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

• 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
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: リアノジン受容体 / K201 / E-C coupling / 致死的不整脈 / EC coupling / calmodulin / ryanodine receptor / 興奮収縮連関

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) Issue: 1 Pages: 1-7
  • DOI: 10.1016/j.bbrc.2014.03.152
  • Peer Reviewed / Open Access
• [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) Issue: 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
  • 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 Pages: 682-694
  • 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] 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: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [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: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [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: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [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: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [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: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [Presentation] Dantrolene may Suppress Arrhythmogenesis by Inhibition of CaMKII-mediated Aberrant Ca2+ Release within Ryanodine Receptor in Cardiac Troponin T-related Hypertrophic Cardiomyopathy (2014)
  • Author(s): Shinichi Okuda, Masakazu Fukuda, Takayoshi Katoh, Shigehiko Nishimura, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第78回日本循環器学会学術集会
  • Place of Presentation: 東京（東京国際フォーラム）
• [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] カテコラミン誘発性多形性心室頻拍関連遺伝子変異を有する異常なリアノジン受容体において、カルモジュリン結合能改善は催不整脈性を抑制する (2013)
  • Author(s): 福田昌和，山本 健，加藤孝佳，村上和華子，立石裕樹，土居正浩，奥田真一，小林茂樹，矢野雅文
  • Organizer: 第102回日本循環器学会中国・四国合同地方会
  • Place of Presentation: 高松（サンポートホール高松）
• [Presentation] カテコラミン誘発性多形性心室頻拍関連の遺伝子変異を持つリアノジン受容体におけるカルモジュリンの効果について (2013)
  • Author(s): 福田昌和，山本 健，西村滋彦，明連武樹，加藤孝佳，村上和華子，大野 誠，小田哲郎，奥田真一，土居正浩，小林茂樹，矢野雅文
  • Organizer: 第61回日本心臓病学会学術集会
  • Place of Presentation: 熊本（ホテル日航熊本）
• [Presentation] Dissociation of Calmodulin from RyR2 Plays a Key Role in Diastolic Ca2+ Leak from Sarcoplasmic Reticulum in Pressure-overload Heart Failure (2013)
  • Author(s): Takayoshi Katoh, Takeshi Yamamoto, Shigehiko Nishimura, Masakazu Fukuda, Makoto Ohno, Hiroki Tateishi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第17回日本心不全学会学術集会
  • Place of Presentation: 埼玉（大宮ソニックシティ）
• [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,Tx, USA
• [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,Tx, USA
• [Presentation] A Novel Selective EP4 Receptor Agonist Improves Intracellular Ca2+ Handling and Cardiomyocyte Function in Intact Failing Cardiomyocytes (2013)
  • Author(s): Wakako Murakami, Shigeki Kobayashi, Takeki Myoren, Shigehiko Nishimura, Takayoshi Katoh, Masakazu Fukuda, Makoto Ono, Hiroki Tateishi, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 86th Scientific Session of American Heart Association
  • Place of Presentation: Dallas,Tx, USA
• [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
• [Presentation] Acceleration of the Early Diastolic Filing by Cardiac Re-synchronization is Important for Improving Symptoms of Severe Heart Failure (2012)
  • Author(s): Takeshi Yamamoto
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles (USA)
• [Presentation] Fixing Ca2+ Leakage From Cardiac Ryanodine Receptor by Low-dose of β Blocker Safely Enhances Inotropic Response to Milrinone in Acute Heart Failure (2012)
  • Author(s): Shigeki Kobayashi
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles (USA)
• [Presentation] CaMKII-mediated Aberrant Ca2+ Release May Play a Key Role in hte Arrhythmogenesis in Cardiac Troponin T-related Familial Hypertrophic Cardiomyopathy (2012)
  • Author(s): Shinichi Okuda
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles (USA)
• [Presentation] Enhanced Binding of Calmodulin to RyR2 Inhibits Aberrant Ca2+ Release and Arrhythmogenesis in CPVT-Associated Mutation (2012)
  • Author(s): Masakazu Fukuda
  • Organizer: 85th Scientific Session of American Heart Association
  • Place of Presentation: Los Angeles (USA)
• [Presentation] Enhancement of Calmodulin Binding to RyR2 Inhibits Aberrant Ca2+ Release in CPVT-Associated Mutation (2011)
  • Author(s): Masakazu Fukuda, Masafumi Yano, Takayoshi Kato, Akihiro Hino, Takeshi Suetomi, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Masunori Matsuzaki
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Florida (USA)
• [Presentation] Coupled Conformational Changes in the Local and Global Inter-Domain Interactions Trigger Diastolic Ca2+ Release and Lethal Arrhythmia in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) (2011)
  • Author(s): Takeshi Suetomi, Masafumi Yano, Takayoshi Kato, Masakazu Fukuda, Akihiro Hino, Masahiro Doi, Shinichi Okuda, Shigeki Kobayashi, Yasuhiro Ikeda, Takeshi Yamamoto, Masunori Matsuzaki
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Florida (USA)