Current view on regulation of voltage‐gated sodium channels by calcium and auxiliary proteins

In cardiac and skeletal myocytes, and in most neurons, the opening of voltage‐gated Na+ channels (NaV channels) triggers action potentials, a process that is regulated via the interactions of the channels’ intercellular C‐termini with auxiliary proteins and/or Ca2+. The molecular and structural details for how Ca2+ and/or auxiliary proteins modulate NaV channel function, however, have eluded a concise mechanistic explanation and details have been shrouded for the last decade behind controversy about whether Ca2+ acts directly upon the NaV channel or through interacting proteins, such as the Ca2+ binding protein calmodulin (CaM). Here, we review recent advances in defining the structure of NaV intracellular C‐termini and associated proteins such as CaM or fibroblast growth factor homologous factors (FHFs) to reveal new insights into how Ca2+ affects NaV function, and how altered Ca2+‐dependent or FHF‐mediated regulation of NaV channels is perturbed in various disease states through mutations that disrupt CaM or FHF interaction.