Novel therapeutic strategy of the fatal arrhythmia targeting specific domain in the ryanodine receptor molecle

• Project/Area Number: 20590868
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YAMAMOTO Takeshi Yamaguchi University, 大学院・医学系研究科, 助教 (50363122)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Shigeki 山口大学, 医学部附属病院, 助教 (90397993)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 分子心臓病態学 / 致死的不整脈 / リアノジン受容体 / 興奮収縮連関 / 心不全 / 心室性不整脈

Research Abstract

We identified the important RyR2 domain for the stabilization of the RyR2 channel as domain 2114-2149 and its counterpart. The counterpart of domain 2114-2149 is in the central portion of the RyR2. The compound which affect these two domains might be novel medicines for heart failure of fatal arrhythmias.

Research Products

• [Journal Article] Isoform-specific roles of protein phosphatase 1 catalytic subunits in sarcoplasmic reticulum-mediated Ca2+ cycling. (2011)
  • Author(s): Aoyama H, Ikeda Y, Miyazaki Y, Yoshimura K, Nishino S, Yamamoto T, Yano M, Inui M, Aoki H, Matsuzaki M.
  • Journal Title: Cardiovasc Res. 89(1) Pages: 79-88
  • Peer Reviewed
• [Journal Article] Urinary 8-Hydroxy-2' -Deoxyguanosine Reflects Symptomatic Status and Severity of Systolic Dysfunction in Patients with Chronic Heart Failure. (2011)
  • Author(s): Kobayashi S, Susa T, Tanaka T, Wada Y, Okuda S, Doi M, Nao T, Yoshiga Y, Yamada J, Okamura T, Ueyama T, Kawamura S, Yano M, Matsuzaki M.
  • Journal Title: Eur J Heart Fail. 13(1) Pages: 29-36
  • Peer Reviewed
• [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(12) Pages: 2579-2584
  • NAID: 10027424202
  • 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(4) Pages: 609-617
  • 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, lkeda Y, lkemoto N, Matsuzaki M.
  • Journal Title: Biochem Biophys Res Commun. 394(3) 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, lkeda Y, Ohkusa T, lkemoto N, Matsuzaki M.
  • Journal Title: Circ Res. 106(8) Pages: 1413-1424
  • Peer Reviewed
• [Journal Article] Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure. (2010)
  • Author(s): Ando M, Yamamoto T, Hino A, Sato T, Nakamura Y, Matsuzaki M.
  • Journal Title: J Nucl Cardiol. 17(5) Pages: 868-873
  • Peer Reviewed
• [Journal Article] Norepinephrine spillover during exercise as a novel parameter to evaluate the severity of heart failure (2010)
  • Author(s): Ando M
  • Journal Title: J Nucl Cardiol Volume: 17 Pages: 868-873
  • 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
  • Journal Title: Circ Res Volume: 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
  • Journal Title: Cardiovasc Res Volume: 87 Pages: 609-617
  • 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
  • Journal Title: Biochem Biophys Res Commun 393 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
  • Journal Title: Circ Res. 106 Pages: 1413-1424
  • 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, lkemoto N, Matsuzaki M.
  • Journal Title: J Am Coll Cardiol. 53(21) Pages: 1993-2005
  • Peer Reviewed
• [Journal Article] Role of ryanodine receptor as a Ca2+ regulatory center in normal and failing hearts. (2009)
  • Author(s): Yano M, Yamamoto T, Kobayashi S, Matsuzaki M.
  • Journal Title: J Cardiol. 53(1) Pages: 1-7
  • NAID: 10025182309
  • Peer Reviewed
• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • Author(s): Tateishi H, Yano M, Mochizuki M, Suetomi T, Ono M, Xu X, Uchinoumi H, Okuda S, Oda T, Kobayashi S, Yamamoto T, Ikeda Y, Ohkusa T, Ikemoto N, Matsuzaki M.
  • Journal Title: Cardiovasc Res. 81(3) Pages: 536-545
  • 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
  • Journal Title: Journal of the American College of Cardiology 53 Pages: 1993-2005
  • Peer Reviewed
• [Journal Article] Defective domain-domain interactions within the ryanodine receptor as a critical cause of diastolic Ca2+ leak in failing hearts. (2009)
  • Author(s): Tateishi H
  • Journal Title: Cardiovascular Research 81 Pages: 536-545
  • Peer Reviewed
• [Journal Article] Defective Ca2+ cycling as a key pathogenic mechanism of heart failure. (2008)
  • Author(s): Yano M, Yamamoto T, Kobayashi S, Ikeda Y, Matsuzaki M.
  • Journal Title: Circ J. 72
  • NAID: 110006935628
  • Peer Reviewed
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • Author(s): Yamamoto T, Yano M, Xu X, Uchinoumi H, Tateishi H, Mochizuki M, Oda T, Kobayashi S, Ikemoto N, Matsuzaki M.
  • Journal Title: Circulation. 117(6) Pages: 762-772
  • Peer Reviewed
• [Journal Article] Role of ryanodine receptor as a Ca(2+)regulatory center in normal and failing hearts. (2008)
  • Author(s): Yano M
  • Journal Title: J Cardiol 53 Pages: 1-7
  • Peer Reviewed
• [Journal Article] Identification of target domains of the cardiac ryanodine receptor to correct channel disorder in failing hearts. (2008)
  • Author(s): Yamamoto T
  • Journal Title: Circulation 117 Pages: 762-72
  • Peer Reviewed
• [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): Takeshi Yamamoto, Masafumi Yano, Masahiro Fukuda, Akihiro Hino, Takeshi Suetomi, Masahiro Doi, Shinich Okuda, Shigeki Kobayashi, Masunori Matsuzaki
  • Organizer: American Heart Association Scientific Sessions
  • Place of Presentation: Chicago IL, USA
  • Year and Date: 2010-11-15
• [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): Takeshi Yamamoto
  • Organizer: American Heart Association Scientific Sessions 2010
  • Place of Presentation: Chicago IL
  • Year and Date: 2010-11-15
• [Presentation] Role of Domain(2114-2149) Within RyR2 for Channel Stabilization in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2009)
  • Author(s): Yamamoto T
  • Organizer: Basic Cardiovascular Sciences Annual Conference
  • Place of Presentation: Lake LasVegas, NV, USA
  • Year and Date: 2009-07-27
• [Presentation] Domain2114-2149 Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • Author(s): Yamamoto, T, Yano, M, Suedomi, T, Ohno, M, Xu, XJ, Tateishi, H, Okuda, S, Kobayashi, S, Ikeda, Y, Matsuzaki, M
  • Organizer: Scientific Sessions 2008 of American Heart Association
  • Place of Presentation: NewOrleans, USA
• [Presentation] Identification of Target Domains of the Cardiac Ryanodine Receptor to Correct Channel Disorder in Failing Hearts (2008)
  • Author(s): Yamamoto, T, Yano, M, Suedomi, T, Ohno, M, Xu, XJ, Tateishi, H, Okuda, S, Kobayashi, S, Ikeda, Y, Matsuzaki, M
  • Organizer: Basic Cardiovascular Sciences Annual Conference 2009-Molecular Mechanisms of Cardiovascular Disease.
  • Place of Presentation: Keystone, USA
• [Presentation] Domain^<2114-2149> Within RyR2 Plays a Key Role for Correcting Channel Disorder in Catecholaminergic Polymorphic Ventricular Tachycardia(CPVT) (2008)
  • Author(s): Yamamoto T
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Protein Phosphatase I Beta is Most Abundant Isoform in the Longitudinal Sarcoplasmic Reticulum and Regulates Phospholamban Phosphorylation in Cardiomyocytes (2008)
  • Author(s): Aoyama H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Mutation-Linked, Defective Inter-Domain Interaction within the Cardiac Ryanodine Receptor as a Critical Cause of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2008)
  • Author(s): Uchinoumi H
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Decreased Affinity of Calmodulin Binding to RyR2 May Cause Leaky Channel in CPVT-Associated Mutation : Insight from RyR2 R2474s/+Knock-In Mouse Model (2008)
  • Author(s): Xu X
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Presentation] Abnormally Tight Domain-Domain Interaction at Mutation Site Could be a Primary Cause of Catecholaminergic Polymorphic Ventricular Tachycardia : Insight from RyR2^<S2246L/+> Knock-In Mouse Model (2008)
  • Author(s): Suetomi T
  • Organizer: AHA Scientific Session
  • Place of Presentation: New Orleans, USA
• [Book] Heart Failure Pathophyiology in upportive Care in Heart Failure. (2008)
  • Author(s): Ikeda Y, Yamamoto T, Yano M, Matsuzaki M.
  • Publisher: Oxford University Press. Ch.
• [Remarks] ホームページ等 なし