title: Stabilization of cardiac ryanodine receptor prevents intracellular calcium leak and arrhythmias.
abstract: Catecholaminergic polymorphic ventricular tachycardia is a form of exercise-induced sudden cardiac death that has been linked to mutations in the cardiac Ca2+ release channel/ryanodine receptor (RyR2) located on the sarcoplasmic reticulum (SR). We have shown that catecholaminergic polymorphic ventricular tachycardia-linked RyR2 mutations significantly decrease the binding affinity for calstabin-2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. We have proposed that RyR2-mediated diastolic SR Ca2+ leak triggers ventricular tachycardia (VT) and sudden cardiac death. In calstabin-2-deficient mice, we have now documented diastolic SR Ca2+ leak, monophasic action potential alternans, and bidirectional VT. Calstabin-deficient cardiomyocytes exhibited SR Ca2+ leak-induced aberrant transient inward currents in diastole consistent with delayed after-depolarizations. The 1,4-benzothiazepine JTV519, which increases the binding affinity of calstabin-2 for RyR2, inhibited the diastolic SR Ca2+ leak, monophasic action potential alternans and triggered arrhythmias. Our data suggest that calstabin-2 deficiency is as a critical mediator of triggers that initiate cardiac arrhythmias.
authors: Department of Physiology, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY 10032, USA.
authors: Stephan E
authors: SE
authors: Lehnart
authors: Cecile
authors: C
authors: Terrenoire
authors: Steven
authors: S
authors: Reiken
authors: Xander H T
authors: XH
authors: Wehrens
authors: Long-Sheng
authors: LS
authors: Song
authors: Erik J
authors: EJ
authors: Tillman
authors: Salvatore
authors: S
authors: Mancarella
authors: James
authors: J
authors: Coromilas
authors: W J
authors: WJ
authors: Lederer
authors: Robert S
authors: RS
authors: Kass
authors: Andrew R
authors: AR
authors: Marks