Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia
Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia
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DOI：
10.1074/jbc.m801944200
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发表时间：
2008-07-25
影响因子：
4.8
通讯作者：
Chen, S. R. Wayne
中科院分区：
文献类型：
--
作者：
Jiang, Dawei;Chen, Wenqian;Chen, S. R. Wayne
骨骼肌Ca2+释放通道/ryanodine受体RyR1中自然发生的突变与恶性高热（MH）有关，恶性高热是一种危及生命的全身麻醉并发症。虽然人们早就认识到MH是由肌浆网不受控制或自发的Ca2+释放引起的，但MH RyR1突变如何使肌浆网易受挥发性麻醉诱导的自发Ca2+释放的影响尚不清楚。在这里，我们研究了猪MH突变R615C对RyR1通道的内在特性的影响，以及在储存Ca2+过载期间自发释放Ca2+的倾向，这一过程我们称之为储存超载诱导Ca2+释放（SOICR）。单通道分析显示，R615C突变显著增强了RyR1的腔内Ca2+激活。此外，与表达野生型RyR1的细胞相比，表达R615C突变体的HEK293细胞SOICR阈值降低。此外，氢激发剂氟烷增强了RyR1对腔内Ca2+和SOICR的响应。相反，有效治疗H的丹曲林在表达R615C突变体的HEK293细胞中抑制SOICR，而在表达RyR2突变体的细胞中没有抑制SOICR。这些数据表明，R615C突变通过降低腔内Ca2+激活和SOICR的阈值赋予MH易感性，而挥发性麻醉剂通过进一步降低阈值触发MH，丹曲林通过增加SOICR阈值抑制MH。总之，我们的数据支持一种观点，即改变腔内Ca2+调节RyR1代表MH的主要因果机制。
Naturally occurring mutations in the skeletal muscle Ca2+ release channel/ryanodine receptor RyR1 are linked to malignant hyperthermia (MH), a life-threatening complication of general anesthesia. Although it has long been recognized that MH results from uncontrolled or spontaneous Ca2+ release from the sarcoplasmic reticulum, how MH RyR1 mutations render the sarcoplasmic reticulum susceptible to volatile anestheticinduced spontaneous Ca2+ release is unclear. Here we investigated the impact of the porcine MH mutation, R615C, the human equivalent of which also causes MH, on the intrinsic properties of the RyR1 channel and the propensity for spontaneous Ca2+ release during store Ca2+ overload, a process we refer to as store overload-induced Ca2+ release (SOICR). Single channel analyses revealed that the R615C mutation markedly enhanced the luminal Ca2+ activation of RyR1. Moreover, HEK293 cells expressing the R615C mutant displayed a reduced threshold for SOICR compared with cells expressing wild type RyR1. Furthermore, the MH-triggering agent, halothane, potentiated the response of RyR1 to luminal Ca2+ and SOICR. Conversely, dantrolene, an effective treatment for H, suppressed SOICR in HEK293 cells expressing the R615C mutant, but not in cells expressing an RyR2 mutant. These data suggest that the R615C mutation confers MH susceptibility by reducing the threshold for luminal Ca2+ activation and SOICR, whereas volatile anesthetics trigger MH by further reducing the threshold, and dantrolene suppresses MH by increasing the SOICR threshold. Together, our data support a view in which altered luminal Ca2+ regulation of RyR1 represents a primary causal mechanism of MH.