Colleen E. Clancy, Michihiro Tateyama, Robert S. Kass
J Clin Invest.
2002;
110(9):1251–1262
doi:10.1172/JCI15928
This article Copyright © 2002, The American Society for Clinical Investigation
Abstract
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C
ongenital 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 α 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 (Isus), which can delay repolarization and prolong the QT interval. However, the mechanism of heart-rate dependence of Isus 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 Isus 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 Isus inverse heart-rate dependence.
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