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Potential link between Ca2+-activated cation TRPM4 channels and Ist in cardiac pacemaker cells

Research Project

Project/Area Number 17K08537
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General physiology
Research InstitutionShiga University of Medical Science

Principal Investigator

Toyoda Futoshi  滋賀医科大学, 医学部, 助教 (90324574)

Co-Investigator(Kenkyū-buntansha) 松浦 博  滋賀医科大学, 医学部, 理事 (60238962)
林 維光  滋賀医科大学, 医学部, 助教 (80242973)
Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords心臓 / イオンチャネル / 心筋 / パッチクランプ / 洞房結節細胞 / イオン透過性 / ペースメーカー細胞 / 細胞内カルシウム / ペースメーカー活動 / 生理学
Outline of Final Research Achievements

We have recently reported that L-type CaV1.3 Ca2+ channels are required for the generation of a dihydropyridine-sensitive Na+ current, previously described as the sustained inward current, Ist, in heart pacemaker cells. However, currently available recombinant CaV1.3 channels are highly selective for Ca2+ and it remains a challenge to elucidate the molecular mechanism allowing Cav1.3 channels to generate a Na+ conductance. In the present study, we show that Ist is inhibited by 9-phenathrol and flufenamic acid, both are known to block TRPM4 Ca2+-activated cation channels. In addition, simultaneous measurements of whole-cell membrane currents and intracellular Ca2+ revealed that Ist activation was accompanied by a sustained elevation of intracellular Ca2+. However, patch-clamp measurements of Ist were not affected by TRPM4 gene ablation. In conclusion, we failed to provide the evidence for the potential link between TRPM4 and Ist.

Academic Significance and Societal Importance of the Research Achievements

持続性内向きNa電流(Ist)は心拍リズムの調整に強く関わることが示唆されており、その分子機構の解明は心臓の拍動リズムの仕組みという根源的な問いにも触れる生理学的に重要な課題である。本研究は、持続性内向きNa電流(Ist)の分子機構としてひとつのもっともらしい可能性を検証する試みである。結果として当該仮説は否定されたが、Istの分子機構の全容解明に向けて着実な一歩となる。重症心不全や心房細動といった心臓疾患ではリズムコントロールが重要である。Istの分子機構の解明は創薬への可能性を開き、臨床に還元され得る展開が期待される。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (9 results)

All 2021 2020 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (2 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (5 results) (of which Int'l Joint Research: 1 results)

  • [Int'l Joint Research] CNRS/Inserm/Montpellier Univ(フランス)

    • Related Report
      2018 Research-status Report
  • [Int'l Joint Research] CNRS/INSERM/モンペリエ大学(フランス)

    • Related Report
      2017 Research-status Report
  • [Journal Article] CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current2017

    • Author(s)
      Toyoda Futoshi、Mesirca Pietro、Dubel Stefan、Ding Wei-Guang、Striessnig Joerg、Mangoni Matteo E.、Matsuura Hiroshi
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 7869-7869

    • DOI

      10.1038/s41598-017-08191-8

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Heterogeneous functional expression of the sustained inward Na+ current in guinea pig sinoatrial node cells2017

    • Author(s)
      Toyoda Futoshi、Wei-Guang Ding、Matsuura Hiroshi
    • Journal Title

      Pflugers Archiv - European Journal of Physiology

      Volume: 470 Issue: 3 Pages: 481-490

    • DOI

      10.1007/s00424-017-2091-y

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Cav1.3L型カルシウムチャネルのイオン透過ならびに選択機構2021

    • Author(s)
      豊田 太、野間昭典、姫野友紀子、丁維光、松浦博
    • Organizer
      第98回日本生理学会大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Cav1.3L型カルシウムチャネルのCa2+およびNa+透過機構2020

    • Author(s)
      豊田 太・野間昭典・丁 維光・松浦 博
    • Organizer
      第97回日本生理学会大会(誌上開催)
    • Related Report
      2019 Research-status Report
  • [Presentation] Potential link between Ca2+-activated TRPM4 channels and Its in mouse cardiac pacemaker2019

    • Author(s)
      Toyoda F, DIng WG, Matsuura H
    • Organizer
      9th FAOPS Congress, 2019, Kobe
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] A potential link between L-type CaV1.3 channel and TRPM4 Ca2+-activated nonselective cation channel in cardiac pacemaker cells2018

    • Author(s)
      Toyoda F, Ding WG, Matsuura H
    • Organizer
      第95回日本生理学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 心臓ペースメーカー細胞のL型Ca2+チャネルはNa+電流を誘発して拍動リズムの形成に寄与する2017

    • Author(s)
      豊田 太、丁 維光、松浦 博
    • Organizer
      2017年度生命科学系学会合同年次大会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2022-01-27  

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