Molecular mechanism of cardiac ryanodine receptor (RyR2) in catecholaminergic polymorphic ventricular tachycardia (CPVT)

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15849
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Yamaguchi University
• Principal Investigator: Uchinoumi Hitoshi 山口大学, 医学部附属病院, 助教 (80815655)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: カテコラミン誘発性心室頻拍 / 致死性不整脈 / リアノジン受容体 / カルシウムリーク / カルモジュリン / ダントロレン

Outline of Final Research Achievements

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal arrhythmia mainly caused by single point mutations in cardiac ryanodine receptor (RyR2). These mutations are distributed in three hot spots (N-terminal, central and C-terminal) of RyR2. Diastolic calcium (Ca) leak via RyR2 can cause ventricular arrhythmia such as CPVT. We have already showed that reduced calmodulin (CaM)-RyR2 affinity destabilizes RyR2 channel, and causes Ca leak in a central RyR2-CPVT Knock-in (KI) mouse (R2474S/+). To further understand the pathophysiology of RyR2 mutation on CaM-RyR2 affinity in N-terminal RyR2-CPVT KI mouse (R176Q/+) and C-terminal RyR2-CPVT KI mouse (R4496C/+), Our results suggest that reduced CaM-RyR2 affinity causes Ca leak in N-terminal RyR2-CPVT mutation, but C-terminal RyR2-CPVT mutation causes Ca leak independent of CaM-RyR2 affinity.

Free Research Field

循環器内科

Academic Significance and Societal Importance of the Research Achievements

カテコラミン誘発性心室頻拍(CPVT)では高率に突然死する症例も少なくないため、突然死予防に植込み型除細動器が用いられており、今なお決定的に有効な薬物療法はない。CPVTの発症機序をRyR2点突然変異の部位ごとに解明することで、点突然変異部位に応じたオーダメイド薬物治療が可能となる。