{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:02:52Z","timestamp":1791244972517,"version":"4.1.0"},"reference-count":42,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,5,15]]},"abstract":"<jats:p>\n                    Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release in skeletal muscle and a potentially fatal rise in perioperative body temperature. Mutations causing MH susceptibility have been identified in two proteins critical for excitation\u2013contraction (EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1, the principal subunit of the L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel. All of the mutations that have been characterized previously augment EC coupling and\/or increase the rate of L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry. The Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1 mutation R174W associated with MH susceptibility occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca\n                    <jats:sub>V<\/jats:sub>\n                    channels [Carpenter D, et al. (2009)\n                    <jats:italic>BMC Med Genet<\/jats:italic>\n                    10:104\u2013115.]. To define the functional consequences of this mutation, we expressed it in\n                    <jats:italic>dysgenic<\/jats:italic>\n                    (Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1 null) myotubes. Unlike previously described MH-linked mutations in Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1 R174W-expressing myotubes, resting myoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    levels were elevated, and sarcoplasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1. Our results indicate that Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyR1-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    leak from the SR, and that perturbation of Ca\n                    <jats:sub>V<\/jats:sub>\n                    1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1119207109","type":"journal-article","created":{"date-parts":[[2012,5,1]],"date-time":"2012-05-01T00:46:44Z","timestamp":1335833204000},"page":"7923-7928","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":89,"title":["Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca\n                    <sup>2+<\/sup>\n                    channel and the type 1 ryanodine receptor"],"prefix":"10.1073","volume":"109","author":[{"given":"Jose Miguel","family":"Eltit","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115;"},{"name":"Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger A.","family":"Bannister","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ong","family":"Moua","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of Colorado Denver\u2013Anschutz Medical Campus, Aurora, CO 80045;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Altamirano","sequence":"additional","affiliation":[{"name":"Centro de Estudios Moleculares de la C\u00e9lula, Instituto de Ciencias Biom\u00e9dicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile 8380453;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Malignant Hyperthermia Investigation Unit, Leeds Institute of Molecular Medicine, St. James\u2019s University Hospital, Leeds LS9 7TF, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac N.","family":"Pessah","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, Center for Children\u2019s Environmental Health and Disease Prevention, School of Veterinary Medicine, University of California, Davis, CA 95616; 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