RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)
RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)
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DOI：
10.1073/pnas.0402388101
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发表时间：
2004-08-31
影响因子：
11.1
通讯作者：
Chen, SRW
中科院分区：
文献类型：
--
作者：
Jiang, DW;Xiao, BL;Chen, SRW
心脏ryanodine受体（RyR2）控制肌浆网Ca2+的释放，从而引发肌肉收缩。RyR2突变与室性心动过速（VT）和猝死有关，但确切的分子机制尚不清楚。众所周知，当肌浆网储存Ca2+含量达到临界水平时，会发生自发的Ca2+释放，我们将这一过程称为储存超载诱导的Ca2+释放（SOICR）。鉴于SOICR的致心律失常特性，我们表征了致病RyR2突变对人胚胎肾（HEK）293细胞SOICR的影响，并发现，在细胞外Ca2+水平升高时，表达RyR2的HEK293细胞表现出SOICR，其方式与在心脏细胞中观察到的几乎相同。通过这个细胞模型，我们证明了与VT和猝死相关的RyR2突变N4104K、R4496C和N14895D显著增加了SOICR的发生。在分子水平上，我们发现这些RyR2突变增加了单个RyR2通道对腔内Ca2+激活的敏感性，并提高了[H-3]ryanodine结合的基础水平。我们得出结论，致病的RyR2突变，通过增强RyR2腔内Ca2+激活，降低SOICR的阈值，从而增加诱发心律失常的倾向。异常RyR2腔内Ca2+激活可能有助于在各种心脏疾病（包括心力衰竭）中常见的SOICR增强，并可能代表Ca2+超载相关VT的统一机制。
The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from the sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but the precise molecular mechanism is unclear. It is known that when the sarcoplasmic reticulum store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs, a process we refer to as store-overload-induced Ca2+ release (SOICR). In view of the well documented arrhythmogenic nature of SOICR, we characterized the effects of disease-causing RyR2 mutations on SOICR in human embryonic kidney (HEK)293 cells and found that, at elevated extracellular Ca2+ levels, HEK293 cells expressing RyR2 displayed SOICR in a manner virtually identical to that observed in cardiac cells. Using this cell model, we demonstrated that the RyR2 mutations linked to VT and sudden death, N4104K, R4496C, and N14895D, markedly increased the occurrence of SOICR. At the molecular level, we showed that these RyR2 mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca2+ and enhanced the basal level of [H-3]ryanodine binding. We conclude that disease-causing RyR2 mutations, by enhancing RyR2 luminal Ca2+ activation, reduce the threshold for SOICR, which in turn increases the propensity for triggered arrhythmia. Abnormal RyR2 luminal Ca2+ activation likely contributes to the enhanced SOICR commonly observed in various cardiac conditions, including heart failure, and may represent a unifying mechanism for Ca2+ overload-associated VT.