期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.908867
关键词
voltage-gated sodium channel; cryo-EM; pharmocology; gating mechanism; drug modulation mechanism
资金
- Institute of Physics, Chinese Academy of Sciences [E0VK101]
Voltage-gated sodium channels are crucial for the rapid rising-phase of action potentials, and their mutations can lead to various human diseases. Recent studies using cryo-EM structures have provided valuable insights into the mechanism of eukaryotic Na-V channels, offering templates for drug development.
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.
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