{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T08:40:40Z","timestamp":1784882440321,"version":"3.55.0"},"reference-count":53,"publisher":"Rockefeller University Press","issue":"1","license":[{"start":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T00:00:00Z","timestamp":1576454400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T00:00:00Z","timestamp":1593993600000},"content-version":"vor","delay-in-days":203,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,1,6]]},"abstract":"<jats:p>Type 1 ryanodine receptor (RYR1) is a Ca2+ release channel in the sarcoplasmic reticulum in skeletal muscle and plays an important role in excitation\u2013contraction coupling. Mutations in the RYR1 gene cause severe muscle diseases such as malignant hyperthermia (MH), which is a disorder of CICR via RYR1. Thus far, &amp;gt;300 mutations in RYR1 have been reported in patients with MH. However, owing to a lack of comprehensive analysis of the structure\u2013function relationship of mutant RYR1, the mechanism remains largely unknown. Here, we combined functional studies and molecular dynamics (MD) simulations of RYR1 bearing disease-associated mutations at the N-terminal region. When expressed in HEK293 cells, the mutant RYR1 caused abnormalities in Ca2+ homeostasis. MD simulations of WT and mutant RYR1s were performed using crystal structure of the N-terminal domain (NTD) monomer, consisting of A, B, and C domains. We found that the mutations located around the interdomain region differentially affected hydrogen bonds\/salt bridges. Particularly, mutations at R402, which increase the open probability of the channel, cause clockwise rotation of BC domains with respect to the A domain by alteration of the interdomain interactions. Similar results were also obtained with artificial mutations that mimic alteration of the interactions. Our results reveal the importance of interdomain interactions within the NTD in the regulation of the RYR1 channel and provide insights into the mechanism of MH caused by the mutations at the NTD.<\/jats:p>","DOI":"10.1085\/jgp.201812235","type":"journal-article","created":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T14:43:58Z","timestamp":1576507438000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Insights into channel modulation mechanism of RYR1 mutants using Ca2+ imaging and molecular dynamics"],"prefix":"10.1085","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4368-4794","authenticated-orcid":true,"given":"Toshiko","family":"Yamazawa","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology, The Jikei University School of Medicine, Tokyo, Japan 1"},{"name":"Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5515-1533","authenticated-orcid":true,"given":"Haruo","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3845-2980","authenticated-orcid":true,"given":"Takashi","family":"Murayama","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology, The Jikei University School of Medicine, Tokyo, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideto","family":"Oyamada","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2"},{"name":"Department of Physiology, University of California, San Francisco, San Francisco, CA 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5005-9698","authenticated-orcid":true,"given":"Nagomi","family":"Kurebayashi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Kanemaru","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2"},{"name":"Division of Cellular and Molecular Pharmacology, Nihon University School of Medicine, Tokyo, Japan 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuji","family":"Oguchi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Medicine, Showa University, Tokyo, Japan 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9515-6574","authenticated-orcid":true,"given":"Takashi","family":"Sakurai","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Juntendo University School of Medicine, Tokyo, Japan 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamitsu","family":"Iino","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan 2"},{"name":"Division of Cellular and Molecular Pharmacology, Nihon University School of Medicine, Tokyo, Japan 7"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2019,12,16]]},"reference":[{"key":"2023072705553655400_bib1","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1085\/jgp.118.3.277","article-title":"Functional effects of central core disease mutations in the cytoplasmic region of the skeletal muscle ryanodine receptor","volume":"118","author":"Avila","year":"2001","journal-title":"J. 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