Voltage-Gated Na⁺ Channels: Not Just for Conduction

Abstract

Voltage-gated sodium channels (VGSCs), composed of a pore-forming α subunit and up to two associated β subunits, are critical for the initiation of the action potential (AP) in excitable tissues. Building on the monumental discovery and description of sodium current in 1952, intrepid researchers described the voltage-dependent gating mechanism, selectivity of the channel, and general structure of the VGSC channel. Recently, crystal structures of bacterial VGSC α subunits have confirmed many of these studies and provided new insights into VGSC function. VGSC β subunits, first cloned in 1992, modulate sodium current but also have nonconducting roles as cell-adhesion molecules and function in neurite outgrowth and neuronal pathfinding. Mutations in VGSC α and β genes are associated with diseases caused by dysfunction of excitable tissues such as epilepsy. Because of the multigenic and drug-resistant nature of some of these diseases, induced pluripotent stem cells and other novel approaches are being used to screen for new drugs and further understand how mutations in VGSC genes contribute to pathophysiology.