Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation.
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 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 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. The full text of this article is available online at http://circres.ahajournals.org.
Terrenoire
Cecile
C
Department of Pharmacology, College of Physicians & Surgeons of Columbia University, New York, NY 10032, USA.
Clancy
Colleen E
CE
Cormier
Joseph W
JW
Sampson
Kevin J
KJ
Kass
Robert S
RS
D054758:A Kinase Anchor Proteins; D000200:Action Potentials / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D019943:Amino Acid Substitution; D000818:Animals; D016466:CHO Cells; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D051668:Delayed Rectifier Potassium Channels; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D007700:Kinetics; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology; D008955:Models, Cardiovascular; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D017354:Point Mutation; D011188:Potassium / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D013610:Tachycardia / Q000503:physiopathology; D014162:Transfection
D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D051668:Delayed Rectifier Potassium Channels; C489622:KCNE1 protein, human; C502068:KCNE5 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D011943:Receptors, Adrenergic, beta; D011993:Recombinant Fusion Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011188:Potassium