Calmodulin limits pathogenic Na+ channel persistent current.

Journal Article (Journal Article)

Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na+ (NaV) 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 NaV channel intracellular C-terminal domains (CTDs) limits persistent Na+ current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 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 NaV1.5 and NaV1.2 channels and likewise diminishes the comparatively large persistent Na+ current through WT NaV1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which NaV1.6 promotes a large physiological persistent Na+ current, increased CaM diminishes the persistent Na+ current, suggesting that the endogenous, comparatively weak affinity of NaV1.6 for apoCaM is important for physiological persistent current.

Full Text

Duke Authors

Cited Authors

  • Yan, H; Wang, C; Marx, SO; Pitt, GS

Published Date

  • February 2017

Published In

Volume / Issue

  • 149 / 2

Start / End Page

  • 277 - 293

PubMed ID

  • 28087622

Pubmed Central ID

  • PMC5299624

Electronic International Standard Serial Number (EISSN)

  • 1540-7748

Digital Object Identifier (DOI)

  • 10.1085/jgp.201611721


  • eng

Conference Location

  • United States