Calcium regulates acid-sensing ion channel 3 activation by competing with protons in the channel pore and at an allosteric binding site

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_5A104FD49AAE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Calcium regulates acid-sensing ion channel 3 activation by competing with protons in the channel pore and at an allosteric binding site
Journal
Open Biology
Author(s)
Roy Sophie, Johner Niklaus, Trendafilov Viktor, Gautschi Ivan, Bignucolo Olivier, Molton Ophélie, Bernèche Simon, Kellenberger Stephan
ISSN
2046-2441
ISSN-L
2046-2441
Publication state
Published
Issued date
12/2022
Peer-reviewed
Oui
Volume
12
Number
12
Pages
220243
Language
english
Abstract
The extracellular Ca2+ concentration changes locally under certain physiological and pathological conditions. Such variations affect the function of ion channels of the nervous system, and consequently also neuronal signalling. We investigated here the mechanisms by which Ca2+ controls the activity of acid-sensing ion channel (ASIC) 3. ASICs are neuronal, H+-gated Na+ channels involved in several physiological and pathological processes, including the expression of fear, learning, pain sensation and neurodegeneration after ischemic stroke. It was previously shown that Ca2+ negatively modulates the ASIC pH dependence. While protons are default activators of ASIC3, this channel can also be activated at pH7.4 by removal of the extracellular Ca2+. Two previous studies concluded that low pH opens ASIC3 by displacing Ca2+ ions that block the channel pore at physiological pH. We show here that an acidic residue, distant from the pore, controls, together with pore residues, the modulation of ASIC3 by Ca2+. Our study identifies a new regulatory site in ASIC3 and demonstrates that ASIC3 activation involves an allosteric mechanism together with Ca2+ unbinding from the channel pore. We provide a molecular analysis of a regulatory mechanism found in many ion channels.
Keywords
General Biochemistry, Genetics and Molecular Biology, Immunology, General Neuroscience
Pubmed
Open Access
Yes
Funding(s)
Swiss National Science Foundation / 31003A_172968
Create date
21/12/2022 16:17
Last modification date
05/01/2023 6:48
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