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 Ca(2+) . The molecular and structural details for how Ca(2+) 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 Ca(2+) acts directly upon the NaV channel or through interacting proteins, such as the Ca(2+) 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 Ca(2+) affects NaV function, and how altered Ca(2+) -dependent or FHF-mediated regulation of NaV channels is perturbed in various disease states through mutations that disrupt CaM or FHF interaction.
Cardiovascular Research Institute, Weill Cornell Medicine, New York, NY, 10065.
Geoffrey S
GS
Pitt
Department of Biochemistry, Duke University Medical Center, Durham, North Carolina, 27710.
Seok-Yong
SY
Lee
D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D000072417:Protein Domains; D061566:Voltage-Gated Sodium Channels / Q000235:genetics / Q000378:metabolism*
D002147:Calmodulin; D061566:Voltage-Gated Sodium Channels; D005346:Fibroblast Growth Factors; D002118:Calcium
X-ray crystallography; action potentials; autism; calcium; calmodulin; cardiac arrhythmia; epilepsy; inactivation; ion channels; voltage-gated sodium channels