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 (Na-V 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 Na-V 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 Na-V channel or through interacting proteins, such as the Ca2+ binding protein calmodulin (CaM). Here, we review recent advances in defining the structure of Na-V intracellular C-termini and associated proteins such as CaM or fibroblast growth factor homologous factors (FHFs) to reveal new insights into how Ca2+ affects Na-V function, and how altered Ca2+-dependent or FHF-mediated regulation of Na-V channels is perturbed in various disease states through mutations that disrupt CaM or FHF interaction.