title: Calmodulin limits pathogenic Na+ channel persistent current.
abstract: 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 NaVchannel intracellular C-terminal domains (CTDs) limits persistent Na+current and accelerates inactivation across the NaVfamily. 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.
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710.
authors.forename: Haidun
authors.initials: H
authors.lastname: Yan
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710.
authors.forename: Chaojian
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Cardiology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Steven O
authors.initials: SO
authors.lastname: Marx
authors.affiliation: Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710 geoffrey.pitt@med.cornell.edu.
authors.forename: Geoffrey S
authors.identifier: http://orcid.org/0000-0003-2246-0289
authors.initials: GS
authors.lastname: Pitt
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001665:Binding Sites; D002147:Calmodulin / Q000378:metabolism*; D004827:Epilepsy / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation; D011485:Protein Binding; D061566:Voltage-Gated Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002147:Calmodulin; D061566:Voltage-Gated Sodium Channels