恶性高热
雷亚尔1
去极化
内质网
骨骼肌
化学
生物物理学
肌肉收缩
内分泌学
兰尼定受体
生物化学
内科学
生物
麻醉
医学
作者
Takuya Kobayashi,Toshiko Yamazawa,Nagomi Kurebayashi,Masato Konishi,Jun Tanihata,Masami Sugihara,Y Miki,S. Noguchi,Yukiko Inoue,Takayoshi Inoue,Takashi Sakurai,Takashi Murayama
标识
DOI:10.1073/pnas.2500449122
摘要
Type 1 ryanodine receptor (RyR1) is a Ca 2+ release channel in the sarcoplasmic reticulum in skeletal muscle. In excitation–contraction (E-C) coupling, RyR1 opens by depolarization of transverse tubule membrane via physical interaction with dihydropyridine receptor, which is referred to as depolarization-induced Ca 2+ release (DICR). RyR1 can also be gated via Ca 2+ -induced Ca 2+ release (CICR), in which binding of Ca 2+ directly opens the channel. Thus, RyR1 has two Ca 2+ release modes; DICR and CICR, but the physiological role of CICR has been a matter of debate: whether CICR can amplify Ca 2+ signals in E-C coupling. To address this issue, we created a mouse model carrying a mutation in the Ca 2+ -binding site in RyR1 (RyR1-E3896A), which selectively inhibits CICR. Surprisingly, the homozygous RyR1-E3896A mice show no appreciable changes in E-C coupling, ex vivo muscle contraction, in vivo muscle performance, or muscle fiber type. Gain-of-function mutations in RyR1 cause malignant hyperthermia (MH), which is a lethal disease triggered by inhalational anesthetics. The E3896A mutation conferred resistance to isoflurane-induced MH episodes and severe heat stroke triggered by environmental heat stress. Our data suggest that RyR1-mediated CICR plays a negligible role in E-C coupling of normal skeletal muscle but may increase the risk for muscle diseases when excessively activated.
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