Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2013 Jun;46(6):295-304.
doi: 10.5483/bmbrep.2013.46.6.121.

Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

Hae-Jin Kweon  1 , Byung-Chang Suh
Affiliations
Review

Acid-sensing ion channels (ASICs): therapeutic targets for neurological diseases and their regulation

Hae-Jin Kweon et al. BMB Rep. 2013 Jun.

Abstract

Extracellular acidification occurs not only in pathological conditions such as inflammation and brain ischemia, but also in normal physiological conditions such as synaptic transmission. Acid-sensing ion channels (ASICs) can detect a broad range of physiological pH changes during pathological and synaptic cellular activities. ASICs are voltage-independent, proton-gated cation channels widely expressed throughout the central and peripheral nervous system. Activation of ASICs is involved in pain perception, synaptic plasticity, learning and memory, fear, ischemic neuronal injury, seizure termination, neuronal degeneration, and mechanosensation. Therefore, ASICs emerge as potential therapeutic targets for manipulating pain and neurological diseases. The activity of these channels can be regulated by many factors such as lactate, Zn(2+), and Phe-Met-Arg-Phe amide (FMRFamide)-like neuropeptides by interacting with the channel's large extracellular loop. ASICs are also modulated by G protein-coupled receptors such as CB1 cannabinoid receptors and 5-HT2. This review focuses on the physiological roles of ASICs and the molecular mechanisms by which these channels are regulated.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.. ASIC subunits and activation of ASICs by extracellular acidification. (A) Each subunit has two hydrophobic transmembrane domains, a large cysteine-rich extracellular loop, and short intracellular N- and C- termini. (B) Three subunits assemble to form a functional homo- or hetero- trimeric channel. (C) ASIC currents evoked by extracellular pH fall in tsA cells. ASIC1a, ASIC2a, and ASIC3 were activated by application of pH 6.0, 4.5, and 5.0 solution, respectively. The membrane potential was clamped to −70 mV. The dashed line indicates zero current level.
Fig. 2.
Fig. 2.. ASICs are regulated by signal transduction pathways. 5-HT2 receptors activate PLCβ through the heterotrimeric Gq/11 proteins. PLCβ hydrolyzes membrane PI(4,5)P2 to two second messengers, IP3 and DAG. IP3 releases Ca2+ from the internal Ca2+ stores in ER. DAG activates PKC, which enhances the activity of ASICs by interaction with PICK1. CB1 receptors inhibit ASICs via suppression of AC/cAMP pathway. AC is inhibited by the heterotrimeric Gi/o proteins, and inhibition of AC leads to reduction of the cAMP levels, which in turn inhibits binding of PKA to AKAP150. TrkB activates PI3-K, and enhances the membrane expression of ASICs through Akt proteins. Arachidonic acid directly potentiates the amplitude of ASIC currents. Abbreviations: ASICs: Acid-sensing ion channels, 5-HT2R: 5-HT2 receptor, CB1R: Cannabinoid-1 receptor, PLCβ: phospholipase C β, PI(4,5)P2: phosphatidylinositol 4,5-bisphosphate, PI(3,4,5)P3: phosphatidylinositol 3,4,5-trisphosphate, IP3: inositol 1,4,5-trisphosphate, IP3R: inositol 1,4,5-trisphosphate receptor, DAG: diacylglycerol, PKC: protein kinase C, PICK1: protein interacting with C-kinase, ER: endoplasmic reticulum, AC: adenylyl cyclase, cAMP: cyclic AMP, PKA: protein kinase A, AKAP150: A-kinase anchoring protein 150, TrkB: tropomyosin-related kinase B, BDNF: brain-derived neurotrophic factor, PI3-K: phosphatidylinositol 3-kinase, Akt: protein kinase B, AA: arachidonic acid.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Basbaum A. I., Bautista D. M., Scherrer G., Julius D. Cellular and molecular mechanisms of pain. Cell. (2009);139:267–284. doi: 10.1016/j.cell.2009.09.028. - DOI - PMC - PubMed
    1. Steen K. H., Issberner W., Reeh P. W. Pain due to experimental acidosis in human skin: evidence for non-adapting nociceptor excitation. Neurosci. Lett. (1995);199:29–32. doi: 10.1016/0304-3940(95)12002-L. - DOI - PubMed
    1. Jones N. G., Slater R., Cadiou H., McNaughton P., McMahon S. B. Acid-induced pain and its modulation in humans. J. Neurosci. (2004);24:10974–10979. doi: 10.1523/JNEUROSCI.2619-04.2004. - DOI - PMC - PubMed
    1. Steen K. H., Reeh P. W., Anton F., Handwerker H. O. Protons selectively induce lasting excitation and sensitization to mechanical stimulation of nociceptors in rat skin, in vitro. J. Neurosci. (1992);12:86–95. - PMC - PubMed
    1. Smith M. L., Von Hanwehr R., Siesjo B. K. Changes in extra- and intracellular pH in the brain during and following ischemia in hyperglycemic and in moderately hypoglycemic rats. J. Cereb. Blood Flow Metab. (1986);6:574–583. doi: 10.1038/jcbfm.1986.104. - DOI - PubMed

Publication types

MeSH terms

Substances