Structural mechanism of voltage-gated sodium channel slow inactivation

Huiwen Chen, Zhanyi Xia, Jie Dong, Bo Huang, Jiangtao Zhang, Feng Zhou, Rui Yan, Yiqiang Shi, Jianke Gong, Juquan Jiang (), Zhuo Huang () and Daohua Jiang ()
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Huiwen Chen: Northeast Agricultural University
Zhanyi Xia: Chinese Academy of Sciences
Jie Dong: Peking University Health Science Center
Bo Huang: Beijing StoneWise Technology Co Ltd.
Jiangtao Zhang: Chinese Academy of Sciences
Feng Zhou: Beijing StoneWise Technology Co Ltd.
Rui Yan: Chinese Academy of Sciences
Yiqiang Shi: Peking University Health Science Center
Jianke Gong: Huazhong University of Science and Technology
Juquan Jiang: Northeast Agricultural University
Zhuo Huang: Peking University Health Science Center
Daohua Jiang: Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract Voltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV 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 NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN 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 NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.

Date: 2024
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DOI: 10.1038/s41467-024-48125-3

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