Acid-sensing ion channels in pain and disease

Key Points

  • Acid-sensing ion channels (ASICs) are permeable to Na+ (and other cations), activated by low extracellular pH and widely expressed in the CNS and the peripheral nervous system (PNS). ASICs are formed by homo- and heterotrimeric assemblies of subunits including ASIC1A, ASIC1B, ASIC2A, ASIC2B and ASIC3.

  • In the PNS, potential roles for ASICs in nociception and mechansensation have been investigated.

  • In the CNS, the ASIC1A subunit is largely required for acid-evoked currents and has been implicated in synaptic plasticity, mouse models of behaviour, neurodegenerative diseases, cancer and seizures.

  • ASICs are modulated by an increasing number of endogenous and exogenous compounds, including venoms from a tarantula, sea anemone and at least two snake species.

  • A few genetic studies have linked ASICs to human illnesses, but these associations need further confirmation.

  • ASICs are inhibited by amiloride at concentrations in the micromolar range. Amiloride has been used safely in humans as a diuretic and antihypertensive, and several small studies suggest that it might inhibit ASICs in humans to reduce pain, multiple sclerosis and migraine headache.

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.

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Figure 1: Structure and function of ASIC1A.
Figure 2: Roles for peripheral ASICs in pain.
Figure 3: ASIC1A expression in the mouse brain.
Figure 4: Contrasting roles of brain pH and ASICs in seizures and neurotoxicity.

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Acknowledgements

J.A.W. is supported by the Department of Veterans Affairs (Merit Award), the National Institutes of Mental Health (1R01MH085724 01) and a McKnight Neuroscience of Brain Disorders Award.

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Correspondence to John A. Wemmie.

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Glossary

Degenerin–epithelial Na+ channel family

(DEG–ENaC family). A family of ion channels that includes acid-sensing ion channels and is characterized by two transmembrane domains, a relatively large cysteine-rich extracellular domain and several highly conserved amino acid sequence motifs.

Nociception

Refers to detection of painful and injurious stimuli and translation into a neuronal signal.

Mechanosensation

Refers to detection of mechanical stimuli and translation into a neuronal signal.

Acidosis

A physiological state characterized by acidic pH (high H+ concentration).

Alkalosis

A physiological state characterized by basic pH (low H+ concentration).

Baroreceptors

Receptors that are sensitive to changes in blood pressure.

Long-term potentiation

A long-lasting, activity-dependent strengthening of synaptic transmission.

Postictal depression

The reduction in electroencephalographic activity that occurs immediately after a seizure.

Pentylenetetrazol

A GABA receptor antagonist used to elicit seizures.

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Wemmie, J., Taugher, R. & Kreple, C. Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 14, 461–471 (2013). https://doi.org/10.1038/nrn3529

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