title: Seeing the forest through the trees: towards a unified view on physiological calcium regulation of voltage-gated sodium channels.
abstract: Voltage-gated sodium channels (Na(V)s) underlie the upstroke of the action potential in the excitable tissues of nerve and muscle. After opening, Na(V)s rapidly undergo inactivation, a crucial process through which sodium conductance is negatively regulated. Disruption of inactivation by inherited mutations is an established cause of lethal cardiac arrhythmia, epilepsy, or painful syndromes. Intracellular calcium ions (Ca(2+)) modulate sodium channel inactivation, and multiple players have been suggested in this process, including the cytoplasmic Na(V) C-terminal region including two EF-hands and an IQ motif, the Na(V) domain III-IV linker, and calmodulin. Calmodulin can bind to the IQ domain in both Ca(2+)-bound and Ca(2+)-free conditions, but only to the DIII-IV linker in a Ca(2+)-loaded state. The mechanism of Ca(2+) regulation, and its composite effect(s) on channel gating, has been shrouded in much controversy owing to numerous apparent experimental inconsistencies. Herein, we attempt to summarize these disparate data and propose a novel, to our knowledge, physiological mechanism whereby calcium ions promote sodium current facilitation due to Ca(2+) memory at high-action-potential frequencies where Ca(2+) levels may accumulate. The available data suggest that this phenomenon may be disrupted in diseases where cytoplasmic calcium ion levels are chronically high and where targeted phosphorylation may decouple the Ca(2+) regulatory machinery. Many Na(V) disease mutations associated with electrical dysfunction are located in the Ca(2+)-sensing machinery and misregulation of Ca(2+)-dependent channel modulation is likely to contribute to disease phenotypes.
authors.affiliation: The Department of Biochemistry and Molecular Biology, Vancouver, British Columbia, Canada. filip.vanpetegem@gmail.com
authors.forename: Filip
authors.initials: F
authors.lastname: Van Petegem
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Lobo
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ahern
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D003198:Computer Simulation; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008954:Models, Biological; D012964:Sodium / Q000378:metabolism*; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D061566:Voltage-Gated Sodium Channels; D012964:Sodium; D002118:Calcium