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Review
. 2013 Jul;14(7):461-71.
doi: 10.1038/nrn3529.

Acid-sensing Ion Channels in Pain and Disease

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Free PMC article
Review

Acid-sensing Ion Channels in Pain and Disease

John A Wemmie et al. Nat Rev Neurosci. .
Free PMC article

Abstract

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.

Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. Structure and function of ASIC1A
a| The crystal structure of the chicken acid-sensing ion channel 1 (ASIC1) indicates that three subunits combine into a trimeric channel complex (different colours represent distinct ASIC1 subunits) b| Whole-cell voltage-clamp recordings from neurons in acute amygdala slices showing an absence of pH 5.6-evoked current in neurons lacking ASIC1A. c | ASICs are activated by extracellular protons (H+) and possibly other yet-to-be identified ligands, and are modulated by a number of other factors (TABLE 2). ASIC1A, schematized here, is permeable to cations, primarily Na+ and to a lesser degree Ca2+. Upon activation, an inward current depolarizes the cell membrane, which activates voltage-gated Ca2+ channels (VGCCs) and voltage-gated Na+ channels (VGSCs) and may contribute to NMDA receptor (NMDAR) activation through the release of the voltage-dependent Mg2+ blockade. Thus, Na+ and Ca2+ influx contributes to membrane depolarization, the generation of dendritic spikes and action potentials, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and possibly influence other second-messenger pathways. In addition, a number of intracellular proteins have been suggested to regulate ASICs (see REF. for recent review).
Figure 2
Figure 2. Roles for peripheral ASICs in pain
Recent studies have taken advantage of acid-sensing ion channel (ASIC) agonists (2-guanidine-4-methylquinazoline (GMQ) and MitTx) and an antagonist (mambalgin-1) to clarify the roles of ASICs in pain. When injected into the mouse paw, the synthetic compound GMQ, which activates ASIC3, induced pain behaviours that were absent in ASIC3-knockout mice. These behaviours were not affected by ASIC1A disruption. The Texas coral snake toxin, MitTx, evoked pain-related licking behaviour that depended on ASIC1A and, to a lesser degree, ASIC3 (REF. 48). ASIC1B was also activated by MitTx (dashed line), but its role in MitTx-evoked pain was not investigated. Mambalgin-1, a toxin from black mamba venom, blocked several combinations of ASIC subunits, and when it was injected into the mouse paw, it inhibited flick latency to heat through ASIC1B-containing channels. In addition, another recent study indicated a role for the inflammatory mediator serotonin. Serotonin increased acid-evoked currents through ASIC3 and increased acid-evoked pain-behaviour in the mouse paw, which was attenuated by ASIC3 disruption. A number of other inflammatory mediators have been suggested to modulate ASICs in pain, including arachidonic acid (AA), nitric oxide (NO), ATP and lactate (TABLE 2). DRG, dorsal root ganglion.
Figure 3
Figure 3. ASIC1A expression in the mouse brain
Acid-sensing ion channel 1A (ASIC1A) is widely expressed in the mouse brain and is enriched in the amygdala (Amyg), bed nucleus of the stria terminalis (BNST), periaqueductal grey (PAG), nucleus accumbens (NAc), caudate putamen (CPu), habenula (Hb), olfactory bulb (OB), cerebral cortex layer 2/3 (L2/3) and molecular layer of the cerebellum (Cb),. ASIC1A localization in these brain regions has driven hypotheses about the behavioural roles of ASICs. At the subcellular level, ASIC1A has been detected in postsynaptic dendritic spines (inset), where, in one model, channel activation is caused by protons (H+) coming from acidic neurotransmitter-containing vesicles. Other pH changes, which are due to metabolism or disease, might also activate ASICs in the CNS. In addition, recent studies have highlighted the possibility that various endogenous factors, including neuropeptides and polyamines, modulate and/or activate ASICs (TABLE 2).
Figure 4
Figure 4. Contrasting roles of brain pH and ASICs in seizures and neurotoxicity
Reduced brain pH can be protective or damaging. a | The ability of acidosis to inhibit seizures is thought to be acid-sensing ion channel 1A (ASIC1A)-mediated, possibly owing to abundant ASIC1A expression in GABAergic neurons,,. b | Accumulating evidence suggests that acidosis potentiates cell death, which contributes to ischaemic stroke and neurodegenerative disease and that this depends on ASIC1A. Other factors, such as oxygen and glucose depletion, inflammation and other modulators are likely to play important parts in these processes.

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