Structural Advances in Voltage-Gated Sodium Channels

Daohua Jiang; Jiangtao Zhang; Zhanyi Xia

doi:10.3389/fphar.2022.908867

Structural Advances in Voltage-Gated Sodium Channels

Front Pharmacol. 2022 Jun 3:13:908867. doi: 10.3389/fphar.2022.908867. eCollection 2022.

Authors

Daohua Jiang^{1

2}, Jiangtao Zhang^{1

3}, Zhanyi Xia^{1

2}

Affiliations

¹ Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.

Abstract

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.

Keywords: cryo-EM; drug modulation mechanism; gating mechanism; pharmocology; voltage-gated sodium channel.

Publication types

Review