Structural Elements for the Generation of Sustained Currents by the Acid Pain Sensor ASIC3

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Sep 26

PMID 19778905

Citations 37

Authors

Miguel Salinas

Michel Lazdunski

Eric Lingueglia

Affiliations

Soon will be listed here.

Abstract

ASIC3 is an acid-sensing ion channel expressed in sensory neurons, where it participates in acidic and inflammatory pain. In addition to the "classical" transient current, ASIC3 generates a sustained current essential for pain perception. Using chimeras between the ASIC3 and ASIC1a channels we show that the first transmembrane domain (TM1), combined with the N-terminal domain, is the key structural element generating the low pH (<6.5)-evoked sustained current. The TM1 domain also modulates the pH-dependent activation of the fast transient current thus contributing to a constitutive window current, another type of sustained current present near physiological pH. The C-terminal and the TM2 domains negatively regulate both types of sustained current, and the extracellular loop affects its kinetics. These data provide new information to aid understanding the mechanisms of the multifaceted pH gating of ASIC3. Together with the peak current, both components of the sustained current (window and sustained at pH <6.5) allow ASIC3 to adapt its behavior to a wide range of extracellular pH variations by generating transient and/or sustained responses that contribute to nociceptor excitability.

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References

Deval E, Baron A, Lingueglia E, Mazarguil H, Zajac J, Lazdunski M . Effects of neuropeptide SF and related peptides on acid sensing ion channel 3 and sensory neuron excitability. Neuropharmacology. 2003; 44(5):662-71. DOI: 10.1016/s0028-3908(03)00047-9. 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

Reeh P, Steen K . Tissue acidosis in nociception and pain. Prog Brain Res. 1996; 113:143-51. DOI: 10.1016/s0079-6123(08)61085-7. View

Ettaiche M, Deval E, Pagnotta S, Lazdunski M, Lingueglia E . Acid-sensing ion channel 3 in retinal function and survival. Invest Ophthalmol Vis Sci. 2009; 50(5):2417-26. DOI: 10.1167/iovs.08-3028. View

Paukert M, Chen X, Polleichtner G, Schindelin H, Grunder S . Candidate amino acids involved in H+ gating of acid-sensing ion channel 1a. J Biol Chem. 2007; 283(1):572-581. DOI: 10.1074/jbc.M706811200. View

Sutherland S, Benson C, Adelman J, McCleskey E . Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci U S A. 2000; 98(2):711-6. PMC: 14653. DOI: 10.1073/pnas.98.2.711. View

Smith E, Zhang X, Cadiou H, McNaughton P . Proton binding sites involved in the activation of acid-sensing ion channel ASIC2a. Neurosci Lett. 2007; 426(1):12-7. DOI: 10.1016/j.neulet.2007.07.047. View

Sherwood T, Askwith C . Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a. J Biol Chem. 2007; 283(4):1818-30. DOI: 10.1074/jbc.M705118200. View

Wang W, Chu X, Li M, Seeds J, Simon R, Xiong Z . Modulation of acid-sensing ion channel currents, acid-induced increase of intracellular Ca2+, and acidosis-mediated neuronal injury by intracellular pH. J Biol Chem. 2006; 281(39):29369-78. DOI: 10.1074/jbc.M605122200. View

10.

Bashari E, Qadri Y, Zhou Z, Kapoor N, Anderson S, Meltzer R . Two PKC consensus sites on human acid-sensing ion channel 1b differentially regulate its function. Am J Physiol Cell Physiol. 2008; 296(2):C372-84. PMC: 2643847. DOI: 10.1152/ajpcell.00200.2008. View

11.

Yen Y, Tu P, Chen C, Lin Y, Hsieh S, Chen C . Role of acid-sensing ion channel 3 in sub-acute-phase inflammation. Mol Pain. 2009; 5:1. PMC: 2632618. DOI: 10.1186/1744-8069-5-1. View

12.

Issberner U, Reeh P, Steen K . Pain due to tissue acidosis: a mechanism for inflammatory and ischemic myalgia?. Neurosci Lett. 1996; 208(3):191-4. DOI: 10.1016/0304-3940(96)12576-3. View

13.

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

14.

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

15.

Li T, Yang Y, Canessa C . Interaction of the aromatics Tyr-72/Trp-288 in the interface of the extracellular and transmembrane domains is essential for proton gating of acid-sensing ion channels. J Biol Chem. 2008; 284(7):4689-94. PMC: 2640969. DOI: 10.1074/jbc.M805302200. View

16.

Deval E, Salinas M, Baron A, Lingueglia E, Lazdunski M . ASIC2b-dependent regulation of ASIC3, an essential acid-sensing ion channel subunit in sensory neurons via the partner protein PICK-1. J Biol Chem. 2004; 279(19):19531-9. DOI: 10.1074/jbc.M313078200. View

17.

Jasti J, Furukawa H, Gonzales E, Gouaux E . Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature. 2007; 449(7160):316-23. DOI: 10.1038/nature06163. View

18.

Wemmie J, Price M, Welsh M . Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 2006; 29(10):578-86. DOI: 10.1016/j.tins.2006.06.014. View

19.

Lingueglia E . Acid-sensing ion channels in sensory perception. J Biol Chem. 2007; 282(24):17325-9. DOI: 10.1074/jbc.R700011200. View

20.

Donier E, Rugiero F, Okuse K, Wood J . Annexin II light chain p11 promotes functional expression of acid-sensing ion channel ASIC1a. J Biol Chem. 2005; 280(46):38666-72. DOI: 10.1074/jbc.M505981200. View