RyR1-mediated Ca2+- induced Ca2+release plays a negligible role in excitation-contraction coupling of normal skeletal muscle

• 成果类型: Article
• 署名作者: Kobayashi, Takuya; Yamazawa, Toshiko; Kurebayashi, Nagomi; Konishi, Masato; Tanihata, Jun; Sugihara, Masami; Miki, Yoshifumi; Noguchi, Satoru; Inoue, Yukiko U.; Inoue, Takayoshi; Sakurai, Takashi; Murayama, Takashi
• 署名单位: Jikei University; Juntendo University; Jikei University; Jikei University; Jikei University; Juntendo University; National Center for Neurology & Psychiatry - Japan; National Center for Neurology & Psychiatry - Japan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14500
• DOI: 10.1073/pnas.2500449122
• 发表日期: 2025-08-26
• 关键词: congenital neuromuscular disease; induced calcium-release; uniform type-1 fiber; malignant hyperthermia; ryanodine receptor; sarcoplasmic-reticulum; dihydropyridine receptors; structural basis; ryr1; activation

摘要

Type 1 ryanodine receptor (RyR1) is a Ca2+ 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 Ca2+ release (DICR). RyR1 can also be gated via Ca2+-induced Ca2+ release (CICR), in which binding of Ca2+ directly opens the channel. Thus, RyR1 has two Ca2+ release modes; DICR and CICR, but the physiological role of CICR has been a matter of debate: whether CICR can amplify Ca2+ signals in E-C coupling. To address this issue, we created a mouse model carrying a mutation in the Ca2+- 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.