RyR2 mutation-linked arrhythmogenic diseases and its therapeutic strategies
RyR2 mutation-linked arrhythmogenic diseases and its therapeutic strategies
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DOI：
10.1254/fpj.20017
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发表时间：
2020-04-01
影响因子：
--
通讯作者：
Murayama, Takashi
中科院分区：
文献类型：
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作者：
Kurebayashi, Nagomi;Murayama, Takashi
2型兰尼碱受体（RyR 2）是肌浆网Ca 2+释放通道，在心脏兴奋-收缩偶联中起中心作用。RyR 2的异常活性与心脏细胞中的异常Ca 2+信号传导有关，这通常导致心律失常。例如，已经报道RyR 2中的氨基酸突变引起各种类型的心律失常，包括儿茶酚胺能多态性室性心动过速（CPVT）、特发性心室纤颤和左心室致密化不全。目前，与疾病相关的RyR 2突变总数超过300。此外，在慢性心力衰竭中，通过磷酸化、氧化或S-亚硝基化修饰RyR 2可能导致通道活性异常。这些不同疾病的心律失常机制尚未完全了解。我们最近建立了一种方法，通过使用HEK 293表达系统来定量评估各种致突变和修饰对RyR 2通道的影响。我们发现RyR 2的致突变性可分为两类：通道功能获得型和通道功能丧失型。由于它们在临床诊断中难以区分，因此我们的分析对于RyR 2连锁的致瘤性疾病的诊断和治疗策略的选择非常有用。本文综述了RyR 2突变相关的致瘤性疾病的研究进展和存在的问题。
The type 2 ryanodine receptor (RyR2) is a sarcoplasmic reticulum Ca2+ release channel that plays a central role in cardiac excitation-contraction coupling. Abnormal activity of the RyR2 is linked to abnormal Ca2+ signaling in cardiac cells, which often results in cardiac arrhythmias. For example, amino acid mutations in RyR2 have been reported to cause various types of arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation, and left ventricular non-compaction. At present, the total number of disease-associated RyR2 mutations exceeds 300. In addition, in chronic heart failure, modification of RyR2 by phosphorylation, oxidation or S-nitrosylation may cause abnormal channel activity. Arrhythmogenic mechanisms of these various disorders are not yet fully understood. We have recently established a method to quantitatively evaluate the effects of various arrhythmogenic mutations and modifications on RyR2 channels by using HEK293 expression system. We found that arrhythmogenic mutations in RyR2 are classified into two grpups: gain-of-function and loss-of-function of the channel. Since they are indistinguishable in clinical diagnosis, our analysis is very useful for diagnosis and choice of treatment strategies for RyR2-linked arrhythmogenic diseases. This review describes the current advances and issues of research on RyR2 mutation-related arrhythmogenic disorders.