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.