Gating mechanisms of acid-sensing ion channels

Research output: Contribution to journalArticle

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Abstract

Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout vertebrate central and peripheral nervous systems. Gating of ASICs occurs on a millisecond time scale and the mechanism involves three conformational states: high pH resting, low pH open and low pH desensitized. Existing X-ray structures of ASIC1a describe the conformations of the open and desensitized states, but the structure of the high pH resting state and detailed mechanisms of the activation and desensitization of the channel have remained elusive. Here we present structures of the high pH resting state of homotrimeric chicken (Gallus gallus) ASIC1a, determined by X-ray crystallography and single particle cryo-electron microscopy, and present a comprehensive molecular mechanism for proton-dependent gating in ASICs. In the resting state, the position of the thumb domain is further from the three-fold molecular axis, thereby expanding the 'acidic pocket' in comparison to the open and desensitized states. Activation therefore involves 'closure' of the thumb into the acidic pocket, expansion of the lower palm domain and an iris-like opening of the channel gate. Furthermore, we demonstrate how the β11-β12 linkers that demarcate the upper and lower palm domains serve as a molecular 'clutch', and undergo a simple rearrangement to permit rapid desensitization.

Original languageEnglish (US)
Pages (from-to)397-401
Number of pages5
JournalNature
Volume555
Issue number7696
DOIs
StatePublished - Mar 15 2018

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Acid Sensing Ion Channels
Thumb
Protons
Degenerin Sodium Channels
Chickens
Epithelial Sodium Channels
Cryoelectron Microscopy
X Ray Crystallography
Peripheral Nervous System
Iris
Ion Channels
Vertebrates
Central Nervous System
Sodium
X-Rays

ASJC Scopus subject areas

  • General

Cite this

Gating mechanisms of acid-sensing ion channels. / Yoder, Nate; Yoshioka, Craig; Gouaux, Eric.

In: Nature, Vol. 555, No. 7696, 15.03.2018, p. 397-401.

Research output: Contribution to journalArticle

Yoder, Nate ; Yoshioka, Craig ; Gouaux, Eric. / Gating mechanisms of acid-sensing ion channels. In: Nature. 2018 ; Vol. 555, No. 7696. pp. 397-401.
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