Structural Mechanism of Voltage-gated Sodium Channel Slow Inactivation

Overview

Journal Nat Commun

Specialty Biology

Date 2024 May 1

PMID 38693179

Authors

Huiwen Chen

Zhanyi Xia

Jie Dong

Bo Huang

Jiangtao Zhang

Feng Zhou

Rui Yan

Yiqiang Shi

Jianke Gong

Juquan Jiang

Zhuo Huang

Daohua Jiang

Affiliations

Soon will be listed here.

Abstract

Voltage-gated sodium (Na) channels mediate a plethora of electrical activities. Na channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of Na channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying Na channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaEh (NaEh) results in a slow-inactivated channel, and present cryo-EM structure of NaEh in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaEh structure, NaEh undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into Na channel slow inactivation.

Citing Articles

Multiple gating processes associated with the distal end of the S6 segment of domain II in the Nav channels.

Chen M, Peng S, Xiao Z, Liu Z, Zhou X J Biol Chem. 2024; 301(1):108060.

PMID: 39662825 PMC: 11742611. DOI: 10.1016/j.jbc.2024.108060.

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