β11-12 linker isomerization governs acid-sensing ion channel desensitization and recovery.
acid-sensing ion channel
desensitization
gating
neuroscience
non-canonical amino acid
none
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
07 02 2020
07 02 2020
Historique:
received:
15
08
2019
accepted:
06
02
2020
pubmed:
8
2
2020
medline:
4
5
2021
entrez:
8
2
2020
Statut:
epublish
Résumé
Acid-sensing ion channels (ASICs) are neuronal sodium-selective channels activated by reductions in extracellular pH. Structures of the three presumptive functional states, high-pH resting, low-pH desensitized, and toxin-stabilized open, have all been solved for chicken ASIC1. These structures, along with prior functional data, suggest that the isomerization or flipping of the β11-12 linker in the extracellular, ligand-binding domain is an integral component of the desensitization process. To test this, we combined fast perfusion electrophysiology, molecular dynamics simulations and state-dependent non-canonical amino acid cross-linking. We find that both desensitization and recovery can be accelerated by orders of magnitude by mutating resides in this linker or the surrounding region. Furthermore, desensitization can be suppressed by trapping the linker in the resting state, indicating that isomerization of the β11-12 linker is not merely a consequence of, but a necessity for the desensitization process in ASICs.
Identifiants
pubmed: 32031522
doi: 10.7554/eLife.51111
pii: 51111
pmc: PMC7041949
doi:
pii:
Substances chimiques
Acid Sensing Ion Channels
0
Hazardous Substances
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Cystic Fibrosis Foundation
ID : LUECK18G0
Organisme : NINDS NIH HHS
ID : R00 NS094761
Pays : United States
Organisme : Natural Sciences and Engineering Research Council of Canada
ID : RGPIN 2019-06864
Organisme : NIGMS NIH HHS
ID : T32 GM068411
Pays : United States
Organisme : Canada Research Chairs
ID : 950-232154
Informations de copyright
© 2020, Rook et al.
Déclaration de conflit d'intérêts
MR, AW, JL, MM, DM No competing interests declared
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