Non-equilibrium gating in cardiac Na+ channels: An original mechanism of arrhythmia

Colleen E Clancy, Michihiro Tateyama, Huajun Liu, Xander H T Wehrens, Robert S. Kass

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Background - Many long-QT syndrome (LQTS) mutations in the cardiac Na+ channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (Isus) during depolarization. However, some Na+ channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase Isus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype. Methods and Results - We developed new experimental approaches based on theoretical analyses to investigate Na+ channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation. Conclusions - Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.

Original languageEnglish (US)
Pages (from-to)2233-2237
Number of pages5
JournalCirculation
Volume107
Issue number17
DOIs
StatePublished - May 6 2003
Externally publishedYes

Keywords

  • Arrhythmia
  • Long-QT syndrome
  • Remodeling
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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