Acid-sensing ion channels in pain and disease

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


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.

At a glance


  1. Structure and function of ASIC1A.
    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)30. 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. 17 for recent review).

  2. Roles for peripheral ASICs in pain.
    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 disruption62. 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 channels67. 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 disruption113. 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.

  3. ASIC1A expression in the mouse brain.
    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)21, 102. 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).

  4. Contrasting roles of brain pH and ASICs in seizures and neurotoxicity.
    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 neurons52, 95, 96. 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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Author information

  1. These authors contributed equally to this work.

    • Rebecca J. Taugher &
    • Collin J. Kreple


  1. Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

    • John A. Wemmie
  2. Neurosurgery, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

    • John A. Wemmie
  3. Graduate Program in Neuroscience, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

    • John A. Wemmie &
    • Rebecca J. Taugher
  4. Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

    • John A. Wemmie &
    • Collin J. Kreple
  5. Department of Veterans Affairs Medical Center, Iowa City, Iowa 52242, USA.

    • John A. Wemmie

Competing interests statement

The authors declare no competing interests.

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Author details

  • John A. Wemmie

    John A. Wemmie is a physician scientist at the University of Iowa, Iowa City, USA, and Iowa City Veterans Administration Hospital, USA. He completed his residency in psychiatry at the University of Iowa Hospitals and Clinics. He completed his doctoral training with Scott Moye-Rowley, investigating the molecular mechanisms of pleiotropic drug resistance in Saccharomyces cerevisiae. He completed his postdoctoral training with Michael Welsh, investigating the role of acid-sensing ion channels in mouse brain function.

  • Rebecca J. Taugher

    Rebecca J. Taugher is a fifth year student in the Neuroscience Graduate Program at the University of Iowa, Iowa City, USA. She is interested in molecular and behavioural neuroscience. Upon the completion of her Ph.D., she plans to pursue a postdoctoral fellowship and a career in research.

  • Collin J. Kreple

    Collin J. Kreple is a fifth year student in the Medical Scientist Training Program (M.D./Ph.D.) at the University of Iowa, Iowa City, USA. He is interested in molecular physiology and neuroscience. Following his M.D./Ph.D. training, he plans to complete a medical residency and postdoctoral fellowship with the intention of pursuing a career in academic medicine.

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