title: Insights into the molecular mechanisms of bradycardia-triggered arrhythmias in long QT-3 syndrome.
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.
authors.affiliation: Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
authors.forename: Michihiro
authors.initials: M
authors.lastname: Tateyama
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kass
mesh_terms: D001145:Arrhythmias, Cardiac / Q000209:etiology*; D001919:Bradycardia / Q000150:complications*; D006801:Humans; D015640:Ion Channel Gating; D008133:Long QT Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D008954:Models, Biological; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D015222:Sodium Channels