Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia
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, prim...
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Published in | JCI insight Vol. 4; no. 11 |
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Main Authors | , , , , , , , , , , , , |
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American Society for Clinical Investigation
06.06.2019
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Abstract | 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 (3584-3603 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 - bidirectional or polymorphic ventricular tachycardia, spontaneous Ca2+ transients, and Ca2+ sparks - 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. |
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AbstractList | 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 (3584-3603 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 - bidirectional or polymorphic ventricular tachycardia, spontaneous Ca2+ transients, and Ca2+ sparks - 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. 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 (3584–3603 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 — bidirectional or polymorphic ventricular tachycardia, spontaneous Ca 2+ transients, and Ca 2+ sparks — 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. Enhancement of the calmodulin-binding affinity of the RyR2 by a single amino acid substitution in the calmodulin-binding domain protected against catecholaminergic polymorphic ventricular tachycardia. |
Author | Yamamoto, Takeshi Oda, Tetsuro Nakamura, Yoshihide Tamitani, Masaki Xu, Xiaojuan Okuda, Shinichi Nishimura, Shigehiko Yano, Masafumi Kato, Takayoshi Fukui, Go Hamada, Yoriomi Kobayashi, Shigeki Uchinoumi, Hitoshi |
AuthorAffiliation | 1 Department of Medicine and Clinical Science, Division of Cardiology, and 3 Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China 2 Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan |
AuthorAffiliation_xml | – name: 1 Department of Medicine and Clinical Science, Division of Cardiology, and – name: 2 Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan – name: 3 Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China |
Author_xml | – sequence: 1 givenname: Yoshihide surname: Nakamura fullname: Nakamura, Yoshihide organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 2 givenname: Takeshi surname: Yamamoto fullname: Yamamoto, Takeshi organization: Faculty of Health Sciences, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan – sequence: 3 givenname: Shigeki surname: Kobayashi fullname: Kobayashi, Shigeki organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 4 givenname: Masaki surname: Tamitani fullname: Tamitani, Masaki organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 5 givenname: Yoriomi surname: Hamada fullname: Hamada, Yoriomi organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 6 givenname: Go surname: Fukui fullname: Fukui, Go organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 7 givenname: Xiaojuan surname: Xu fullname: Xu, Xiaojuan organization: Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai, China – sequence: 8 givenname: Shigehiko surname: Nishimura fullname: Nishimura, Shigehiko organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 9 givenname: Takayoshi surname: Kato fullname: Kato, Takayoshi organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 10 givenname: Hitoshi surname: Uchinoumi fullname: Uchinoumi, Hitoshi organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 11 givenname: Tetsuro surname: Oda fullname: Oda, Tetsuro organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 12 givenname: Shinichi surname: Okuda fullname: Okuda, Shinichi organization: Department of Medicine and Clinical Science, Division of Cardiology, and – sequence: 13 givenname: Masafumi surname: Yano fullname: Yano, Masafumi organization: Department of Medicine and Clinical Science, Division of Cardiology, and |
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Cites_doi | 10.1074/jbc.M209564200 10.1038/ncpcardio0419 10.1161/CIRCRESAHA.111.300290 10.1253/circj.CJ-10-0680 10.1016/j.yjmcc.2004.05.026 10.1016/j.bbrc.2014.03.152 10.1242/jcs.064071 10.1161/CIRCRESAHA.109.209312 10.1074/jbc.M700660200 10.1093/cvr/cvq108 10.1124/mol.65.5.1258 10.1016/j.jjcc.2008.10.008 10.1016/j.bbrc.2010.03.046 10.1161/JAHA.117.008155 10.1074/jbc.M704474200 10.2741/A803 10.1016/j.jacc.2009.01.065 10.1161/CIRCRESAHA.110.226845 10.1016/j.yjmcc.2016.06.007 10.1172/JCI29515 10.1093/cvr/cvs271 10.1161/CIRCULATIONAHA.107.718957 10.1016/j.yjmcc.2018.10.011 10.1124/mol.115.097691 10.1161/CIRCULATIONAHA.104.507921 10.1016/j.hrthm.2018.02.006 10.1016/j.ceca.2006.07.011 10.1161/CIRCRESAHA.114.302857 10.1016/j.yjmcc.2015.06.009 |
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Snippet | Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using a... |
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Title | Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia |
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