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Nakamura Yoshihide

Affiliate Master Yamaguchi University

An invited review following the Soujinkai Award : ryanodine receptor bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia

Medical Science & Innovation Volume 70 Issue 1-2 Page 1-6
published_at 2023-06
A050070000101
[fulltext] 2.58 MB
Title
An invited review following the Soujinkai Award : ryanodine receptor bound calmodulin is essential to protect against catecholaminergic polymorphic ventricular tachycardia
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using knock-in mouse (KI) model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitized the channel to agonists, primarily mediated by defective inter-domain 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 was a possible amino-acid substitution within the CaM-binding domain in the RyR2 (3584-3603) that can enhance its binding affinity to CaM, and found that V3599K substitution showed the highest binding affinity of CaM to 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, were inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.
Creators Nakamura Yoshihide
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Creators Yamamoto Takeshi
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Creators Kobayashi Shigeki
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Creators Yano Masafumi
Affiliate Master Yamaguchi University
[kakenhi]15501 grid.268397.1
Source Identifiers
Creator Keywords
catecholaminergic polymorphic ventricular tachycardia ryanodine receptor calmodulin Ca^{2+}
Languages eng
Resource Type departmental bulletin paper
Publishers Yamaguchi University School of Medicine
Date Issued 2023-06
File Version Version of Record
Access Rights open access
Schools 大学院医学系研究科(医学)