Ventricular tachycardia triggered by augumented Ca leak through ryanodine receptor carrying point mutation: In vitro reconstruction of arrhythmogenicity

2017 Fiscal Year Final Research Report

• Project/Area Number: 26460305
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General physiology
• Research Institution: Fukuoka University
• Principal Investigator: Uehara Akira 福岡大学, 医学部, 准教授 (60140745)
• Co-Investigator(Kenkyū-buntansha): 塩谷 孝夫 佐賀大学, 医学部, 助教 (20253594) ; 上原 清子 福岡大学, 医学部, 准教授 (00084244)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 心筋 / リアノジン受容体 / 不整脈 / Ca

Outline of Final Research Achievements

Mechanisms of Ca release from SR/ER through the cardiac RyR2 w a point mutation K4750Q linked to ventricular tachycardia VT were functionally examined by measuring Ca　signals and single RyR2 channel currents. The Ca signals were obtained from HEK293 and cardiac HL-1 cells expressing RyR channels. The single-channel currents were from RyR2 purified proteins. The mutation caused simultaneous functional defects in RyR2 function that include cytosolic Ca hyper-activation/sensitization, loss of cytosolic Ca/Mg-mediated inactivation, and luminal Ca hyper-activation/sensitization. The excessive SR Ca leak in K4750Q-expressing cells reduced [Ca]lum significantly lowering CPVT risk at rest. We thus show that the mutation markedly enhanced multiple RyR2 Ca regulatory mechanisms, which indicates that the K4750 residue resides at a pivotal structural point that synergizes cytosolic and luminal RyR2 control inputs.

Free Research Field

心臓生理