Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse
Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse
复制标题
DOI：
10.1096/fj.05-4497fje
复制
发表时间：
2006-02-01
期刊：
影响因子：
4.8
通讯作者：
Hamilton, Susan L.
中科院分区：
文献类型：
--
作者：
Chelu, Mihail G.;Goonasekera, Sanjeewa A.;Hamilton, Susan L.
恶性高热（MH）是一种危及生命的疾病，其特征是异氟烷或氟烷等卤化麻醉剂导致骨骼肌僵硬和体温升高。 RyR1（主要骨骼肌钙释放通道）的酪氨酸 522 突变为丝氨酸与人类恶性高热有关。在本研究中，发现携带这种突变的小鼠代表了第一个人类恶性高热的小鼠模型。 Y522S 突变纯合小鼠表现出骨骼缺陷，并在胚胎发育过程中或出生后不久死亡。与人类发生的这种突变相对应的杂合小鼠对 MH 很敏感，在接触异氟醚或热应激时会出现全身收缩和核心温度升高。杂合子小鼠的骨骼肌在体外表现出对咖啡因和热诱导的挛缩的敏感性增加。此外，突变的杂合表达导致 RyR1 对温度、咖啡因和电压激活的敏感性增强，但不会导致无代偿的肌浆网钙泄漏或钙储备耗尽。我们得出结论，Y522S 突变的杂合表达赋予对热和麻醉诱导的 MH 反应的敏感性。
Malignant hyperthermia (MH) is a life‐threatening disorder characterized by skeletal muscle rigidity and elevated body temperature in response to halogenated anesthetics such as isoflurane or halothane. Mutation of tyrosine 522 of RyR1 (the predominant skeletal muscle calcium release channel) to serine has been associated with human malignant hyperthermia. In the present study, mice created harboring this mutation were found to represent the first murine model of human malignant hyperthermia. Mice homozygous for the Y522S mutation exhibit skeletal defects and die during embryonic development or soon after birth. Heterozygous mice, which correspond to the human occurrence of this mutation, are MH susceptible, experiencing whole body contractions and elevated core temperatures in response to isoflurane exposure or heat stress. Skeletal muscles from heterozygous mice exhibit increased susceptibility to caffeine‐ and heat‐induced contractures in vitro. In addition, the heterozygous expression of the mutation results in enhanced RyR1 sensitivity to activation by temperature, caffeine, and voltage but not uncompensated sarcoplasmic reticulum calcium leak or store depletion. We conclude that the heterozygous expression of the Y522S mutation confers susceptibility to both heat‐ and anesthetic‐induced MH responses.