{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:21:39Z","timestamp":1789986099884,"version":"4.0.1"},"reference-count":65,"publisher":"Portland Press Ltd.","issue":"16","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,8,15]]},"abstract":"<jats:p>Mutations in the skeletal muscle ryanodine receptor (RyR1) cause malignant hyperthermia (MH) and central core disease (CCD), whereas mutations in the cardiac ryanodine receptor (RyR2) lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). Most disease-associated RyR1 and RyR2 mutations are located in the N-terminal, central, and C-terminal regions of the corresponding ryanodine receptor (RyR) isoform. An increasing body of evidence demonstrates that CPVT-associated RyR2 mutations enhance the propensity for spontaneous Ca2+ release during store Ca2+ overload, a process known as store overload-induced Ca2+ release (SOICR). Considering the similar locations of disease-associated RyR1 and RyR2 mutations in the RyR structure, we hypothesize that like CPVT-associated RyR2 mutations, MH\/CCD-associated RyR1 mutations also enhance SOICR. To test this hypothesis, we determined the impact on SOICR of 12 MH\/CCD-associated RyR1 mutations E2347-del, R2163H, G2434R, R2435L, R2435H, and R2454H located in the central region, and Y4796C, T4826I, L4838V, A4940T, G4943V, and P4973L located in the C-terminal region of the channel. We found that all these RyR1 mutations reduced the threshold for SOICR. Dantrolene, an acute treatment for MH, suppressed SOICR in HEK293 cells expressing the RyR1 mutants R164C, Y523S, R2136H, R2435H, and Y4796C. Interestingly, carvedilol, a commonly used \u03b2-blocker that suppresses RyR2-mediated SOICR, also inhibits SOICR in these RyR1 mutant HEK293 cells. Therefore, these results indicate that a reduced SOICR threshold is a common defect of MH\/CCD-associated RyR1 mutations, and that carvedilol, like dantrolene, can suppress RyR1-mediated SOICR. Clinical studies of the effectiveness of carvedilol as a long-term treatment for MH\/CCD or other RyR1-associated disorders may be warranted.<\/jats:p>","DOI":"10.1042\/bcj20170282","type":"journal-article","created":{"date-parts":[[2017,7,7]],"date-time":"2017-07-07T20:30:24Z","timestamp":1499459424000},"page":"2749-2761","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Reduced threshold for store overload-induced Ca2+ release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease"],"prefix":"10.1042","volume":"474","author":[{"given":"Wenqian","family":"Chen","sequence":"first","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Koop","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Liu","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenting","family":"Guo","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhong","family":"Wei","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruiwu","family":"Wang","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David H.","family":"MacLennan","sequence":"additional","affiliation":[{"name":"Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T.","family":"Dirksen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester, Rochester, NY 14642, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui Rong Wayne","family":"Chen","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta T2N 4N1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2017,8,7]]},"reference":[{"key":"2021112216481951500_BCJ-2017-0282C1","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1152\/physrev.00013.2002","article-title":"Ryanodine receptor calcium release channels","volume":"82","author":"Fill","year":"2002","journal-title":"Physiol. Rev."},{"key":"2021112216481951500_BCJ-2017-0282C2","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation-contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"2021112216481951500_BCJ-2017-0282C3","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.jmb.2014.08.004","article-title":"Ryanodine receptors: allosteric ion channel giants","volume":"427","author":"Van Petegem","year":"2015","journal-title":"J. Mol. Biol."},{"key":"2021112216481951500_BCJ-2017-0282C4","doi-asserted-by":"publisher","first-page":"5291","DOI":"10.1046\/j.1432-1327.2000.01566.x","article-title":"Ca2+ signalling and muscle disease","volume":"267","author":"MacLennan","year":"2000","journal-title":"Eur. J. Biochem."},{"key":"2021112216481951500_BCJ-2017-0282C5","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1002\/humu.20356","article-title":"Mutations in RYR1 in malignant hyperthermia and central core disease","volume":"27","author":"Robinson","year":"2006","journal-title":"Hum. Mutat."},{"key":"2021112216481951500_BCJ-2017-0282C6","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1016\/j.bbamcr.2010.11.009","article-title":"Mechanistic models for muscle diseases and disorders originating in the sarcoplasmic reticulum","volume":"1813","author":"MacLennan","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112216481951500_BCJ-2017-0282C7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s13023-015-0310-1","article-title":"Malignant hyperthermia: a review","volume":"10","author":"Rosenberg","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"2021112216481951500_BCJ-2017-0282C8","doi-asserted-by":"publisher","first-page":"2033","DOI":"10.1172\/JCI25664","article-title":"Cardiac and skeletal muscle disorders caused by mutations in the intracellular Ca2+ release channels","volume":"115","author":"Priori","year":"2005","journal-title":"J. Clin. Invest."},{"key":"2021112216481951500_BCJ-2017-0282C9","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1161\/CIRCRESAHA.110.226845","article-title":"Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis","volume":"108","author":"Priori","year":"2011","journal-title":"Circ. Res."},{"key":"2021112216481951500_BCJ-2017-0282C10","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.yjmcc.2006.08.115","article-title":"Ryanodine receptors and ventricular arrhythmias: emerging trends in mutations, mechanisms and therapies","volume":"42","author":"George","year":"2007","journal-title":"J. Mol. Cell Cardiol."},{"key":"2021112216481951500_BCJ-2017-0282C11","doi-asserted-by":"publisher","first-page":"3113","DOI":"10.1113\/jphysiol.2009.172155","article-title":"Store overload-induced Ca2+ release as a triggering mechanism for CPVT and MH episodes caused by mutations in RYR and CASQ genes","volume":"587","author":"MacLennan","year":"2009","journal-title":"J. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C12","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1161\/01.RES.0000235869.50747.e1","article-title":"Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: insights from a RyR2 R4496C knock-in mouse model","volume":"99","author":"Liu","year":"2006","journal-title":"Circ. Res."},{"key":"2021112216481951500_BCJ-2017-0282C13","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1093\/eurheartj\/ehl543","article-title":"Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves","volume":"28","author":"Paavola","year":"2007","journal-title":"Eur. Heart J.."},{"key":"2021112216481951500_BCJ-2017-0282C14","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/cvr\/26.3.193","article-title":"Functional implications of spontaneous sarcoplasmic reticulum Ca2+ release in the heart","volume":"26","author":"Lakatta","year":"1992","journal-title":"Cardiovasc. Res."},{"key":"2021112216481951500_BCJ-2017-0282C15","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1172\/JCI112701","article-title":"Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle","volume":"78","author":"Marban","year":"1986","journal-title":"J. Clin. Invest."},{"key":"2021112216481951500_BCJ-2017-0282C16","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1038\/304735a0","article-title":"Oscillations of intracellular Ca2+ in mammalian cardiac muscle","volume":"304","author":"Orchard","year":"1983","journal-title":"Nature"},{"key":"2021112216481951500_BCJ-2017-0282C17","doi-asserted-by":"publisher","first-page":"13062","DOI":"10.1073\/pnas.0402388101","article-title":"Ryr2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR)","volume":"101","author":"Jiang","year":"2004","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021112216481951500_BCJ-2017-0282C18","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.1161\/01.RES.0000192146.85173.4b","article-title":"Enhanced store overload-induced Ca2+ release and channel sensitivity to luminal Ca2+ activation are common defects of RyR2 mutations linked to ventricular tachycardia and sudden death","volume":"97","author":"Jiang","year":"2005","journal-title":"Circ. Res."},{"key":"2021112216481951500_BCJ-2017-0282C19","doi-asserted-by":"publisher","first-page":"12179","DOI":"10.1073\/pnas.0600268103","article-title":"Mice with the R176Q cardiac ryanodine receptor mutation exhibit catecholamine-induced ventricular tachycardia and cardiomyopathy","volume":"103","author":"Kannankeril","year":"2006","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021112216481951500_BCJ-2017-0282C20","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1042\/BJ20071287","article-title":"Endoplasmic reticulum Ca2+ measurements reveal that the cardiac ryanodine receptor mutations linked to cardiac arrhythmia and sudden death alter the threshold for store-overload-induced Ca2+ release","volume":"412","author":"Jones","year":"2008","journal-title":"Biochem. J."},{"key":"2021112216481951500_BCJ-2017-0282C21","doi-asserted-by":"crossref","DOI":"10.1093\/cvr\/cvq007","article-title":"Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse cardiomyocytes with a human CPVT mutation","author":"Sedej","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"2021112216481951500_BCJ-2017-0282C22","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1161\/CIRCRESAHA.111.256560","article-title":"Abnormal termination of Ca2+ release is a common defect of RyR2 mutations associated with cardiomyopathies","volume":"110","author":"Tang","year":"2012","journal-title":"Circ. Res."},{"key":"2021112216481951500_BCJ-2017-0282C23","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1042\/BJ20130594","article-title":"The CPVT-associated RyR2 mutation G230C enhances store overloadinduced Ca2+ release and destabilizes the N-terminal domains","volume":"454","author":"Liu","year":"2013","journal-title":"Biochem. J."},{"key":"2021112216481951500_BCJ-2017-0282C24","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1097\/00000542-197503000-00011","article-title":"Porcine malignant hyperthermia: effects of temperature and extracellular calcium concentration on halothane-induced contracture of susceptible skeletal muscle","volume":"42","author":"Nelson","year":"1975","journal-title":"Anesthesiology"},{"key":"2021112216481951500_BCJ-2017-0282C25","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bja\/52.2.139","article-title":"Pathology of muscle","volume":"52","author":"Buxton","year":"1980","journal-title":"Br. J. Anaesth."},{"key":"2021112216481951500_BCJ-2017-0282C26","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/0014-5793(83)80739-X","article-title":"Calcium-induced Ca2+ release from sarcoplasmic reticulum of pigs susceptible to malignant hyperthermia. The effects of halothane and dantrolene","volume":"161","author":"Ohnishi","year":"1983","journal-title":"FEBS Lett."},{"key":"2021112216481951500_BCJ-2017-0282C27","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/S0022-3565(25)23085-3","article-title":"Evidence for intraluminal Ca++ regulatory site defect in sarcoplasmic reticulum from malignant hyperthermia pig muscle","volume":"256","author":"Nelson","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2021112216481951500_BCJ-2017-0282C28","doi-asserted-by":"publisher","first-page":"347","DOI":"10.2174\/1566524023362429","article-title":"Malignant hyperthermia: a pharmacogenetic disease of Ca2+ regulating proteins","volume":"2","author":"Nelson","year":"2002","journal-title":"Curr. Mol. Med."},{"key":"2021112216481951500_BCJ-2017-0282C29","doi-asserted-by":"crossref","DOI":"10.1074\/jbc.M801944200","article-title":"Reduced threshold for luminal Ca2+ activation of RyR1 underlies a causal mechanism of porcine malignant hyperthermia","author":"Jiang","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112216481951500_BCJ-2017-0282C30","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/0165-6147(92)90101-B","article-title":"The genetic basis of malignant hyperthermia","volume":"13","author":"MacLennan","year":"1992","journal-title":"Trends Pharmacol. Sci."},{"key":"2021112216481951500_BCJ-2017-0282C31","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/nm.2406","article-title":"Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release","volume":"17","author":"Zhou","year":"2011","journal-title":"Nat. Med."},{"key":"2021112216481951500_BCJ-2017-0282C32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/0378-1119(89)90358-2","article-title":"Site-directed mutagenesis by overlap extension using the polymerase chain reaction [see comments]","volume":"77","author":"Ho","year":"1989","journal-title":"Gene"},{"key":"2021112216481951500_BCJ-2017-0282C33","doi-asserted-by":"publisher","first-page":"26332","DOI":"10.1074\/jbc.272.42.26332","article-title":"Caffeine and halothane sensitivity of intracellular Ca2+ release is altered by 15 calcium release channel (ryanodine receptor) mutations associated with malignant hyperthermia and\/or central core disease","volume":"272","author":"Tong","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112216481951500_BCJ-2017-0282C34","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1074\/jbc.274.2.693","article-title":"Measurement of resting cytosolic Ca2+ concentrations and Ca2+ store size in HEK-293 cells transfected with malignant hyperthermia or central core disease mutant Ca2+ release channels","volume":"274","author":"Tong","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112216481951500_BCJ-2017-0282C35","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. Gen. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C36","doi-asserted-by":"publisher","first-page":"3193","DOI":"10.1529\/biophysj.104.048447","article-title":"Distinct effects on Ca2+ handling caused by malignant hyperthermia and central core disease mutations in RyR1","volume":"87","author":"Dirksen","year":"2004","journal-title":"Biophys. J."},{"key":"2021112216481951500_BCJ-2017-0282C37","doi-asserted-by":"publisher","first-page":"17404","DOI":"10.1073\/pnas.0408030101","article-title":"Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor","volume":"101","author":"Palmer","year":"2004","journal-title":"Proc. Natl Acad. Sci. U.S.A."},{"key":"2021112216481951500_BCJ-2017-0282C38","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1097\/00000542-200612000-00016","article-title":"Pharmacologic and functional characterization of malignant hyperthermia in the R163C RyR1 knock-in mouse","volume":"105","author":"Yang","year":"2006","journal-title":"Anesthesiology"},{"key":"2021112216481951500_BCJ-2017-0282C39","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.cell.2008.02.042","article-title":"Ryr1 S-nitrosylation underlies environmental heat stroke and sudden death in Y522S RyR1 knockin mice","volume":"133","author":"Durham","year":"2008","journal-title":"Cell"},{"key":"2021112216481951500_BCJ-2017-0282C40","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1124\/mol.110.067959","article-title":"Functional and biochemical properties of ryanodine receptor type 1 channels from heterozygous R163C malignant hyperthermia-susceptible mice","volume":"79","author":"Feng","year":"2011","journal-title":"Mol. Pharmacol."},{"key":"2021112216481951500_BCJ-2017-0282C41","doi-asserted-by":"publisher","first-page":"4439","DOI":"10.1113\/jphysiol.2013.259572","article-title":"Altered Ca2+ concentration, permeability and buffering in the myofibre Ca2+ store of a mouse model of malignant hyperthermia","volume":"591","author":"Manno","year":"2013","journal-title":"J. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C42","doi-asserted-by":"publisher","first-page":"1231","DOI":"10.1002\/humu.23072","article-title":"Genotype-phenotype correlations of malignant hyperthermia and central core disease mutations in the central region of the RYR1 channel","volume":"37","author":"Murayama","year":"2016","journal-title":"Hum. Mutat."},{"key":"2021112216481951500_BCJ-2017-0282C43","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1093\/bja\/52.4.377","article-title":"Site of the muscle cell abnormality in swine susceptible to malignant hyperpyrexia","volume":"52","author":"Okumura","year":"1980","journal-title":"Br. J. Anaesth."},{"key":"2021112216481951500_BCJ-2017-0282C44","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1093\/bja\/62.5.566","article-title":"Effect of diltiazem and dantrolene on the contractility of isolated malignant hyperpyrexia-susceptible porcine skeletal muscle","volume":"62","author":"Foster","year":"1989","journal-title":"Br. J. Anaesth."},{"key":"2021112216481951500_BCJ-2017-0282C45","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1124\/jpet.105.084046","article-title":"Effects of azumolene on Ca2+ sparks in skeletal muscle fibers","volume":"314","author":"Zhang","year":"2005","journal-title":"J. Pharmacol. Exp. Ther.."},{"key":"2021112216481951500_BCJ-2017-0282C46","doi-asserted-by":"publisher","first-page":"26965","DOI":"10.1074\/jbc.272.43.26965","article-title":"Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors","volume":"272","author":"Fruen","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2021112216481951500_BCJ-2017-0282C47","doi-asserted-by":"publisher","first-page":"13810","DOI":"10.1074\/jbc.M006104200","article-title":"Dantrolene inhibition of ryanodine receptor Ca2+ release channels. Molecular mechanism and isoform selectivity","volume":"276","author":"Zhao","year":"2001","journal-title":"J. Biol. Chem."},{"key":"2021112216481951500_BCJ-2017-0282C48","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1124\/mol.115.097691","article-title":"Essential role of calmodulin in RyR inhibition by dantrolene","volume":"88","author":"Oo","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"2021112216481951500_BCJ-2017-0282C49","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1038\/252728a0","article-title":"Effect of dantrolene sodium on calcium movements in single muscle fibres","volume":"252","author":"Hainaut","year":"1974","journal-title":"Nature"},{"key":"2021112216481951500_BCJ-2017-0282C50","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1023\/A:1013644107519","article-title":"Malignant hyperthermia: an inherited disorder of skeletal muscle Ca+ regulation","volume":"21","author":"Louis","year":"2001","journal-title":"Biosci. Rep."},{"key":"2021112216481951500_BCJ-2017-0282C51","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1085\/jgp.118.4.355","article-title":"Effects of dantrolene on steps of excitation-contraction coupling in mammalian skeletal muscle fibers","volume":"118","author":"Szentesi","year":"2001","journal-title":"J .Gen. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C52","doi-asserted-by":"publisher","first-page":"H953","DOI":"10.1152\/ajpheart.00936.2011","article-title":"Dantrolene prevents arrhythmogenic Ca2+ release in heart failure","volume":"302","author":"Maxwell","year":"2012","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C53","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1002\/emmm.201100194","article-title":"Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia","volume":"4","author":"Jung","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"2021112216481951500_BCJ-2017-0282C54","doi-asserted-by":"publisher","first-page":"H818","DOI":"10.1152\/ajpheart.00287.2014","article-title":"Dantrolene suppresses spontaneous Ca2+ release without altering excitation-contraction coupling in cardiomyocytes of aged mice","volume":"307","author":"Domeier","year":"2014","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021112216481951500_BCJ-2017-0282C55","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.yjmcc.2016.06.007","article-title":"CaMKII-dependent phosphorylation of RyR2 promotes targetable pathological RyR2 conformational shift","volume":"98","author":"Uchinoumi","year":"2016","journal-title":"J. Mol. Cell Cardiol."},{"key":"2021112216481951500_BCJ-2017-0282C56","doi-asserted-by":"publisher","first-page":"2579","DOI":"10.1253\/circj.CJ-10-0680","article-title":"Dantrolene, a therapeutic agent for malignant hyperthermia, inhibits catecholaminergic polymorphic ventricular tachycardia in a RyR2(R2474S\/+) knock-in mouse model","volume":"74","author":"Kobayashi","year":"2010","journal-title":"Circ. J."},{"key":"2021112216481951500_BCJ-2017-0282C57","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1111\/jce.12320","article-title":"Dantrolene suppresses ventricular ectopy and arrhythmogenicity with acute myocardial infarction in a langendorff-perfused pacing-induced heart failure rabbit model","volume":"25","author":"Chou","year":"2014","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"2021112216481951500_BCJ-2017-0282C58","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1161\/CIRCULATIONAHA.113.005443","article-title":"Dantrolene improves survival after ventricular fibrillation by mitigating impaired calcium handling in animal models","volume":"129","author":"Zamiri","year":"2014","journal-title":"Circulation"},{"key":"2021112216481951500_BCJ-2017-0282C59","doi-asserted-by":"publisher","first-page":"e0125366","DOI":"10.1371\/journal.pone.0125366","article-title":"Antiarrhythmic effects of dantrolene in patients with catecholaminergic polymorphic ventricular tachycardia and replication of the responses using iPSC models","volume":"10","author":"Penttinen","year":"2015","journal-title":"PLoS ONE"},{"key":"2021112216481951500_BCJ-2017-0282C60","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1016\/j.hrthm.2016.09.014","article-title":"Antiarrhythmic effects of dantrolene in human diseased cardiomyocytes","volume":"14","author":"Hartmann","year":"2017","journal-title":"Heart Rhythm"},{"key":"2021112216481951500_BCJ-2017-0282C61","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nm.3440","article-title":"The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias","volume":"20","author":"Chen","year":"2014","journal-title":"Nat. Med."},{"key":"2021112216481951500_BCJ-2017-0282C62","doi-asserted-by":"crossref","DOI":"10.1126\/science.aah5324","article-title":"Structural basis for the gating mechanism of the type 2 ryanodine receptor RyR2","author":"Peng","year":"2016","journal-title":"Science"},{"key":"2021112216481951500_BCJ-2017-0282C63","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1111\/j.1365-2044.2004.03658.x","article-title":"Dantrolene\u2014a review of its pharmacology, therapeutic use and new developments","volume":"59","author":"Krause","year":"2004","journal-title":"Anaesthesia"},{"key":"2021112216481951500_BCJ-2017-0282C64","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature14063","article-title":"Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution","volume":"517","author":"Yan","year":"2015","journal-title":"Nature"},{"key":"2021112216481951500_BCJ-2017-0282C65","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.cell.2016.08.075","article-title":"Structural basis for gating and activation of RyR1","volume":"167","author":"des Georges","year":"2016","journal-title":"Cell"}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/474\/16\/2749\/691983\/bcj-2017-0282.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/474\/16\/2749\/691983\/bcj-2017-0282.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,21]],"date-time":"2025-06-21T12:19:26Z","timestamp":1750508366000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/474\/16\/2749\/49654\/Reduced-threshold-for-store-overload-induced-Ca2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,7]]},"references-count":65,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2017,8,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bcj20170282","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.727788287.793552462","asserted-by":"object"}]},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,7]]}}}