{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:09:22Z","timestamp":1779196162001,"version":"3.51.4"},"reference-count":29,"publisher":"American Society for Clinical Investigation","issue":"11","funder":[{"DOI":"10.13039\/501100001700","name":"The Ministry of Education, Culture, Sports, Science and Technology, Japan","doi-asserted-by":"crossref","award":["grant Nos. 26293189 to MY,15K09085 to TY,15K09142 to SK"],"award-info":[{"award-number":["grant Nos. 26293189 to MY,15K09085 to TY,15K09142 to SK"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,6,6]]},"abstract":"<jats:p>\n                    Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using a knockin (KI) mouse model (R2474S\/+), we previously reported that a single point mutation within the RyR2 sensitizes the channel to agonists, primarily mediated by defective interdomain interaction within the RyR2 and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there is a possible amino acid substitution within the CaM-binding domain in the RyR2 (3584\u20133603 residues) that can enhance its binding affinity to CaM and found that V3599K substitution showed the highest binding affinity of CaM to the CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K\/+) with a single amino acid substitution in the CaM-binding domain of the RyR2 and crossbred it with the heterozygous CPVT-associated R2474S\/+-KI mouse to obtain a double-heterozygous R2474S\/V3599K-KI mouse model. The CPVT phenotypes \u2014 bidirectional or polymorphic ventricular tachycardia, spontaneous Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients, and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sparks \u2014 were all inhibited in the R2474S\/V3599K mice. Thus, enhancement of the CaM-binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.126112","type":"journal-article","created":{"date-parts":[[2019,6,5]],"date-time":"2019-06-05T11:01:16Z","timestamp":1559732476000},"source":"Crossref","is-referenced-by-count":28,"title":["Ryanodine receptor\u2013bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia"],"prefix":"10.1172","volume":"4","author":[{"given":"Yoshihide","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Medicine and Clinical Science, Division of Cardiology, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, 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