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Science 304 (5668): 292-296

Copyright © 2004 by the American Association for the Advancement of Science

Protection from Cardiac Arrhythmia Through Ryanodine Receptor-Stabilizing Protein Calstabin2

Xander H. T. Wehrens,1,2* Stephan E. Lehnart,1,2* Steven R. Reiken,1,2 Shi-Xian Deng,3 John A. Vest,1,2,3 Daniel Cervantes,3 James Coromilas,3 Donald W. Landry,3 Andrew R. Marks1,2,3{dagger}

Abstract: Ventricular arrhythmias can cause sudden cardiac death (SCD) in patients with normal hearts and in those with underlying disease such as heart failure. In animals with heart failure and in patients with inherited forms of exercise-induced SCD, depletion of the channel-stabilizing protein calstabin2 (FKBP12.6) from the ryanodine receptor–calcium release channel (RyR2) complex causes an intracellular Ca2+ leak that can trigger fatal cardiac arrhythmias. A derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca2+ leak that triggers arrhythmias. Thus, enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias.

1 Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
2 Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
3 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

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* These authors contributed equally to this paper.

{dagger} To whom correspondence should be addressed. E-mail: arm42{at}columbia.edu

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