Kinetic analysis of ASIC1a delineates conformational signaling from proton-sensing domains to the channel gate.

Details

Ressource 1Download: elife-66488-v2.pdf (6179.44 [Ko])
State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_E64FD4132061
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Kinetic analysis of ASIC1a delineates conformational signaling from proton-sensing domains to the channel gate.
Journal
eLife
Author(s)
Vullo S., Ambrosio N., Kucera J.P., Bignucolo O., Kellenberger S.
ISSN
2050-084X (Electronic)
ISSN-L
2050-084X
Publication state
Published
Issued date
17/03/2021
Peer-reviewed
Oui
Volume
10
Pages
e66488
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Acid-sensing ion channels (ASICs) are neuronal Na <sup>+</sup> channels that are activated by a drop in pH. Their established physiological and pathological roles, involving fear behaviors, learning, pain sensation, and neurodegeneration after stroke, make them promising targets for future drugs. Currently, the ASIC activation mechanism is not understood. Here, we used voltage-clamp fluorometry (VCF) combined with fluorophore-quencher pairing to determine the kinetics and direction of movements. We show that conformational changes with the speed of channel activation occur close to the gate and in more distant extracellular sites, where they may be driven by local protonation events. Further, we provide evidence for fast conformational changes in a pathway linking protonation sites to the channel pore, in which an extracellular interdomain loop interacts via aromatic residue interactions with the upper end of a transmembrane helix and would thereby open the gate.
Keywords
Acid Sensing Ion Channels/chemistry, Humans, Kinetics, Molecular Conformation, Protons, Signal Transduction, conformational change, human, ion channel, kinetic model, molecular biophysics, molecular dynamics, neuroscience, structural biology, voltage-clamp fluorometry
Pubmed
Web of science
Open Access
Yes
Create date
17/03/2021 9:43
Last modification date
22/09/2021 6:38
Usage data