{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:55:10Z","timestamp":1775818510889,"version":"3.50.1"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"1","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,7,1]]},"abstract":"<jats:p>CASQ2 (cardiac calsequestrin) is commonly believed to serve as the SR (sarcoplasmic reticulum) luminal Ca2+ sensor. Ablation of CASQ2 promotes SCWs (spontaneous Ca2+ waves) and CPVT (catecholaminergic polymorphic ventricular tachycardia) upon stress but not at rest. How SCWs and CPVT are triggered by stress in the absence of the CASQ2-based luminal Ca2+ sensor is an important unresolved question. In the present study, we assessed the role of the newly identified RyR2 (ryanodine receptor 2)-resident luminal Ca2+ sensor in determining SCW propensity, CPVT susceptibility and cardiac hypertrophy in Casq2-KO (knockout) mice. We crossbred Casq2-KO mice with RyR2 mutant (E4872Q+\/\u2212) mice, which lack RyR2-resident SR luminal Ca2+ sensing, to generate animals with both deficiencies. Casq2+\/\u2212 and Casq2\u2212\/\u2212 mice showed stress-induced VTs (ventricular tachyarrhythmias), whereas Casq2+\/\u2212\/E4872Q+\/\u2212 and Casq2\u2212\/\u2212\/E4872Q+\/\u2212 mice displayed little or no stress-induced VTs. Confocal Ca2+ imaging revealed that Casq2\u2212\/\u2212 hearts frequently exhibited SCWs after extracellular Ca2+ elevation or adrenergic stimulation, whereas Casq2\u2212\/\u2212\/E4872Q+\/\u2212 hearts had few or no SCWs under the same conditions. Cardiac hypertrophy developed and CPVT susceptibility increased with age in Casq2\u2212\/\u2212 mice, but not in Casq2\u2212\/\u2212\/E4872Q+\/\u2212 mice. However, the amplitudes and dynamics of voltage-induced Ca2+ transients in Casq2\u2212\/\u2212 and Casq2\u2212\/\u2212\/E4872Q+\/\u2212 hearts were not significantly different. Our results indicate that SCWs, CPVT and hypertrophy in Casq2-null cardiac muscle are governed by the RyR2-resident luminal Ca2+ sensor. This implies that defects in CASQ2-based lumi-nal Ca2+ sensing can be overridden by the RyR2-resident luminal Ca2+ sensor. This makes this RyR2-resident sensor a promising molecular target for the treatment of Ca2+-mediated arrhythmias.<\/jats:p>","DOI":"10.1042\/bj20140126","type":"journal-article","created":{"date-parts":[[2014,4,24]],"date-time":"2014-04-24T08:45:17Z","timestamp":1398329117000},"page":"99-106","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The cardiac ryanodine receptor luminal Ca2+ sensor governs Ca2+ waves, ventricular tachyarrhythmias and cardiac hypertrophy in calsequestrin-null mice"],"prefix":"10.1042","volume":"461","author":[{"given":"Jingqun","family":"Zhang","sequence":"first","affiliation":[{"name":"Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Mi","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang","family":"Guo","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Tan","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guogen","family":"Wu","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander\u00a0W.","family":"Chen","sequence":"additional","affiliation":[{"name":"Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW Calgary, AB, Canada, T2N 4N1"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Fill","sequence":"additional","affiliation":[{"name":"Rush University Medical Center, 1750 West Harrison Street, 1229 JS, Chicago, IL 60612, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long-Sheng","family":"Song","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. 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