Calmodulin limits pathogenic Na+ channel persistent current

Increased “persistent” current, caused by delayed inactivation, through voltage-gated Na + (Na V ) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within Na V channel intracellular C-terminal domains (CTDs) limits persistent Na + current and accelerates inactivation across the Na V family. Arrhythmia or epilepsy mutations located in Na V 1.5 or Na V 1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD–CTD interchannel interactions. Boosting the availability of CaM, thus shifting its binding equilibrium, restores wild-type (WT)–like inactivation in mutant Na V 1.5 and Na V 1.2 channels and likewise diminishes the comparatively large persistent Na + current through WT Na V 1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which Na V 1.6 promotes a large physiological persistent Na + current, increased CaM diminishes the persistent Na + current, suggesting that the endogenous, comparatively weak affinity of Na V 1.6 for apoCaM is important for physiological persistent current.