Structure, Function, and Pharmacology of Acid-sensing Ion Channels (ASICs): Focus on ASIC1a

Overview

Journal Int J Physiol Pathophysiol Pharmacol

Date 2011 Mar 9

PMID 21383888

Citations 97

Authors

Stefan Grunder

Xuanmao Chen

Affiliations

Soon will be listed here.

Abstract

Acid-sensing ion channels (ASICs) are H(+)-gated Na(+) channels, which are present in most, if not all, neurons. The typical ASIC current is transient and is elicited by a rapid drop in the extracellular pH. In the human genome, four genes for ASICs are present: asic1 - 4. In this review, we will focus on ASIC1a, one of the key subunits in the central nervous system. We will describe the structure of this channel, a topic that has enormously profited from the recent elucidation of the first crystal structure of an ASIC. We will then relate the ASIC1 structure to current models of the gating mechanism of ASICs. Finally, we will review the pharmacology of ASIC1a. Advances in the pharmacological inhibition of individual ASIC currents have greatly contributed to our current knowledge of the functional roles of this channel in physiology, including learning, memory, and fear conditioning, and in pathophysiological states, including the neurodegeneration accompanying stroke, and axonal degeneration in autoimmune inflammation.

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References

IKARI N, Sakai Y, Hitomi Y, Fujii S . New synthetic inhibitor to the alternative complement pathway. Immunology. 1983; 49(4):685-91. PMC: 1454324. View

Escoubas P, Bernard C, Lambeau G, Lazdunski M, Darbon H . Recombinant production and solution structure of PcTx1, the specific peptide inhibitor of ASIC1a proton-gated cation channels. Protein Sci. 2003; 12(7):1332-43. PMC: 2323924. DOI: 10.1110/ps.0307003. View

Baron A, Waldmann R, Lazdunski M . ASIC-like, proton-activated currents in rat hippocampal neurons. J Physiol. 2002; 539(Pt 2):485-94. PMC: 2290154. DOI: 10.1113/jphysiol.2001.014837. View

Chen X, Kalbacher H, Grunder S . The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J Gen Physiol. 2005; 126(1):71-9. PMC: 2266618. DOI: 10.1085/jgp.200509303. View

Szeto T, Smith R, Connor M, Christie M, King G, Nicholson G . Isolation and pharmacological characterisation of delta-atracotoxin-Hv1b, a vertebrate-selective sodium channel toxin. FEBS Lett. 2000; 470(3):293-9. DOI: 10.1016/s0014-5793(00)01339-9. View

Meng Q, Wang W, Chen X, Xu T, Zhou J . Distribution of acid-sensing ion channel 3 in the rat hypothalamus. Neuroscience. 2009; 159(3):1126-34. DOI: 10.1016/j.neuroscience.2009.01.069. View

Coryell M, Ziemann A, Westmoreland P, Haenfler J, Kurjakovic Z, Zha X . Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit. Biol Psychiatry. 2007; 62(10):1140-8. DOI: 10.1016/j.biopsych.2007.05.008. View

Carnally S, Dev H, Stewart A, Barrera N, van Bemmelen M, Schild L . Direct visualization of the trimeric structure of the ASIC1a channel, using AFM imaging. Biochem Biophys Res Commun. 2008; 372(4):752-5. DOI: 10.1016/j.bbrc.2008.05.100. View

Chen X, Grunder S . Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a. J Physiol. 2007; 579(Pt 3):657-70. PMC: 2151377. DOI: 10.1113/jphysiol.2006.120733. View

10.

Yagi J, Wenk H, Naves L, McCleskey E . Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ Res. 2006; 99(5):501-9. DOI: 10.1161/01.RES.0000238388.79295.4c. View

11.

Yermolaieva O, Leonard A, Schnizler M, Abboud F, Welsh M . Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci U S A. 2004; 101(17):6752-7. PMC: 404117. DOI: 10.1073/pnas.0308636100. View

12.

Afshan Shaikh S, Tajkhorshid E . Potential cation and H+ binding sites in acid sensing ion channel-1. Biophys J. 2008; 95(11):5153-64. PMC: 2586576. DOI: 10.1529/biophysj.108.141606. View

13.

Baron A, Voilley N, Lazdunski M, Lingueglia E . Acid sensing ion channels in dorsal spinal cord neurons. J Neurosci. 2008; 28(6):1498-508. PMC: 6671562. DOI: 10.1523/JNEUROSCI.4975-07.2008. View

14.

Pietra F . Docking and MD simulations of the interaction of the tarantula peptide psalmotoxin-1 with ASIC1a channels using a homology model. J Chem Inf Model. 2009; 49(4):972-7. DOI: 10.1021/ci800463h. View

15.

Canessa C, Merillat A, Rossier B . Membrane topology of the epithelial sodium channel in intact cells. Am J Physiol. 1994; 267(6 Pt 1):C1682-90. DOI: 10.1152/ajpcell.1994.267.6.C1682. View

16.

Paukert M, Sidi S, Russell C, Siba M, Wilson S, Nicolson T . A family of acid-sensing ion channels from the zebrafish: widespread expression in the central nervous system suggests a conserved role in neuronal communication. J Biol Chem. 2004; 279(18):18783-91. DOI: 10.1074/jbc.M401477200. View

17.

Swartz K, Mackinnon R . An inhibitor of the Kv2.1 potassium channel isolated from the venom of a Chilean tarantula. Neuron. 1995; 15(4):941-9. DOI: 10.1016/0896-6273(95)90184-1. View

18.

Pfister Y, Gautschi I, Takeda A, van Bemmelen M, Kellenberger S, Schild L . A gating mutation in the internal pore of ASIC1a. J Biol Chem. 2006; 281(17):11787-91. DOI: 10.1074/jbc.M513692200. View

19.

Chen X, Kalbacher H, Grunder S . Interaction of acid-sensing ion channel (ASIC) 1 with the tarantula toxin psalmotoxin 1 is state dependent. J Gen Physiol. 2006; 127(3):267-76. PMC: 2151504. DOI: 10.1085/jgp.200509409. View

20.

Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M . A proton-gated cation channel involved in acid-sensing. Nature. 1997; 386(6621):173-7. DOI: 10.1038/386173a0. View