Novel therapy of arrhythmia targeting key domain in ryanodine receptor

• Project/Area Number: 15K09085
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Yamaguchi University
• Principal Investigator: YAMAMOTO Takeshi 山口大学, 大学院医学系研究科, 教授 (50363122)
• Co-Investigator(Kenkyū-buntansha): 小田 哲郎 山口大学, 医学部附属病院, 助教 (40569290) ; 小林 茂樹 山口大学, 大学院医学系研究科, 准教授 (90397993)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: リアノジン受容体 / カルモジュリン / 不整脈 / E-C coupling / 筋小胞体

Outline of Final Research Achievements

Applicants made 28 kinds of peptides incorporating point mutations in the peptide of CaM BD. Among the mutated peptides of many prepared CaM BDs, those with the strongest binding to CaM were screened by two methods. The creation of KI mouse incorporating the CaM high affinity RyR2 mutation incorporating the selected mutation was completed and the affinity of RyR2 and CaM was high in this mouse and it was found that CaM was not easily removed from RyR2 even when phosphorylated. Arrhythmia in CaM high affinity KI mice: Multiplying CaI high-affinity RyR2 mutated KI mice with RyR-R 2474 S CPVT mice resulted in a dramatic decrease in exercise burden and arrhythmia frequency at drug loading.

Research Products

• [Journal Article] Mutation-linked, excessively tight interaction between the calmodulin binding domain and the C-terminal domain of the cardiac ryanodine receptor as a novel cause of catecholaminergic polymorphic ventricular tachycardia. (2018)
  • Author(s): Nishimura S, Yamamoto T, Nakamura Y, Kohno M, Hamada Y, Sufu Y, Fukui G, Nanno T, Ishiguchi H, Kato T, Xu X, Ono M, Oda T, Okuda S, Kobayashi S, Yano M.
  • Journal Title: Heart Rhythm Volume: 印刷中 Issue: 6 Pages: 905-914
  • DOI: 10.1016/j.hrthm.2018.02.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] CaMKII-mediated phosphorylation of RyR2 plays a crucial role in aberrant Ca 2+ release as an arrhythmogenic substrate in cardiac troponin T-related familial hypertrophic cardiomyopathy (2018)
  • Author(s): Okuda Shinichi、Sufu-Shimizu Yoko、Kato Takayoshi、Fukuda Masakazu、Nishimura Shigehiko、Oda Tetsuro、Kobayashi Shigeki、Yamamoto Takeshi、Morimoto Sachio、Yano Masafumi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 496 Issue: 4 Pages: 1250-1256
  • DOI: 10.1016/j.bbrc.2018.01.181
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Correction of impaired calmodulin binding to RyR2 as a novel therapy for lethal arrhythmia in the pressure-overloaded heart failure. (2017)
  • Author(s): Kato T, Yamamoto T, Nakamura Y, Nanno T, Fukui G, Sufu Y, Hamada Y, Maeda T, Nishimura S, Ishiguchi H, Murakami W, Fukuda M, Xu X, Hino A, Ono M, Oda T, Okuda S, Kobayashi S, Koseki N, Kyushiki H, Yano M.
  • Journal Title: Heart Rhythm Volume: 14 Issue: 1 Pages: 120-127
  • DOI: 10.1016/j.hrthm.2016.10.019
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficacy and Safety of an Orally Administered Selective Prostacyclin Receptor Agonist, Selexipag, in Japanese Patients With Pulmonary Arterial Hypertension (2017)
  • Author(s): Tanabe N, Ikeda S, Tahara N, Fukuda K, Hatano M, Ito H, Nakayama T, Anzai T, Hashimoto A, Inoue T, Kajinami K, Kihara Y, Kinoshita H, Kuwahara K, Murohara T, Okazaki O, Sakai S, Satoh T, Takeda Y, Takeishi Y, Taniguchi M, Watanabe H, Yamamoto T, Yamauchi-Takihara K, Yoshioka K, Sasayama S.
  • Journal Title: Circulation Journal Volume: 81 Issue: 9 Pages: 1360-1367
  • DOI: 10.1253/circj.CJ-16-1348
  • NAID: 130006003900
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recombinant Atrial Natriuretic Peptide Prevents Aberrant Ca2+ Leakage through the Ryanodine Receptor by Suppressing Mitochondrial Reactive Oxygen Species Production Induced by Isoproterenol in Failing Cardiomyocytes. (2016)
  • Author(s): Murakami W, Kobayashi S, Susa T, Nanno T, Ishiguchi H, Myoren T, Nishimura S, Kato T, Hino A, Oda T, Okuda S, Yamamoto T, Yano M.
  • Journal Title: PLoS One Volume: 11 Issue: 9 Pages: e0163250-e0163250
  • DOI: 10.1371/journal.pone.0163250
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity. (2015)
  • Author(s): Oda T, Yang Y, Uchinoumi H, Thomas DD, Chen-Izu Y, Kato T, Yamamoto T, Yano M, Cornea RL, Bers DM.
  • Journal Title: J Mol Cell Cardiol Volume: 85 Pages: 240-248
  • DOI: 10.1016/j.yjmcc.2015.06.009
  • Peer Reviewed
• [Presentation] Stabilization of CaMKII-phosphorylated RyR2Prevents the Development of Age-related Car-diomyopathy Caused by Transgenic CaMKII δ cOverexpression (2018)
  • Author(s): Yoko Sufu, Shinichi Okuda, Yoko Okamoto, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Dantrolene Prevents Right Ventricular Hypertro-phy without Reducing Pulmonary Arterial Pres-sure in Monocrotaline-Induced PAH in Mice (2018)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Go Fukui, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Ryanodine Receptor Targeting Therapy InhibitsCardiomyocyte Hypertrophy and RelaxationImpairment in the Compensated Pressure-Overloaded Heart (2018)
  • Author(s): Michiaki Kono, Shigeki Kobayashi, Toshiro Kajii, Takuma Nanno, Hironori Ishiguchi, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Takeshi Yamamoto, Masafumi Yano
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Stabilization of Camkii-Phosphorylated Ryr2 by Dantrolene Prevents the Development of Age-Related Cardiomyopathy Caused by CamkiiδC Overexpression (2017)
  • Author(s): Yoko S Shimizu, Shinichi Okuda, Yoko Okamoto, Shigehiko Nishimura, Takayoshi Kato, Tetsuro Oda, Shigeki Kobayashi, Takeshi Yamamoto and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Channel Pore Mutation of RyR2 Cause Calcium Leak Independent of FKBP12.6-RyR2 and Calmodulin-RyR2 Affinity in R4496C/+ Knock-in Mouse (2017)
  • Author(s): Hitoshi Uchinoumi, Ivanita Stefanon, Yi Yang, Mena Said, Xiaoqiong Dong, Rogerio Faustino, Jose L Puglisi, Ye Chen-Izu, Razvan L Cornea, Xander H Wehrens, Wayne S Chen, Takeshi Yamamoto, Yano Masafumi and Donald M Bers
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Effect of Site Dependent RyR Stabilizers; a Clue to Trace a Signal Transmission Pathway Inside the RyR Molecule (2017)
  • Author(s): Go Fukui, Takeshi Yamamoto, Michiaki Kono, Yoshihide Nakamura, Takuma Nanno, Yoriomi Hamada, Yoko Sufu, Hironori Ishiguchi, Shigehiko Nishimura, Hitoshi Uchinoumi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi and Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Dantrolene Prevents Right Ventricular Hypertrophy Without Reducing Pulmonary Arterial Pressure In Monocrotaline-induced PAH In Mice (2017)
  • Author(s): Yoshihide Nakamura, Takeshi Yamamoto, Michiaki kono, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Hironori Ishiguchi, Shigehiko Nishimura, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 90th Scientific Session of American Heart Association
• [Presentation] Correction Of Impaired Calmodulin Binding To Ryr2 As A Novel Therapy Of Lethal Arrhythmia In The Pressure-overloaded Heart Failure (2016)
  • Author(s): Yoshihide Nakamura,Takeshi Yamamoto, Yamaguchi Univ Graduate Sch of Med, Une, Japan; Takayoshi Kato, Yoriomi Hamada, Go Fukui, Yoko Sufu, Takuma Nanno, Shigehiko Nishimura, Hironori Ishiguchi, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: 89th Scientific Session of American Heart Association
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-11-12
  • Int'l Joint Research
• [Presentation] Ryanodine Receptor Bound Calmodulin as a Novel Therapeutic Target of Heart Failure and Cardiac Hypertrophy (2016)
  • Author(s): 山本 健
  • Organizer: 日本循環器学会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] Dantrolene Enhances Binding of Calmodulin to RyR2 in CPVT Which Mutation Located at Central Domain but Does Not Enhance That in CPVT with Mutation at CaM-like Domain (2015)
  • Author(s): Shigehiko Nishimura, Takeshi Yamamoto, Go Fukui, Takako Maeda, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation Is Located at CaM-like Domain of RyR2 (2015)
  • Author(s): Shigehiko Nishimura, Takeshi Yamamoto, Go Fukui, Takako Maeda, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Dantrolene Cannot Inhibit Aberrant Ca2+ Release and Arrhythmias Without Calmodulin in Pressure Overload Heart Failure. (2015)
  • Author(s): Go Fukui, Takeshi Yamamoto, Takayoshi Kato, Takako Maeda, Shigehiko Nishimura, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
  • Organizer: AHA Scientific Sessions 2015
  • Place of Presentation: Orlando, FL (USA)
  • Year and Date: 2015-11-07
  • Int'l Joint Research