Calmodulin limits pathogenic Na+ channel persistent current.

Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na (Na) 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 channel intracellular C-terminal domains (CTDs) limits persistent Na current and accelerates inactivation across the Na family. Arrhythmia or epilepsy mutations located in Na1.5 or Na1.2 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 Na1.5 and Na1.2 channels and likewise diminishes the comparatively large persistent Na current through WT Na1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which Na1.6 promotes a large physiological persistent Na current, increased CaM diminishes the persistent Na current, suggesting that the endogenous, comparatively weak affinity of Na1.6 for apoCaM is important for physiological persistent current.