Ryanodine receptor-bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia
| Autor: | Xiaojuan Xu, Tetsuro Oda, Yoshihide Nakamura, Hitoshi Uchinoumi, Shinichi Okuda, Takayoshi Kato, Yoriomi Hamada, Go Fukui, Shigeki Kobayashi, Masafumi Yano, Shigehiko Nishimura, Takeshi Yamamoto, Masaki Tamitani |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Calmodulin Mice Transgenic Catecholaminergic polymorphic ventricular tachycardia Ventricular tachycardia Ryanodine receptor 2 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Myocytes Cardiac Gene Knock-In Techniques Cells Cultured Binding Sites biology Voltage-dependent calcium channel Ryanodine receptor Chemistry Point mutation Ryanodine Receptor Calcium Release Channel General Medicine medicine.disease musculoskeletal system Phenotype Molecular biology Mice Inbred C57BL Disease Models Animal 030104 developmental biology Amino Acid Substitution 030220 oncology & carcinogenesis biology.protein cardiovascular system Tachycardia Ventricular Calcium tissues Protein Binding Research Article |
| Zdroj: | JCI insight. 4(11) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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