Impaired interaction between skeletal ryanodine receptors in malignant hyperthermia.
Impaired interaction between skeletal ryanodine receptors in malignant hyperthermia.
复制标题
恶性高热中骨骼兰尼碱受体之间的相互作用受损。
DOI：
10.1039/b907812f
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Parness,Jerome
中科院分区：
文献类型：
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作者：
Liang,Xin;Chen,Keying;Fruen,Bradley;Hu,Jun;Ma,Jianjie;Hu,Xiaofang;Parness,Jerome
成簇膜受体之间的功能耦合已被确定为改善许多生理过程中信号传导性能的新机制。然而，缺陷型受体间偶联在疾病发病机制中的潜在作用此前尚未被探索过。 Ryanodine 受体 (RyRs) 是肌肉的主要钙释放通道，通常在肌浆网膜中形成有序的二维阵列。众所周知，RyR 突变会导致骨骼肌和心脏中的许多严重疾病。在这里，我们提出了一个模型，展示了相邻突变体 RyR1R615C 通道之间功能耦合受损如何可能导致药物遗传学骨骼肌敏感性、恶性高热 (MH)。我们发现，与 RyR1WT 相比，从 MH 易感猪骨骼肌中纯化的 RyR1R615C 显示出显着减少的寡聚化，表明内在分子间控制的潜在损失。 MH 触发挥发性麻醉剂氟烷将 RyR1R615C 和 RyR1WT 激活至类似程度，使用 [3H]ryanodine 结合作为激活量度。使用经过修改的参数对 RyR1 阵列函数进行建模，以模拟功能性 RyR 间耦合的损失，概括了 MH 分子表型 - RyR1 通道在静息时泄漏到 Ca2+ 以及暴露于氟烷后的长开放时间。我们的工作表明 RyR1 间偶联缺陷是研究 MH 发病机制的一个新方向。
Functional coupling between clustered membrane receptors has been identified as a novel mechanism to improve signaling performance in a number of physiological processes. The potential role of defective inter-receptor coupling in the pathogenesis of disease, however, has not previously been explored. Ryanodine receptors (RyRs), the primary calcium release channel of muscle, usually form ordered two-dimensional arrays in the sarcoplasmic reticulum membranes. Mutations in RyRs are known to cause a number of severe diseases both in skeletal muscle and in heart. Here we present a model demonstrating how impaired functional coupling between neighboring mutant RyR1R615Cchannels may contribute to the pharmacogenetic skeletal muscle sensitivity, malignant hyperthermia (MH). We find that purified RyR1R615Cfrom MH susceptible porcine skeletal muscle shows significantly reduced oligomerization when compared to RyR1WT, indicating a potential loss of intrinsic intermolecular control. The MH-triggering volatile anesthetic, halothane, activates RyR1R615Cand RyR1WTto a similar extent, using [3H]ryanodine binding as a measure of activation. Modeling RyR1 array function with parameters modified to simulate the loss of functional inter-RyR coupling recapitulates the MH molecular phenotype-RyR1 channels leaky to Ca2+at rest and long open-times following exposure to halothane. Our work suggests that a defect in inter-RyR1 coupling is a novel direction for research into the pathogenesis of MH.