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(Circulation Research. 2005;96:e25.)
© 2005 American Heart Association, Inc.

UltraRapid Communications

Autonomic Control of Cardiac Action Potentials

Role of Potassium Channel Kinetics in Response to Sympathetic Stimulation

Cecile Terrenoire^*, Colleen E. Clancy^*, Joseph W. Cormier^*, Kevin J. Sampson, Robert S. Kass

From the Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, NY. Present address for Colleen E. Clancy is the Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, NY.

Correspondence to Robert S. Kass, PhD, Department of Pharmacology, College of Physicians & Surgeons of Columbia University, 630 W 168th St PH 7W 318, New York, NY 10032. E-mail rsk20{at}columbia.edu

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 - (KCNQ1) and ß- (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. ß-adrenergic stimulation increases I_Ks 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 ß-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 ß-adrenergic stimulation on channel kinetics. We then developed theoretical models of I_Ks in the absence and presence of ß-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. The full text of this article is available online at http://circres.ahajournals.org.

Key Words: I_Ks • sympathetic nervous system • electrophysiology • ion channels • Long-QT syndrome

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