Shanghai Jiao Tong University, China.
Integr Biol (Camb). 2009 Sep;1(8-9):533-9. doi: 10.1039/b907812f. Epub 2009 Jun 24.
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 RyR1(R615C) channels may contribute to the pharmacogenetic skeletal muscle sensitivity, malignant hyperthermia (MH). We find that purified RyR1(R615C) from MH susceptible porcine skeletal muscle shows significantly reduced oligomerization when compared to RyR1(WT), indicating a potential loss of intrinsic intermolecular control. The MH-triggering volatile anesthetic, halothane, activates RyR1(R615C) and RyR1(WT) to a similar extent, using [(3)H]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 Ca(2+) 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.
簇状膜受体之间的功能偶联已被确定为改善许多生理过程中信号转导性能的一种新机制。然而，受体间偶联缺陷在疾病发病机制中的潜在作用尚未得到探索。兰尼碱受体（RyR）是肌肉中主要的钙释放通道，通常在肌浆网膜中形成有序的二维阵列。已知 RyR 的突变会导致骨骼肌和心脏的多种严重疾病。在这里，我们提出了一个模型，演示了相邻突变 RyR1（R615C）通道之间功能偶联受损如何导致药理学遗传骨骼肌敏感性，恶性高热（MH）。我们发现，与 RyR1（WT）相比，来自 MH 易感猪骨骼肌的纯化 RyR1（R615C）显示出明显减少的寡聚化，表明可能失去了内在的分子间控制。MH 触发挥发性麻醉剂，氟烷，以类似的程度激活 RyR1（R615C）和 RyR1（WT），使用[（3）H]ryanodine 结合作为激活的衡量标准。用模拟功能丧失的功能间 RyR 偶联的参数对 RyR1 阵列功能进行建模，再现了 MH 的分子表型 - RyR1 通道在休息时对 Ca（2+）渗漏，并且在暴露于氟烷后具有较长的开放时间。我们的工作表明，RyR1 之间的偶联缺陷是研究 MH 发病机制的一个新方向。
