Correction of the defective inter-domain interaction of cardiac ryanodine receptor prevents catecholaminergic polymorphic ventricular tachycardia

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790726
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: OKUDA Shinichi Yamaguchi University, 医学部附属病院, 医員 (90530212)
• Project Period (FY): 2009 – 2010
• Keywords: カテコラミン誘発性心室頻拍 / リアンジン受容体 / 興奮収縮連関 / カルモジュリンキナーゼ

Research Abstract

Catecholaminergic polymorphic ventricular tachycardia(CPVT )is known to be caused by single point mutation taking place in well defined regions of the cardiac ryanodine receptor (RyR2). CPVT mutation causes defective interdomain interaction of RyR2, which reduces the threshold of luminal [Ca2+] for channel activation, sensitizes to the protein kinase A- dependent phosphorylation, and in turn leads to CPVT. In a human CPVT-associated RyR2^<R2474S/+> knock-in (KI) mouse model, CPVT might be able to be prevented by correcting the defective inter-domain interaction of RyR2 and inhibiting Ca2+ leak.

Research Products

• [Journal Article] Dantrolene, a Therapeutic Agent for Malignant Hyperthermia, Inhibits Catecholaminergic Polymorphic Ventricular Tachycardia in a RyR2(R2474S/+) Knock-In Mouse Model. (2010)
  • Author(s): Kobayashi S, Yano M, Uchinoumi H, Suetomi T, Susa T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Yamamoto T, Matsuzaki M.
  • Journal Title: Circ J. 74 Pages: 2579-2584
  • Peer Reviewed
• [Journal Article] Defective calmodulin binding to the cardiac ryanodine receptor plays a key role in CPVT-associated channel dysfunction. (2010)
  • Author(s): Xu X, Yano M, Uchinoumi H, Hino A, Suetomi T, Ono M, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ikemoto N, Matsuzaki M.
  • Journal Title: Biochem Biophys Res Commun. 394 Pages: 660-666
  • Peer Reviewed
• [Journal Article] Catecholaminergic Polymorphic Ventricular Tachycardia Is Caused by Mutation-Linked Defective Conformational Regulation of the Ryanodine Receptor. (2010)
  • Author(s): Uchinoumi H, Yano M, Suetomi T, Ono M, Xu X, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • Journal Title: Cir Res. 106 Pages: 1413-1424
  • Peer Reviewed
• [Journal Article] Dissociation of calmodulin from cardiac ryanodine receptor causes aberrant Ca2+ release in heart failure. (2010)
  • Author(s): Ono M, Yano M, Hino A, Suetomi T, Xu X, Susa T, Uchinoumi H, Tateishi H, Oda T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.
  • Journal Title: Cardiovasc Res. 87 Pages: 609-617
  • Peer Reviewed
• [Journal Article] Dantrolene, a therapeutic agent for malignant hyperthermia, markedly improves the function of failing cardiomyocytes by stabilizing interdomain interactions within the ryanodine receptor. (2009)
  • Author(s): Kobayashi S, Yano M, Suetomi T, Ono M, Tateishi H, Mochizuki M, Xu X, Uchinoumi H, Okuda S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M.
  • Journal Title: J Am Coll Cardiol. 53 Pages: 1993-2005
  • Peer Reviewed
• [Presentation] Increased Affinity of Calmodulin Binding to Cardiac Ryanodine Receptor Corrects the Defective Channel Gating in Failing Hearts (2010)
  • Author(s): Hino A, Yano M, Fukuda M, Suetomi T, Ono M, Xu X, Uchinoumi H, Susa T, Doi M, Okuda S, Kobayashi S, Yamamoto T, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: シカゴ アメリカ合衆国
  • Year and Date: 2010-11-23
• [Presentation] Correction of Defective Calmodulin Binding to Cardiac Ryanodine Receptor Inhibits Aberrant Ca2+ Release in CPVT-associated Mutation (2010)
  • Author(s): Fukuda M, Yano M, Hino A, Suetomi T, Xu X, Ono M, Uchinoumi H, Doi M, Okuda S, Kobayashi S, Yamamoto T, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: シカゴ アメリカ合衆国
  • Year and Date: 2010-11-23
• [Presentation] Mutation-linked Defective Domain Interaction within the Ryanodine Receptor Causes Ca2+ Leak Leading to Catecholaminergic Polymorphic Ventricular Tachycardia (2010)
  • Author(s): Suetomi T, Yano M, Fukuda M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: シカゴ アメリカ合衆国
  • Year and Date: 2010-11-23
• [Presentation] Interruption of Novel Inter-domain Interaction Within RyR2 as a Common Therapeutic Target by Channel Stabilization in Heart Failure and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2010)
  • Author(s): Yamamoto T, Yano M, Fukuda M, Hino A, Suetomi T, Doi M, Okuda S, Kobayashi S, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: シカゴ アメリカ合衆国
  • Year and Date: 2010-11-23
• [Presentation] Correction of Defective Inter-domain Interaction Within the Cardiac Ryanodine Receptor as a New Therapeutic Strategy Against Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2009)
  • Author(s): Uchinoumi H, Yano M, Hino A, Suetomi T, Ono M, Xu X, Oda T, Doi M, Okuda S, Kobayashi S, Yamamoto T, Ikeda Y, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: オーランド アメリカ合衆国
  • Year and Date: 20091116-20091118
• [Presentation] Low-dose of β Blocker Improves Cardiac Function in Patients With Acute Heart Failure Partly by Inhibiting Ca2+ Leak Through the Ryanodine Receptor (2009)
  • Author(s): Kobayashi S, Tanaka T, Susa T, Ono M, Uchinoumi H, Okuda S, Doi M, Kawamura S, Yamamoto T, Yano M, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: オーランド アメリカ合衆国
  • Year and Date: 20091116-20091118
• [Presentation] Decreased Affinity of Calmodulin to RyR2 May Be a Sauce Mechanism of Leaky Channel in CPVT-associated Mutation (2009)
  • Author(s): Xu X, Yano M, Hino A, Suetomi T, Ono M, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Ohkusa T, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: オーランド アメリカ合衆国
  • Year and Date: 20091116-20091118
• [Presentation] Mutation-linked Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is Caused by Abnormally Tight Domain-Domain Interaction in RyR2 (2009)
  • Author(s): Suetomi T, Yano M, Hino A, Ono M, Xu X, Susa T, Uchinoumi H, Oda T, Doi M, Okuda S, Kobayashi S, Ikeda Y, Yamamoto T, Matsuzaki M.
  • Organizer: Circulation
  • Place of Presentation: オーランド アメリカ合衆国
  • Year and Date: 20091116-20091118
• [Book] シグナル伝達系からみた心不全の機序と治療戦略 (2011)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 129-137
  • Publisher: Cardioligy Frontier
• [Book] 慢性心不全の治療 (2011)
  • Author(s): 奥田真一、矢野雅文
  • Publisher: Medicament News
• [Book] 不全心筋における逆リモデリングの分子生物学的機序呼吸と循環 (2010)
  • Author(s): 奥田真一、矢野雅文
  • Total Pages: 657-666
  • Publisher: 医学書院
• [Remarks] ホームページ等