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Updated: Mar 8, 2026

Pull-down of Calmodulin-binding Proteins
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Published on: January 23, 2012

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Calmodulin limits pathogenic Na+ channel persistent current

Haidun Yan1, Chaojian Wang1, Steven O Marx2,3

  • 1Ion Channel Research Unit, Duke University Medical Center, Durham, NC 27710.

The Journal of General Physiology
|January 15, 2017
PubMed

Insights

Calmodulin (CaM) binding to sodium channel C-terminal domains limits persistent current, preventing arrhythmias and epilepsy. Restoring CaM binding corrects defects in voltage-gated Na+ channels.

Area of Science:

  • Molecular neuroscience
  • Ion channel biophysics
  • Cardiac and neurological channelopathies

Background:

  • Delayed inactivation of voltage-gated sodium (NaV) channels causes persistent Na+ current, linked to cardiac arrhythmias and epilepsy.
  • The molecular mechanisms underlying NaV channel inactivation defects remain largely unknown.

Purpose of the Study:

  • To investigate the role of calmodulin (CaM) in regulating NaV channel inactivation.
  • To identify molecular contributors to NaV channel inactivation defects and potential therapeutic targets.

Main Methods:

  • Investigated CaM binding to NaV channel intracellular C-terminal domains (CTDs).
  • Analyzed effects of disease-associated mutations on CaM binding and channel function.
  • Utilized electrophysiology and biochemical assays to assess CaM's impact on NaV channel activity.

Main Results:

  • CaM binding to NaV CTDs limits persistent Na+ current and accelerates inactivation across the NaV family.
  • Mutations causing arrhythmias (NaV1.5) or epilepsy (NaV1.2) reduce CaM binding to CTDs.
  • Increasing CaM availability restores normal inactivation in mutant channels and reduces persistent current in wild-type NaV1.6.

Conclusions:

  • CaM acts as a critical regulator of NaV channel inactivation by binding to CTDs.
  • Reduced CaM binding due to mutations contributes to channelopathies like arrhythmias and epilepsy.
  • Modulating CaM availability may offer a therapeutic strategy for treating NaV channel-related disorders.

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