Development of novel arrhythmia therapy using K201 binding core in RyR2 molecle

2013 Fiscal Year Final Research Report

• Project/Area Number: 23591082
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YAMAMOTO Takeshi 山口大学, 医学(系)研究科(研究院), 准教授 (50363122)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Shigeki 山口大学, 医学部附属病院, 講師 (90397993)
• Project Period (FY): 2011 – 2013
• Keywords: リアノジン受容体 / K201 / E-C coupling / 致死的不整脈

Research Abstract

We revealed that S2246L mutation site and K201 binding site are making loop and interacting each other. We further analyze the calmodulin binding to RyR2 and find that K201 binding core signal transmitted to calmoulin binding site, and then transmitted to the channel pore. From these data, we find two new target domains for the arrhythmia treatment.

Research Products

• [Journal Article] Enhanced binding of calmodulin to RyR2 corrects arrhythmogenic channel disorder in CPVT-associated myocytes (2014)
  • Author(s): Fukuda M, Yamamoto T, Nishimura S, Kato T, Murakami W, Hino A, Ono M, Tateishi H, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M
  • Journal Title: Biochem Biophys Res Commun Volume: 448(1) Pages: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • Peer Reviewed
• [Journal Article] Enhanced binding of calmodulin to the ryanodine receptor corrects contractile dysfunction in failing hearts (2012)
  • Author(s): Hino A, Yano M, Kato T, Fukuda M, Suetomi T, Ono M, Murakami W, Susa T, Okuda S, Doi M, Kobayashi S, Yamamoto T, Koseki N, Kyushiki H, Ikemoto N, Matsuzaki M
  • Journal Title: Cardiovasc Res. Volume: 96(3) Pages: 433-43
  • DOI: 10.1093/cvr/cvs271
  • Peer Reviewed
• [Journal Article] Mutation-linked defective interdomain interactions within ryanodine receptor cause aberrant Ca²⁺release leading to catecholaminergic polymorphic ventricular tachycardia (2011)
  • Author(s): Suetomi T, Yano M, Uchinoumi H, Fukuda M, Hino A, Ono M, Xu X, Tateishi H, Okuda S, Doi M, Kobayashi S, Ikeda Y, Yamamoto T, Ikemoto N, Matsuzaki M
  • Journal Title: Circulation Volume: 124(6) Pages: 682-94
  • DOI: 10.1161/CIRCULATIONAHA
  • Peer Reviewed
• [Presentation] Symposium Dissociation of Calmodulin from RyR2 Plays a Key Role in Diastolic Ca2+ Leak from Sarcoplasmic Reticulum in Pressure-overload Heart Failure (2014)
  • Author(s): Takeshi Yamamoto
  • Organizer: The 78th Annual scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2014-03-21
• [Presentation] Cardiomyocyte Ryanodine Receptor (RyR2) Oxidation in situ Causes Defective Interdomain Interaction and Reduces Calmodulin (CaM) Binding (2014)
  • Author(s): Tetsuro Oda, Takeshi Yamamoto, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: The 78th Annual scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2014-03-21
• [Presentation] Mapping the Binding Site of RyR2"Unzipping"Peptide (DPc10) by Fluorescence Resonance Energy Transfer (FRET) in Permeabilized Cardiomyocytes (2014)
  • Author(s): Tetsuro Oda, Takeshi Yamamoto, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: The 78th Annual scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2014-03-21
• [Presentation] Dantrolene Corrects Aberrant Ca2+ Release and Improves Calmodulin Bindingto RyR2 in CPVT-associated Mutation (2014)
  • Author(s): Masakazu Fukuda, Takeshi Yamamoto, Shigehiko Nishimura, Takayoshi Katoh, Shinichi Okuda, Tetsurou Oda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: The 78th Annual scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2014-03-21
• [Presentation] Enhanced Binding of Calmodulin to the Ryanodine Receptor Corrects Abnormal Calcium Handling in Pressure Over Loaded Heart Failure (2014)
  • Author(s): Takayoshi Katoh, Takeshi Yamamoto, Shigehiko Nishimura, Takeki Myoren, Wakako Murakami, Masakazu Fukuda, Makoto Ohno, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: The 78th Annual scientific Meeting of the Japanese Circulation Society
  • Place of Presentation: 東京国際フォーラム,東京
  • Year and Date: 2014-03-21
• [Presentation] Dantrolene May Suppress Arrhythmogenesis by Inhibition of CaMKII-mediated Aberrant Ca2+ Release Within the Ryanodine Receptor in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2013)
  • Author(s): Shinichi Okuda, Masakazu Fukuda, Takayoshi Katoh, Shigehiko Nishimura, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas USA(Poster)
  • Year and Date: 2013-11-16
• [Presentation] Dantrolene Inhibits Aberrant Ca2+ Release and Arrhythmogenesis via Enhancing Binding of Calmodulin to RyR2 in CPVT-Associated Mutation (2013)
  • Author(s): Masakazu Fukuda, Takeshi Yamamoto, Shigehiko Nishimura, Takeki Myouren, Takayoshi Katoh, Wakako Murakami, Makoto Ono, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas USA(Oral)
  • Year and Date: 2013-11-16
• [Presentation] Fixing Ca2+ Leakage From Cardiac Ryanodine Receptor by Low-dose ofβBlocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure (2012)
  • Author(s): Shigeki Kobayashi, Wakako Murakami, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Hiroki Tateishi, Takeshi Yamamoto, Masafumi Yano, Masunori Matsuzaki
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles USA(Oral)
  • Year and Date: 2012-11-03