Intracellular Calcium Attenuates Late Current Conducted by Mutant Human Cardiac Sodium Channels

Franck Potet*, Thomas M. Beckermann, Jennifer D. Kunic, Alfred L. George

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background - Mutations of the cardiac voltage-gated sodium channel (SCN5A gene encoding voltage-gated sodium channel [Na V 1.5]) cause congenital long-QT syndrome type 3 (LQT3). Most Na V 1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to increased late sodium current (I NaL), which is directly responsible for delayed repolarization and prolongation of the QT interval. LQT3 patients have highest risk of arrhythmia during sleep or during periods of slow heart rate. During exercise (high heart rate), there is elevated steady-state intracellular free calcium (Ca 2+) concentration. We hypothesized that higher levels of intracellular Ca 2+ may lower arrhythmia risk in LQT3 subjects through effects on I NaL. Methods and Results - We tested this idea by examining the effects of varying intracellular Ca 2+ concentrations on the level of I NaL in cells expressing a typical LQT3 mutation, delKPQ, and another SCN5A mutation, R225P. We found that elevated intracellular Ca 2+ concentration significantly reduced I NaL conducted by mutant channels but not wild-type channels. This attenuation of I NaL in delKPQ expressing cells by Ca 2+ was not affected by the CaM kinase II inhibitor KN-93 but was partially attenuated by truncating the C-terminus of the channel. Conclusions - We conclude that intracellular Ca 2+ contributes to the regulation of I NaL conducted by Na V 1.5 mutants and propose that, during excitation-contraction coupling, elevated intracellular Ca 2+ suppresses mutant channel I NaL and protects cells from delayed repolarization. These findings offer a plausible explanation for the lower arrhythmia risk in LQT3 subjects during fast heart rates.

Original languageEnglish (US)
Pages (from-to)933-941
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume8
Issue number4
DOIs
StatePublished - Aug 22 2015

Keywords

  • Na+ current
  • NaV1.5 voltage-gated sodium channel
  • SCN5A protein
  • calcium
  • electrophysiology
  • human
  • long QT syndrome

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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