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

• 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
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• 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.

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。

Research Products

• [Presentation] The Difference of Calmodulin-Ryanodine Receptor Affinity Between N-terminal, Central and C-terminal RyR2-CPVT Knock-in Mice (2019)
  • Author(s): Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Mena Said, Rogerio Faustino, Razvan L. Cornea, Xander H. T. Wehrens, Takeshi Yamamoto, Masafumi Yano, Donald M. Bers.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Calmodulin-RyR2 Affinity in N-terminal, Central, and C-terminal CPVT Knock-in Mice (2018)
  • Author(s): Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Mena Said, Rogerio Faustino, Razvan L. Cornea, Xander H.T. Wehrens, Takeshi Yamamoto, Masafumi Yano, Donald M, Bers
  • Organizer: The 9th Asian Pacific Congress of Heart Failure (APCHF 2018)
  • Int'l Joint Research
• [Presentation] RyR2 R4496C CPVT Mutation Causes Calcium Leak Independent Of Calmodulin-RyR2 Affinity In R4496C/+ Knock-in Mouse (2018)
  • Author(s): Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Mena Said, Rogerio Faustino, Razvan L. Cornea, Xander H.T. Wehrens, Takeshi Yamamoto, Masafumi Yano, Donald M. Bers
  • Organizer: The 22nd Annual Scientific Meeting of the Japanese Heart Failure Society
• [Presentation] RyR2-R4496C C-Terminal CPVT Mutation Causes Calcium Leak Independent of Calmodulin-RyR2 Affinity (2018)
  • Author(s): Hitoshi Uchinoumi, Xiaoqiong Dong, Ivanita Stefanon, Yi Yang, Mena Said, Rogerio Faustino, Razvan L. Cornea, Xander H.T. Wehrens, Takeshi Yamamoto, Masafumi Yano, Donald M. Bers
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research