Structural basis of cytoplasmic Na_V1.5 and Na_V1.4 regulation

Voltage-gated sodium channels (Na_Vs) are membrane proteins responsible for the rapid upstroke of the action potential in excitable cells. There are nine human voltage-sensitive Na_V1 isoforms that, in addition to their sequence differences, differ in tissue distribution and specific function. This review focuses on isoforms Na_V1.4 and Na_V1.5, which are primarily expressed in skeletal and cardiac muscle cells, respectively. The determination of the structures of several eukaryotic Na_Vs by single-particle cryo-electron microscopy (cryo-EM) has brought new perspective to the study of the channels. Alignment of the cryo-EM structure of the transmembrane channel pore with x-ray crystallographic structures of the cytoplasmic domains illustrates the complementary nature of the techniques and highlights the intricate cellular mechanisms that modulate these channels. Here, we review structural insights into the cytoplasmic C-terminal regulation of Na_V1.4 and Na_V1.5 with special attention to Ca²⁺ sensing by calmodulin, implications for disease, and putative channel dimerization.