Structural Advances in Voltage-Gated Sodium Channels

Voltage-gated sodium (Na V ) channels are responsible for the rapid rising-phase of action potentials in excitable cells. Over 1,000 mutations in Na V channels are associated with human diseases including epilepsy, periodic paralysis, arrhythmias and pain disorders. Natural toxins and clinically-use...

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Bibliographic Details
Published in:Frontiers in pharmacology 2022-06, Vol.13, p.908867-908867
Main Authors: Jiang, Daohua, Zhang, Jiangtao, Xia, Zhanyi
Format: Article
Language:English
Subjects:
cryo-EM
drug modulation mechanism
gating mechanism
Pharmacology
pharmocology
voltage-gated sodium channel
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Summary:Voltage-gated sodium (Na V ) channels are responsible for the rapid rising-phase of action potentials in excitable cells. Over 1,000 mutations in Na V channels are associated with human diseases including epilepsy, periodic paralysis, arrhythmias and pain disorders. Natural toxins and clinically-used small-molecule drugs bind to Na V channels and modulate their functions. Recent advances from cryo-electron microscopy (cryo-EM) structures of Na V channels reveal invaluable insights into the architecture, activation, fast inactivation, electromechanical coupling, ligand modulation and pharmacology of eukaryotic Na V channels. These structural analyses not only demonstrate molecular mechanisms for Na V channel structure and function, but also provide atomic level templates for rational development of potential subtype-selective therapeutics. In this review, we summarize recent structural advances of eukaryotic Na V channels, highlighting the structural features of eukaryotic Na V channels as well as distinct modulation mechanisms by a wide range of modulators from natural toxins to synthetic small-molecules.
ISSN:1663-9812
1663-9812
DOI:10.3389/fphar.2022.908867