{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T17:51:06Z","timestamp":1793641866233,"version":"4.5.1"},"reference-count":63,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,11,16]],"date-time":"2012-11-16T00:00:00Z","timestamp":1353024000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR052534"],"award-info":[{"award-number":["AR052534"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2013,3]]},"abstract":"<jats:p>\n                    Malignant hyperthermia (MH) susceptibility has been attributed to a leaky sarcoplasmic reticulum (SR) caused by missense mutations in\n                    <jats:italic>RYR1<\/jats:italic>\n                    or\n                    <jats:italic>CACNA1S<\/jats:italic>\n                    , and the MH crisis has been attributed solely to massive self\u2010sustaining release of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    from SR stores elicited by triggering agents. Here, we show in muscle cells from MH\u2010RyR1\n                    <jats:sup>R163C<\/jats:sup>\n                    knock\u2010in mice that increased passive SR Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak causes an enlarged basal influx of sarcolemmal Ca\n                    <jats:sup>2+<\/jats:sup>\n                    that results in chronically elevated myoplasmic free Ca\n                    <jats:sup>2+<\/jats:sup>\n                    concentration ([Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    ) at rest. We discovered that Gd\n                    <jats:sup>+3<\/jats:sup>\n                    and GsMTx\u20104 were more effective than BTP2 or expression of the dominant\u2010negative Orai1\n                    <jats:sup>E190Q<\/jats:sup>\n                    in reducing both Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry and [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    , implicating a non\u2010STIM1\/Orai1 SOCE pathway in resetting resting [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    . Indeed, two nonselective cationic channels, TRPC3 and TRPC6, are overexpressed, and [Na]\n                    <jats:sub>i<\/jats:sub>\n                    is chronically elevated in MH\u2010RyR1\n                    <jats:sup>R163C<\/jats:sup>\n                    muscle cells. [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    and [Na\n                    <jats:sup>+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    are persistently elevated\n                    <jats:italic>in vivo<\/jats:italic>\n                    and further increased by halothane in MH\u2010RyR1\n                    <jats:sup>R163C\/WT<\/jats:sup>\n                    muscle. These increases are markedly attenuated by local perfusion of Gd\n                    <jats:sup>+3<\/jats:sup>\n                    or GsMTx\u20104 and completely suppressed by dantrolene. These results contribute a new paradigm for understanding MH pathophysiology by demonstrating that nonselective sarcolemmal cation channel activity plays a critical role in causing myoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and Na\n                    <jats:sup>+<\/jats:sup>\n                    overload both at rest and during the MH crisis.\u2014Eltit, J. M., Ding, X., Pessah, I. N., Allen, P. D., Lopez, J. R. Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia.\n                    <jats:italic>FASEB J.<\/jats:italic>\n                    27, 991\u20131000 (2013).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.12-218354","type":"journal-article","created":{"date-parts":[[2012,11,17]],"date-time":"2012-11-17T02:37:27Z","timestamp":1353119847000},"page":"991-1000","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":82,"title":["Nonspecific sarcolemmal cation channels are critical for the pathogenesis of malignant hyperthermia"],"prefix":"10.1096","volume":"27","author":[{"given":"Jos\u00e9 M.","family":"Eltit","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics Virginia Commonwealth University Richmond Virginia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac N.","family":"Pessah","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences School of Veterinary Medicine University of California\u2013Davis Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 R.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,11,16]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1566524023362429"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2044.2004.03658.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/343559a0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(91)90461-M"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4598(200001)23:1<4::AID-MUS3>3.0.CO;2-D"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20356"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00173.2004"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00008.2010"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-10-104"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880080502"},{"key":"e_1_2_7_12_1","first-page":"85","article-title":"[Ca2+]i in muscles of malignant hyperthermia susceptible pigs determined in vivo with Ca2+\u2010selective microelectrodes","volume":"9","author":"Lopez J. 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