{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:10:59Z","timestamp":1790759459760,"version":"4.1.0"},"reference-count":44,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["1R01AR067738"],"award-info":[{"award-number":["1R01AR067738"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["R03AR066359"],"award-info":[{"award-number":["R03AR066359"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Australian National Health and Medical Research Council","award":["APP1020589"],"award-info":[{"award-number":["APP1020589"]}]},{"name":"Australian National Health and Medical Research Council","award":["APP1002589"],"award-info":[{"award-number":["APP1002589"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2018,3,1]]},"abstract":"<jats:p> Malignant hyperthermia (MH) susceptibility has been recently linked to a novel variant of \u03b2<jats:sub>1a<\/jats:sub> subunit of the dihydropyridine receptor (DHPR), a channel essential for Ca<jats:sup>2+<\/jats:sup> regulation in skeletal muscle. Here we evaluate the effect of the mutant variant V156A on the structure\/function of DHPR \u03b2<jats:sub>1a<\/jats:sub> subunit and assess its role on Ca<jats:sup>2+<\/jats:sup> metabolism of cultured myotubes. Using differential scanning fluorimetry, we show that mutation V156A causes a significant reduction in thermal stability of the Src homology 3\/guanylate kinase core domain of \u03b2<jats:sub>1a<\/jats:sub> subunit. Expression of the variant subunit in \u03b2<jats:sub>1<\/jats:sub>-null mouse myotubes resulted in increased sensitivity to caffeine stimulation. Whole cell patch-clamp analysis of \u03b2<jats:sub>1a<\/jats:sub>-V156A-expressing myotubes revealed a \u22122 mV shift in voltage dependence of channel activation, but no changes in Ca<jats:sup>2+<\/jats:sup> conductance, current kinetics, or sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> load were observed. Measurement of resting free Ca<jats:sup>2+<\/jats:sup> and Na<jats:sup>+<\/jats:sup> concentrations shows that both cations were significantly elevated in \u03b2<jats:sub>1a<\/jats:sub>-V156A-expressing myotubes and that these changes were linked to increased rates of plasmalemmal Ca<jats:sup>2+<\/jats:sup> entry through Na<jats:sup>+<\/jats:sup>\/Ca<jats:sup>2+<\/jats:sup> exchanger and\/or transient receptor potential canonical channels. Overall, our data show that mutant variant V156A results in instability of protein subdomains of \u03b2<jats:sub>1a<\/jats:sub> subunit leading to a phenotype of Ca<jats:sup>2+<\/jats:sup> dysregulation that partly resembles that of other MH-linked mutations of DHPR \u03b1<jats:sub>1S<\/jats:sub> subunit. These data prove that homozygous expression of variant \u03b2<jats:sub>1a<\/jats:sub>-V156A has the potential to be a pathological variant, although it may require other gene defects to cause a full MH phenotype. <\/jats:p>","DOI":"10.1152\/ajpcell.00187.2017","type":"journal-article","created":{"date-parts":[[2017,12,6]],"date-time":"2017-12-06T15:20:19Z","timestamp":1512573619000},"page":"C323-C333","source":"Crossref","is-referenced-by-count":13,"title":["Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-\u03b2<sub>1a<\/sub> subunit (CACNB1)"],"prefix":"10.1152","volume":"314","author":[{"given":"Claudio F.","family":"Perez","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Eltit","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, Virginia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose R.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, University of California, Davis, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00f3ra","family":"Bodn\u00e1r","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela F.","family":"Dulhunty","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, Australian National University, Canberra, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouvik","family":"Aditya","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, Australian National University, Canberra, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco G.","family":"Casarotto","sequence":"additional","affiliation":[{"name":"John Curtin School of Medical Research, Australian National University, Canberra, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1097\/00000542-199201000-00019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.550764"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.03.035"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200910329"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.307926"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(99)77336-4"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(97)78113-X"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X1604400625"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2012.08.028"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2350-10-104"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20131553"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1301087110"},{"key":"B13","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1093\/bja\/45.6.638","volume":"45","author":"Ellis FR","year":"1973","journal-title":"Br J Anaesth"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119207109"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-218354"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.164525"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.615526"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018380108"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2011.01.005"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.107300"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00311.2003"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X1504300204"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.24.13961"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2013.11.4503"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nature22366"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-002-0871-5"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2741\/3053"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-211334"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.07.019"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/227680a0"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1001\/jama.293.23.2918"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880080502"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/mus.880110113"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1996.76.2.537"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1086\/515454"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.2174\/1566524023362429"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.763896"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00008.2010"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.01.022"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20356"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2017.07.017"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00173.2004"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00133.2006"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M302165200"}],"container-title":["American Journal of Physiology-Cell Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.physiology.org\/doi\/pdf\/10.1152\/ajpcell.00187.2017","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T15:55:06Z","timestamp":1718639706000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.physiology.org\/doi\/10.1152\/ajpcell.00187.2017"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,1]]},"references-count":44,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,3,1]]}},"alternative-id":["10.1152\/ajpcell.00187.2017"],"URL":"https:\/\/doi.org\/10.1152\/ajpcell.00187.2017","relation":{},"ISSN":["0363-6143","1522-1563"],"issn-type":[{"value":"0363-6143","type":"print"},{"value":"1522-1563","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,1]]}}}