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Mathematical analysis of arrhythmogenesis for bradycardia

Research Project

Project/Area Number 17H04018
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field General physiology
Research InstitutionOsaka University

Principal Investigator

Kurachi Yoshihisa  大阪大学, 国際医工情報センター, 教授 (30142011)

Co-Investigator(Kenkyū-buntansha) 稲野辺 厚  大阪大学, 医学系研究科, 准教授 (00270851)
津元 国親  金沢医科大学, 医学部, 准教授 (70353331)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥10,010,000 (Direct Cost: ¥7,700,000、Indirect Cost: ¥2,310,000)
Keywords心臓徐脈 / 心臓不整脈 / 心臓電気生理 / 数理解析 / 生理学 / シグナル伝達
Outline of Final Research Achievements

G protein-gated inwardly rectifying K+ (KG) channel is a model effector for studying the signaling through GPCRs, G proteins and their effectors. Previously we have developed mathematical models for the bradycardia by combining the models representing molecular interactions and electrical activity of myocytes. While atypical KG channel activity was reported in patients with some supraventricular arrhythmias, previous models has a limitation to reproduce the pathological conditions without any hypotheses. In this study, we planned to uncover physiological modulators of KG channel function. We identified acridine derivatives which blocked KG channels in multiple modes of binding. They would assist to classify the activity of Kir channel members in living cells. We also found an endogenous blocker which binds at a crevasse of cytoplasmic domain of a KG channel subunit member Kir3.2. This novel drug-channel interaction was expected to be involved in physiological regulation.

Academic Significance and Societal Importance of the Research Achievements

副交感神経の活動が活発になると、心臓ではKGチャネルが活性化し、心臓の拍動は緩やかになります。我々はチャネルの活性制御と心臓の拍動を共役させる統合的数理モデルを開発してきました。しかし、そのモデルでは心臓不整脈のチャネルの活動を再現出来ないため、拡張性の高い数理モデルの構築には新たなチャネル活性調節機構を想定する必要がありました。本研究では、チャネルを阻害する新規の薬物を同定すると共に、情報科学的に内因性の低分子が新規薬物結合部位に結合し、チャネル活性を阻害することを見出しました。以上の知見は、既存のモデルの改善と拡張性の高いモデルの構築の手掛かりになることが期待されます。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (14 results)

All 2019 2018 2017

All Journal Article (12 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 12 results,  Open Access: 11 results) Presentation (2 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Integrative and theoretical research on the architecture of a biological system and its disorder2019

    • Author(s)
      Shinichi Uchida, Yoshiyuki Asai, Yoshiaki Kariya, Kunichika Tsumoto, Hiroshi Hibino, Masashi Honma, Takeshi Abe, Fumiaki Nin, Yasutaka Kurata, Kazuharu Furutani, Hiroshi Suzuki, Hiroaki Kitano, Ryuji Inoue, Yoshihisa Kurachi
    • Journal Title

      The Journal of Physiological Sciences

      Volume: 69 Issue: 3 Pages: 443-451

    • DOI

      10.1007/s12576-019-00667-8

    • NAID

      40021874158

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Facilitation of IKr current by some hERG channel blockers suppresses early afterdepolarizations2019

    • Author(s)
      Kazuharu Furutani, Kunichika Tsumoto, I-Shan Chen, Kenichiro Handa, Yuko Yamakawa, Jon Sack, Yoshihisa Kurachi.
    • Journal Title

      Journal of General Physiology

      Volume: 151 Issue: 2 Pages: 214-230

    • DOI

      10.1085/jgp.201812192

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Systematic Expression Analysis of Genes Related to Generation of Action Potentials in Human iPS Cell-Derived Cardiomyocytes2019

    • Author(s)
      Masami Kodama, Kazuharu Furutani, Reiko Kimura, Tomoko Ando, Kazuho Sakamoto, Shushi Nagamori, Takashi Ashihara, Yoshihisa Kurachi, Yuko Sekino, Tetsushi Furukawa, Yasunari Kanda, Junko Kurokawa
    • Journal Title

      Journal of Pharmacological Sciences

      Volume: 140 Issue: 4 Pages: 325-330

    • DOI

      10.1016/j.jphs.2019.06.006

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019

    • Author(s)
      Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
    • Journal Title

      Circulation

      Volume: In press Issue: 18 Pages: 2157-2169

    • DOI

      10.1161/circulationaha.118.036761

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Kir Channel Blockages by Proflavine Derivatives via Multiple Modes of Interaction2018

    • Author(s)
      Inanobe A, Itamochi H, Kurachi Y.
    • Journal Title

      Mol Pharmacol.

      Volume: 93 Issue: 6 Pages: 592-600

    • DOI

      10.1124/mol.117.111377

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of Inwardly Rectifying Potassium (Kir) 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF) Expression in Astrocytes2017

    • Author(s)
      Kinboshi Masato、Mukai Takahiro、Nagao Yuki、Matsuba Yusuke、Tsuji Yoshimi、Tanaka Shiho、Tokudome Kentaro、Shimizu Saki、Ito Hidefumi、Ikeda Akio、Inanobe Atsushi、Kurachi Yoshihisa、Inoue Seiji、Ohno Yukihiro
    • Journal Title

      Frontiers in Molecular Neuroscience

      Volume: 10 Pages: 408-408

    • DOI

      10.3389/fnmol.2017.00408

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hysteretic Dynamics of Multi-Stable Early Afterdepolarisations with Repolarisation Reserve Attenuation: A Potential Dynamical Mechanism for Cardiac Arrhythmias2017

    • Author(s)
      Tsumoto Kunichika、Kurata Yasutaka、Furutani Kazuharu、Kurachi Yoshihisa
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 10771-10771

    • DOI

      10.1038/s41598-017-11355-1

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Computer modeling defines the system driving a constant current crucial for homeostasis in the mammalian cochlea by integrating unique ion transports2017

    • Author(s)
      Nin F, et al.
    • Journal Title

      npj Systems Biology and Applications

      Volume: 3 Issue: 1 Pages: 4-4

    • DOI

      10.1038/s41540-017-0025-0

    • NAID

      130007901272

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Integrative Approach with Electrophysiological and Theoretical Methods Reveals a New Role of S4 Positively Charged Residues in PKD2L1 Channel Voltage-Sensing2017

    • Author(s)
      Numata Tomohiro、Tsumoto Kunichika、Yamada Kazunori、Kurokawa Tatsuki、Hirose Shinichi、Nomura Hideki、Kawano Mitsuhiro、Kurachi Yoshihisa、Inoue Ryuji、Mori Yasuo
    • Journal Title

      Sci. Rep.

      Volume: 7 Issue: 1 Pages: 9760-9760

    • DOI

      10.1038/s41598-017-10357-3

    • NAID

      120006364088

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural determinants at the M2 muscarinic receptor modulate the RGS4-GIRK response to pilocarpine by impairment of the receptor voltage sensitivity.2017

    • Author(s)
      Chen IS, Furutani K, Kurachi Y.
    • Journal Title

      Sci Rep

      Volume: 7(1) Issue: 1 Pages: 6110-6110

    • DOI

      10.1038/s41598-017-05128-z

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HD Physiology Project -Japanese Efforts to Promote Multilevel Integrative Systems Biology and Physiome Research-.2017

    • Author(s)
      Furutani K, Tsumoto K, Kurachi Y.
    • Journal Title

      npj Systems Biology and Applications

      Volume: 3 Issue: 1 Pages: 1-1

    • DOI

      10.1038/s41540-016-0001-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The number of microvascular complications is associated with an increased risk for severity of periodontitis in type 2 diabetes patients: Results of a multicenter hospital-based cross-sectional study2017

    • Author(s)
      Nitta Hiroshi、et al.
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 8 Issue: 5 Pages: 677-686

    • DOI

      10.1111/jdi.12633

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] Probing conformational change in inward rectifier K+ (Kir) channels by small molecules.2018

    • Author(s)
      稲野辺厚,倉智嘉久
    • Organizer
      第95回日本生理学会大会
    • Related Report
      2017 Annual Research Report
  • [Presentation] APPLICATION OF A PROTEIN FRAGMENT COMPLEMENTATION ASSAY TO REVEAL MOLECULAR ORIENTATION WITHIN HETERO-OLIGOMERIC MEMBRANE PROTEIN ASSEMBLY2018

    • Author(s)
      Inanobe A., Kurachi Y.
    • Organizer
      Biophysical Society 62nd Annual Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2021-02-19  

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