Lehnart Stephan E, Terrenoire Cecile, Reiken Steven, Wehrens Xander H T, Song Long-Sheng, Tillman Erik J, Mancarella Salvatore, Coromilas James, Lederer W J, Kass Robert S, Marks Andrew R
Department of Physiology, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 2006 May 16;103(20):7906-10. doi: 10.1073/pnas.0602133103. Epub 2006 May 3.
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.
儿茶酚胺能多形性室性心动过速是运动诱发的心源性猝死的一种形式，它与位于肌浆网（SR）上的心脏Ca2+释放通道/兰尼碱受体（RyR2）的突变有关。我们已经表明，与儿茶酚胺能多形性室性心动过速相关的RyR2突变显著降低了与钙稳定蛋白-2（FKBP12.6）的结合亲和力，钙稳定蛋白-2是一种稳定通道关闭状态的亚基。我们提出，RyR2介导的舒张期SR Ca2+渗漏触发室性心动过速（VT）和心源性猝死。在缺乏钙稳定蛋白-2的小鼠中，我们现在记录到了舒张期SR Ca2+渗漏、单相动作电位交替和双向VT。缺乏钙稳定蛋白的心肌细胞在舒张期表现出SR Ca2+渗漏诱导的异常瞬时内向电流，这与延迟后去极化一致。1,4-苯并噻氮䓬类药物JTV519增加了钙稳定蛋白-2与RyR2的结合亲和力，抑制了舒张期SR Ca2+渗漏、单相动作电位交替并触发心律失常。我们的数据表明，钙稳定蛋白-2缺乏是引发心律失常的触发因素的关键介质。
