Referenced in: none

Automatically associated channels: Kv7.1 , Nav1.5 , Slo1

Title: Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.

Authors: Colleen E Clancy, Michihiro Tateyama, Robert S Kass

Journal, date & volume: J. Clin. Invest., 2002 Nov , 110, 1251-62

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/12417563

Abstract
Congenital long QT syndrome is a rare disease in which the electrocardiogram QT interval is prolonged due to dysfunctional ventricular repolarization. Variant 3 (LQT-3) is associated with mutations in SCN5A, the gene coding for the heart Na(+) channel alpha subunit. Arrhythmias in LQT-3 mutation carriers are more likely to occur at rest, when heart rate is slow. Several LQT-3 Na(+) channel mutations exert their deleterious effects by promoting a mode of Na(+) channel gating wherein a fraction of channels fails to inactivate. This gating mode, termed "bursting, " results in sustained macroscopic inward Na(+) channel current (I(sus)), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of I(sus) has been unresolved at the single-channel level. We investigate an LQT-3 mutant (Y1795C) using experimental and theoretical frameworks to elucidate the molecular mechanism of I(sus) rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. Our results indicate that mutation-induced changes in the length of time mutant channels spend bursting, rather than how readily they burst, determines I(sus) inverse heart-rate dependence. These results link mutation-induced changes in Na+ channel gating mode transitions to heart rate-dependent changes in cellular electrical activity underlying a key LQT-3 clinical phenotype.