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-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.