PNa/PK= 14.0; PNa>>PCa; rapid activation rate (9.9 ms), rapid inactivation rate (0.9–1.7 s) at pH 6.0, slow recovery (4.4–7.7 s) at pH 7.4	γ∼ 10.4–13.4 pS; PNa/PK= 10, PNa/PCa= 20; rapid activation rate, moderate inactivation rate (3.3–5.5 s) at pH 5	γ∼ 13–15 pS; biphasic response consisting of rapidly inactivating transient and sustained components; very rapid activation (<5 ms) and inactivation (0.4 s); fast recovery (0.4–0.6 s) at pH 7.4, transient component partially inactivated at pH 7.2
Probes	[125I]-PcTx1 (ASIC1a KD= 213 pM)

Psalmotoxin 1 (PcTx1) inhibits ASIC1a by modifying activation and desensitization by H⁺, but promotes ASIC1b opening. PcTx1 has little effect upon ASIC2a, ASIC3 or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 (Escoubas et al., 2000; Diochot et al., 2007). Blockade of ASIC1a by PcTx1 activates the endogenous enkephalin pathway and has very potent analgesic effects in rodents (Mazzuca et al., 2007). 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 (Diochot et al., 2004; 2007). IC₅₀ values for A-317567 are inferred from blockade of ASIC channels native to dorsal root ganglion neurones (Dube et al., 2005). 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 by Lingueglia et al., 2006). 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 (Waldmann et al., 1997b; de Weille et al., 1998; Babinski et al., 1999). The transient and sustained current components mediated by rASIC3 are selective for Na⁺ (Waldmann et al., 1997b); for hASIC3 the transient component is Na⁺-selective (P_Na/P_K > 10) whereas the sustained current appears non-selective (P_Na/P_K= 1.6) (de Weille et al., 1998; Babinski et al., 1999). 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 (Andrey et al., 2005; Chu et al., 2006) whereas oxidation, through the formation of inter-subunit disulphide bonds, reduces currents mediated by ASIC1a (Zha et al., 2009). ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage (Vukicevic et al., 2006). Non-steroidal anti-inflammatory drugs are direct blockers of ASIC currents at therapeutic concentrations (reviewed by Voilley, 2004). Extracellular Zn²⁺ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels (Baron et al., 2001). However, removal of contaminating Zn²⁺ by chealation reveals a high-affinity block of homomeric ASIC1a and heteromeric ASIC1a + ASIC2 channels by Zn²⁺ indicating complex biphasic actions of the divalent (Chu et al., 2004). Nitric oxide potentiates submaximal currents activated by H⁺ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 (Cadiou et al., 2007). Ammonium activates ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia (Pidoplichko and Dani, 2006). 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 by Lingueglia et al. (2006). Inflammatory conditions and particular pro-inflammatory mediators induce overexpression of ASIC-encoding genes, enhance ASIC currents (Mamet et al., 2002), and in the case of arachidonic acid directly activate the channel (Smith et al., 2007; Deval et al., 2008). The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of arachidonic acid (Deval et al., 2008).

Glossary

Abbreviations:

A-317567

C-{6-[2-(1-Isopropyl-2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-cyclopropyl]-naphthalen-2-yl}-methanediamine

EIPA

ethylisopropylamiloride

FMRFamide

Phe-Met-Arg-Phe-amide

neuropeptide FF

Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-amide

neuropeptide SF

Ser-Leu-Ala-Pro-Gln-Arg-Phe-amide

Further Reading

Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M (2007). Peptides inhibitors of acid-sensing ion channels. Toxicon49: 271–284.

Dubé GR, Elagoz A, Mangat H (2009). Acid sensing ion channels and acid nociception. Curr Pharm Des15: 1750–1766.

Kress M, Waldmann R (2006) Acid sensing ionic channels. Curr Top Membr57: 241–276.

Krishtal O (2003). The ASICs: signaling molecules? Modulators? Trends Neurosci26: 477–483.

Lingueglia E (2007). Acid-sensing ion channels in sensory perception. J Biol Chem282: 17325–17329.

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. Peptides27: 1138–1152.

Reeh PW, Kress M (2001). Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol1: 45–51.

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 Allerg, 3: 71–79.

Waldmann R, Lazdunski M (1998). H⁺-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels Curr Opin Neurobiol8: 418–424.

Waldmann R (2001). Proton-gated cation channels-neuronal acid sensors in the central and peripheral nervous system. Adv Exp Med Biol502: 293–304.

Wemmie JA, Price MP, Welsh MJ (2006). Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci29: 578–586.

Xiong ZG, Chu XP, Simon RP (2007). Acid sensing ion channels – novel therapeutic targets for ischemic brain injury. Front Biosci12: 1376–1386.

Xiong ZG, Pignataro G, Li M, Chang SY, Simon RP (2008). Acid-sensing ion channels as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol8: 25–32.

Xu TL, Duan B (2009). Calcium-permeable acid-sensing ion channel in nociceptive plasticity: a new target for pain control. Prog Neurobiol87: 171–180.

Xu TL, Xiong ZG (2007). Dynamic regulation of acid-sensing ion channels by extracellular and intracellular modulators. Curr Med Chem14: 1753–1763.