RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice
RyR1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice
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DOI：
10.1016/j.cell.2008.02.042
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发表时间：
2008-04-04
期刊：
影响因子：
64.5
通讯作者：
Hamilton, Susan L.
中科院分区：
文献类型：
--
作者：
Durham, William J.;Aracena-Parks, Paula;Hamilton, Susan L.
ryanodine受体（RyR1）发生恶性高热突变（Y522S）的小鼠在环境温度升高时表现出肌肉挛缩、横纹肌溶解和死亡。我们证明RyR1中的这种突变导致Ca2+泄漏，从而驱动活性氮物种（RNS）的产生增加。随后突变体RyR1的s -亚硝基化增加了其对激活的温度敏感性，在暴露于高温时产生肌肉收缩。人类的Y522S突变与核心疾病有关。杂合子Y522S小鼠肌肉中有许多线粒体肿胀和畸形。随着年龄的增长，突变的肌肉表现出减少的力量生产和增加的线粒体脂质过氧化。长期用n -乙酰半胱氨酸治疗可以防止线粒体氧化损伤和力量生成的下降。我们提出了一种前馈循环机制，该机制增加了RyR1激活的温度敏感性，并成为中暑和猝死的基础。这个循环最终产生线粒体受损的肌病。
Mice with a malignant hyperthermia mutation (Y522S) in the ryanodine receptor (RyR1) display muscle contractures, rhabdomyolysis, and death in response to elevated environmental temperatures. We demonstrate that this mutation in RyR1 causes Ca2+ leak, which drives increased generation of reactive nitrogen species (RNS). Subsequent S-nitrosylation of the mutant RyR1 increases its temperature sensitivity for activation, producing muscle contractures upon exposure to elevated temperatures. The Y522S mutation in humans is associated with central core disease. Many mitochondria in the muscle of heterozygous Y522S mice are swollen and misshapen. The mutant muscle displays decreased force production and increased mitochondrial lipid peroxidation with aging. Chronic treatment with N-acetylcysteine protects against mitochondrial oxidative damage and the decline in force generation. We propose a feed-forward cyclic mechanism that increases the temperature sensitivity of RyR1 activation and underlies heat stroke and sudden death. The cycle eventually produces a myopathy with damaged mitochondria.