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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,26]]},"abstract":"<jats:p>\n                    Type 1 ryanodine receptor (RyR1) is a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release channel in the sarcoplasmic reticulum in skeletal muscle. In excitation\u2013contraction (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\n                    <jats:sup>2+<\/jats:sup>\n                    release (DICR). RyR1 can also be gated via Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -induced Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release (CICR), in which binding of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    directly opens the channel. Thus, RyR1 has two Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release modes; DICR and CICR, but the physiological role of CICR has been a matter of debate: whether CICR can amplify Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signals in E-C coupling. To address this issue, we created a mouse model carrying a mutation in the Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2500449122","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T14:13:09Z","timestamp":1755785589000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["RyR1-mediated Ca\n                    <sup>2+<\/sup>\n                    -induced Ca\n                    <sup>2+<\/sup>\n                    release plays a negligible role in excitation\u2013contraction coupling of normal skeletal muscle"],"prefix":"10.1073","volume":"122","author":[{"given":"Takuya","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine","place":["Tokyo, 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