Calmodulin limits pathogenic Na+ channel persistent current.

ABSTRACT: 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_V1.5 or Na_V1.2 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)-lik

SUBMITTER: Yan H 

PROVIDER: S-EPMC5299624 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature