doi: 10.1161/01.CIR.0000162461.67140.4C
(Circulation. 2005;111:2025-2032.)
© 2005 American Heart Association, Inc.
Arrhythmia/Electrophysiology |
Defective Cardiac Ryanodine Receptor Regulation During Atrial Fibrillation
From the Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology (J.A.V., X.H.T.W., S.R.R., S.E.L., A.R.M.), Cardiology Division, Department of Medicine (J.A.V., A.R.M.), and Department of Pharmacology (P.C., P.D., M.R.R.), Columbia University College of Physicians and Surgeons, New York, NY; and Department of Pharmacology and Toxicology Medical Faculty, Dresden University of Technology, Dresden, Germany (D.D., U.R.).
Correspondence to Andrew R. Marks, MD, Department of Physiology and Cellular Biophysics, Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, P&S 9-401, Box 65, 630 W 168th St, New York, NY 10032. E-mail arm42{at}columbia.edu
Received August 17, 2004; revision received December 7, 2004; accepted January 5, 2005.
Background— Ca2+ leak from the sarcoplasmic reticulum (SR) may play an important role in triggering and/or maintaining atrial arrhythmias, including atrial fibrillation (AF). Protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2) resulting in dissociation of the channel-stabilizing subunit calstabin2 (FK506-binding protein or FKBP12.6) causes SR Ca2+ leak in failing hearts and can trigger fatal ventricular arrhythmias. Little is known about the role of RyR2 dysfunction in AF, however.
Methods and Results— Left and right atrial tissue was obtained from dogs with AF induced by rapid right atrial pacing (n=6 for left atrial, n=4 for right atrial) and sham instrumented controls (n=6 for left atrial, n=4 for right atrial). Right atrial tissue was also collected from humans with AF (n=10) and sinus rhythm (n=10) and normal cardiac function. PKA phosphorylation of immunoprecipitated RyR2 was determined by back-phosphorylation and by immunoblotting with a phosphospecific antibody. The amount of calstabin2 bound to RyR2 was determined by coimmunoprecipitation. RyR2 channel currents were measured in planar lipid bilayers. Atrial tissue from both the AF dogs and humans with chronic AF showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel. Channels isolated from dogs with AF exhibited increased open probability under conditions simulating diastole compared with channels from control hearts, suggesting that these AF channels could predispose to a diastolic SR Ca2+ leak.
Conclusions— SR Ca2+ leak due to RyR2 PKA hyperphosphorylation may play a role in initiation and/or maintenance of AF.
Key Words: arrhythmia • atrium • fibrillation • calcium • ion channels
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