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Calmodulin limits pathogenic Na+ channel persistent current.

Publication ,  Journal Article
Yan, H; Wang, C; Marx, SO; Pitt, GS
Published in: J Gen Physiol
February 2017

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.

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Published In

J Gen Physiol

DOI

EISSN

1540-7748

Publication Date

February 2017

Volume

149

Issue

2

Start / End Page

277 / 293

Location

United States

Related Subject Headings

  • Voltage-Gated Sodium Channels
  • Protein Binding
  • Physiology
  • Mutation
  • Humans
  • HEK293 Cells
  • Epilepsy
  • Calmodulin
  • Binding Sites
  • Arrhythmias, Cardiac
 

Citation

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Yan, H., Wang, C., Marx, S. O., & Pitt, G. S. (2017). Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol, 149(2), 277–293. https://doi.org/10.1085/jgp.201611721
Yan, Haidun, Chaojian Wang, Steven O. Marx, and Geoffrey S. Pitt. “Calmodulin limits pathogenic Na+ channel persistent current.J Gen Physiol 149, no. 2 (February 2017): 277–93. https://doi.org/10.1085/jgp.201611721.
Yan H, Wang C, Marx SO, Pitt GS. Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol. 2017 Feb;149(2):277–93.
Yan, Haidun, et al. “Calmodulin limits pathogenic Na+ channel persistent current.J Gen Physiol, vol. 149, no. 2, Feb. 2017, pp. 277–93. Pubmed, doi:10.1085/jgp.201611721.
Yan H, Wang C, Marx SO, Pitt GS. Calmodulin limits pathogenic Na+ channel persistent current. J Gen Physiol. 2017 Feb;149(2):277–293.

Published In

J Gen Physiol

DOI

EISSN

1540-7748

Publication Date

February 2017

Volume

149

Issue

2

Start / End Page

277 / 293

Location

United States

Related Subject Headings

  • Voltage-Gated Sodium Channels
  • Protein Binding
  • Physiology
  • Mutation
  • Humans
  • HEK293 Cells
  • Epilepsy
  • Calmodulin
  • Binding Sites
  • Arrhythmias, Cardiac