{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T05:17:51Z","timestamp":1774329471247,"version":"3.50.1"},"reference-count":44,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2016,11,1]]},"abstract":"<jats:p>Channel activities of skeletal muscle ryanodine receptor (RyR1) are activated by micromolar Ca<jats:sup>2+<\/jats:sup>and inactivated by higher (\u223c1 mM) Ca<jats:sup>2+<\/jats:sup>. To gain insight into a mechanism underlying Ca<jats:sup>2+<\/jats:sup>-dependent inactivation of RyR1 and its relationship with skeletal muscle diseases, we constructed nine recombinant RyR1 mutants carrying malignant hyperthermia or centronuclear myopathy-associated mutations and determined RyR1 channel activities by [<jats:sup>3<\/jats:sup>H]ryanodine binding assay. These mutations are localized in or near the RyR1 domains which are responsible for Ca<jats:sup>2+<\/jats:sup>-dependent inactivation of RyR1. Four RyR1 mutations (F4732D, G4733E, R4736W, and R4736Q) in the cytoplasmic loop between the S2 and S3 transmembrane segments (S2\u2013S3 loop) greatly reduced Ca<jats:sup>2+<\/jats:sup>-dependent channel inactivation. Activities of these mutant channels were suppressed at 10\u2013100 \u03bcM Ca<jats:sup>2+<\/jats:sup>, and the suppressions were relieved by 1 mM Mg<jats:sup>2+<\/jats:sup>. The Ca<jats:sup>2+<\/jats:sup>- and Mg<jats:sup>2+<\/jats:sup>-dependent regulation of S2\u2013S3 loop RyR1 mutants are similar to those of the cardiac isoform of RyR (RyR2) rather than wild-type RyR1. Two mutations (T4825I and H4832Y) in the S4\u2013S5 cytoplasmic loop increased Ca<jats:sup>2+<\/jats:sup>affinities for channel activation and decreased Ca<jats:sup>2+<\/jats:sup>affinities for inactivation, but impairment of Ca<jats:sup>2+<\/jats:sup>-dependent inactivation was not as prominent as those of S2\u2013S3 loop mutants. Three mutations (T4082M, S4113L, and N4120Y) in the EF-hand domain showed essentially the same Ca<jats:sup>2+<\/jats:sup>-dependent channel regulation as that of wild-type RyR1. The results suggest that nine RyR1 mutants associated with skeletal muscle diseases were differently regulated by Ca<jats:sup>2+<\/jats:sup>and Mg<jats:sup>2+<\/jats:sup>. Four malignant hyperthermia-associated RyR1 mutations in the S2\u2013S3 loop conferred RyR2-type Ca<jats:sup>2+<\/jats:sup>- and Mg<jats:sup>2+<\/jats:sup>-dependent channel regulation.<\/jats:p>","DOI":"10.1152\/ajpcell.00134.2016","type":"journal-article","created":{"date-parts":[[2016,8,25]],"date-time":"2016-08-25T03:09:13Z","timestamp":1472094553000},"page":"C749-C757","source":"Crossref","is-referenced-by-count":24,"title":["Malignant hyperthermia-associated mutations in the S2-S3 cytoplasmic loop of type 1 ryanodine receptor calcium channel impair calcium-dependent inactivation"],"prefix":"10.1152","volume":"311","author":[{"given":"Angela C.","family":"Gomez","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina; and"},{"name":"Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy W.","family":"Holford","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina; and"},{"name":"Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohiro","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina; and"},{"name":"Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina, and Clemson University, Charleston, South Carolina"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/01.anes.0000299431.81267.3e"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.307926"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.10.1515"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-1-18"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00275.2006"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1994.266.6.C1485"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.16.11778"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.37.26120"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.012688999"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature13916"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411136200"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4160(02)00138-0"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(97)00781-3"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1021\/bi401586h"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.693325"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R800054200"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.09.006"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200606000-00008"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2014.00339"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2007.01.016"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2741\/A899"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/BF00240306"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20231"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-5793(99)01232-6"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(90)80399-4"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200709870"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20356"},{"key":"B28","volume-title":"Malignant Hyperthermia Susceptibility","author":"Rosenberg H"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-200503000-00007"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3181d69283"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e31828cebfe"},{"key":"B32","first-page":"870","volume":"12","author":"Schoenmakers TJ","year":"1992","journal-title":"Biotechniques"},{"key":"B33","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0031-6997(24)01313-9","volume":"49","author":"Sutko JL","year":"1997","journal-title":"Pharmacol Rev"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/339439a0"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.2.693"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.42.26332"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(96)79831-4"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1021\/bi971198b"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.105.066092"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1021\/bi051251t"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nature14063"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302165200"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-197582"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature13950"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00134.2016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T13:44:06Z","timestamp":1749563046000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00134.2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,1]]},"references-count":44,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2016,11,1]]}},"alternative-id":["10.1152\/ajpcell.00134.2016"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00134.2016","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,1]]}}}