期刊
CIRCULATION RESEARCH
卷 96, 期 5, 页码 E25-E34出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000160555.58046.9a
关键词
I-Ks; sympathetic nervous system; electrophysiology; ion channels; Long-QT syndrome
资金
- NHLBI NIH HHS [R01 HL044365-13, R01 HL044365, 1P01-HL-30557, 1R01-HL 44365] Funding Source: Medline
I-Ks, the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the alpha- (KCNQ1) and beta- (KCNE1) subunits of I-Ks underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. beta-adrenergic stimulation increases IKs and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I-Ks regulates action potential duration (APD) during beta-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I-Ks in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of beta-adrenergic stimulation on channel kinetics. We then developed theoretical models of I-Ks in the absence and presence of beta-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation ( speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I-Ks and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I-KS kinetics in this electrical dysfunction.
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