FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death
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DOI：
10.1016/s0092-8674(03)00434-3
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发表时间：
2003-06-27
期刊：
影响因子：
64.5
通讯作者：
Marks, AR
中科院分区：
文献类型：
--
作者：
Wehrens, XHT;Lehnart, SE;Marks, AR
心律失常是心脏性猝死的常见原因，可发生在结构正常的心脏中，尽管其机制尚不清楚。在心肌中，肌浆网上的兰尼碱受体（RyR 2）释放肌肉收缩所需的钙。FK 506结合蛋白（FKBP12.6）稳定RyR 2，防止在心动周期的静息期异常激活通道。我们发现，在运动过程中，cAMP依赖性蛋白激酶A（PKA）的RyR 2磷酸化部分解离FKBP12.6从通道，增加细胞内Ca 2+释放和心肌收缩力。FKBP 12.6（-/-）小鼠持续表现出运动诱导的室性心律失常，导致心脏性猝死。与运动诱导的心律失常相关的RyR 2突变（在儿茶酚胺能多形性室性心动过速[CPVT]患者中）降低了FKBP 12.6对RyR 2的亲和力，并在模拟运动的条件下增加了单通道活性。这些数据表明，“泄漏”RyR 2通道可以触发致命的心律失常，为CPVT提供了一个可能的解释。
Arrhythmias, a common cause of sudden cardiac death, can occur in structurally normal hearts, although the mechanism is not known. In cardiac muscle, the ryanodine receptor (RyR2) on the sarcoplasmic reticulum releases the calcium required for muscle contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation of the channel during the resting phase of the cardiac cycle. We show that during exercise, RyR2 phosphorylation by cAMP-dependent protein kinase A (PKA) partially dissociates FKBP12.6 from the channel, increasing intracellular Ca2+ release and cardiac contractility. FKBP12.6(-/-) mice consistently exhibited exercise-induced cardiac ventricular arrhythmias that cause sudden cardiac death. Mutations in RyR2 linked to exercise-induced arrhythmias (in patients with catecholaminergic polymorphic ventricular tachycardia [CPVT]) reduced the affinity of FKBP12.6 for RyR2 and increased single-channel activity under conditions that simulate exercise. These data suggest that "leaky" RyR2 channels can trigger fatal cardiac arrhythmias, providing a possible explanation for CPVT.