Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice
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DOI：
10.1172/jci35346
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发表时间：
2008-06-01
影响因子：
15.9
通讯作者：
Marks, Andrew R.
中科院分区：
文献类型：
--
作者：
Lehnart, Stephan E.;Mongillo, Marco;Marks, Andrew R.
Ca 2+释放通道Ryanodine受体2（RyR 2）是心脏兴奋-收缩偶联所必需的，也存在于大脑中。RyR 2的突变与运动诱发的心脏性猝死（儿茶酚胺能多形性室性心动过速[CPVT]）有关。CPVT相关的RyR 2突变导致“渗漏”RyR 2通道，这是由于钙稳定蛋白2（FKBP12.6）亚基的结合减少，其稳定了通道的闭合状态。我们发现Ryr 2中R2474 S突变的杂合子小鼠（Ryr 2-R2474 S小鼠）表现出自发性全身强直阵挛性癫痫发作（在没有心律失常的情况下发生），运动诱导的室性心律失常和心脏性猝死。用一种新的RyR 2特异性化合物（S107）治疗，增强钙蛋白2与突变型Ryr 2-R2474 S通道的结合，抑制通道泄漏，防止心律失常，提高癫痫发作阈值。因此，脑中CPVT相关突变渗漏Ryr 2-R2474 S通道可引起小鼠癫痫发作，与心律失常无关。基于这些数据，我们提出CPVT是一种神经心脏疾病，其中大脑中的RyR 2通道泄漏导致癫痫，心脏中的相同泄漏通道导致运动诱导的心脏性猝死。
The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.