{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T18:40:03Z","timestamp":1759862403328,"version":"build-2065373602"},"reference-count":109,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"907","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2025,10,7]]},"abstract":"<jats:p>\n            Ryanodine receptor 1 (RYR1) is the sarcoplasmic reticulum (SR) Ca\n            <jats:sup>2+<\/jats:sup>\n            release channel required for both skeletal muscle contraction and Ca\n            <jats:sup>2+<\/jats:sup>\n            leak. Mutations in\n            <jats:italic toggle=\"yes\">RYR1<\/jats:italic>\n            cause malignant hyperthermia susceptibility (MHS) and enhanced sensitivity to heat stroke (ESHS), which can result in death due to excessive skeletal muscle thermogenesis upon exposure to volatile anesthetics or heat. Here, we investigated the molecular and physiological functions of phosphorylation of RYR1 at Ser\n            <jats:sup>2902<\/jats:sup>\n            by the kinase striated muscle preferentially expressed protein (SPEG). Muscle from SPEG-deficient mice expressing RYR1 with a Ser\n            <jats:sup>2902<\/jats:sup>\n            \u2192Asp\n            <jats:sup>2902<\/jats:sup>\n            (S2902D) point mutation to mimic phosphorylation by SPEG showed decreased SR Ca\n            <jats:sup>2+<\/jats:sup>\n            sparks. Muscle from mice homozygous for the S2902D point mutation had reduced SR Ca\n            <jats:sup>2+<\/jats:sup>\n            transients and small changes in force generation but overall mild phenotypic changes. YS mice, which are heterozygous for a Tyr\n            <jats:sup>524<\/jats:sup>\n            \u2192Ser\n            <jats:sup>524<\/jats:sup>\n            point mutation in RYR1, show increased Ca\n            <jats:sup>2+<\/jats:sup>\n            leak and are a model of MHS and ESHS. Crossing YS mice with S2902D mice led to decreased SR Ca\n            <jats:sup>2+<\/jats:sup>\n            leak and desensitized the mice to both volatile anesthetics and heat. Thus, SPEG inhibits SR Ca\n            <jats:sup>2+<\/jats:sup>\n            leak in skeletal muscle by phosphorylating Ser\n            <jats:sup>2902<\/jats:sup>\n            on RYR1, and mutation of Ser\n            <jats:sup>2902<\/jats:sup>\n            to Asp\n            <jats:sup>2902<\/jats:sup>\n            to mimic this phosphorylation event rescues YS mice from heat-induced death.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adx3087","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T17:58:13Z","timestamp":1759859893000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylation of RYR1 at Ser\n            <sup>2902<\/sup>\n            decreases Ca\n            <sup>2+<\/sup>\n            leak in skeletal muscle and susceptibility to malignant hyperthermia and heat stroke"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6737-1947","authenticated-orcid":true,"given":"Rachel Sue Zhen","family":"Yee","sequence":"first","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7513-7621","authenticated-orcid":true,"given":"Chang Seok","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0634-6478","authenticated-orcid":true,"given":"Ting","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1521-7977","authenticated-orcid":true,"given":"Sung Yun","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Yousif","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Courtney","family":"Cavazos","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Colyer","sequence":"additional","affiliation":[{"name":"Badrilla Ltd., Leeds LS1 3HB, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2728-8537","authenticated-orcid":true,"given":"Filip","family":"Van Petegem","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T1Z3, Canada."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6968-1516","authenticated-orcid":true,"given":"George G.","family":"Rodney","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0241-9369","authenticated-orcid":true,"given":"Susan L.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0609473103"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2741\/dirksen"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201812152"},{"key":"e_1_3_2_5_2","first-page":"420","article-title":"Critical role of intracellular RyR1 calcium release channels in skeletal muscle function and disease","volume":"6","author":"Hern\u00e1ndez-Ochoa E. O.","year":"2015","unstructured":"E. O. Hern\u00e1ndez-Ochoa, S. J. P. Pratt, R. M. Lovering, M. F. Schneider, Critical role of intracellular RyR1 calcium release channels in skeletal muscle function and disease. Front. Physiol. 6, 420 (2015).","journal-title":"Front. Physiol."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2119203119"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202213113"},{"key":"e_1_3_2_8_2","article-title":"A mathematical model to quantify RYR Ca2+ leak and associated heat produciton in resting human skeletal muscle fibers","volume":"154","author":"Barclay C. J.","year":"2022","unstructured":"C. J. Barclay, B. S. Launikonis, A mathematical model to quantify RYR Ca2+ leak and associated heat produciton in resting human skeletal muscle fibers. J. Gen. Physiol. 154, e202112994 (2022).","journal-title":"J. Gen. 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