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The analyses of the interaction between the intracellular domains to control the slow deactivation of hERG channel

Research Project

Project/Area Number 17K15567
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field General physiology
Research InstitutionOita University

Principal Investigator

Kume Shinichiro  大分大学, 医学部, 助教 (90794579)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsイオンチャネル / hERGチャネル / 構造機能連関 / 分子生物学 / 電気生理学
Outline of Final Research Achievements

The hERG channel belonging to the voltage-gated potassium channel family has electrostatic interaction sites in the C-terminal cytoplasmic domains. When these electrostatic interaction sites of the hERG channel were disrupted by the mutagenesis, the slow deactivation characteristic were accelerated significantly. In this study, we analyzed these properties of electrostatic interactions to reveal its structure-function relationships. We found that these electrostatic interactions were within the intra-subunit, and that forming them in all subunits was necessary for the slow deactivation. Furthermore, we revealed that the disruption of the electrostatic interactions declined the interaction between the N-terminal- and the C-terminal-cytoplasmic domains, which plays the main role for the mechanisms of the deactivation, leading to an acceleration of the deactivation.

Academic Significance and Societal Importance of the Research Achievements

hERGチャネルは心筋の活動電位の調節に関与し、ヒト心臓の正常な生理機能において極めて重要な役割を担う。例えば、突然変異等により、その特徴的な遅い脱活性化に異常が生じると、致死性不整脈のリスクを伴うQT延長症候群のような疾患の原因となり得ることが知られている。したがって、本研究の成果として得られたhERGチャネルの遅い脱活性化に関する構造機能連関の新しい知見は、イオンチャネル研究の発展に役立つだけでなく、このようなヒト心臓の疾患に対する予防や治療への貢献も期待できる。

Report

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

    (11 results)

All 2020 2019 2018

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (9 results)

  • [Journal Article] Asparagine-linked glycosylation modifies voltage-dependent gating properties of CaV3.1-T-type Ca2+ channel2019

    • Author(s)
      Liu Yangong、Wang Pu、Ma Fangfang、Zheng Mingqi、Liu Gang、Kume Shinichiro、Kurokawa Tatsuki、Ono Katsushige
    • Journal Title

      The Journal of Physiological Sciences

      Volume: 69 Issue: 2 Pages: 335-343

    • DOI

      10.1007/s12576-018-0650-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Two mutations at different positions in the CNBH domain of the hERG channel accelerate deactivation and impair the interaction with the EAG domain2018

    • Author(s)
      Shinichiro Kume, Takushi Shimomura, Michihiro Tateyama, Yoshihiro Kubo
    • Journal Title

      The Journal of Physiology

      Volume: 596 Pages: 4629-4650

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Presentation] Asparagine-linked glycosylation as a key regulator of gating properties in cardiac Nav1.5 channels2020

    • Author(s)
      Pu Wang, Yangong Liu, Mengyan Wei, Shinichiro Kume, Tatsuki Kurokawa, Katsushige Ono
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] α-mannosidase I-dependent N-linked glycosylation modifies distinct gating properties of the hERG channel2020

    • Author(s)
      Mengyan Wei, Yangong Liu, Pu Wang, Shinichiro Kume, Tatsuki Kurokawa, Katsushige Ono
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] N-glycosylation inhibition attenuates heart automaticity by deranging T-type Ca2+ current and HCN current2020

    • Author(s)
      Yangong Liu, Pu Wang, Mengyan Wei, Shinichiro Kume, Tatsuki Kurokawa, Katsushige Ono
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Asparagine-linked glycosylation modifies voltage-dependent gating properties of Cav3.1-T-type Ca2+ channel2020

    • Author(s)
      Shinichiro Kume, Yangong Liu, Pu Wang, Tatsuki Kurokawa, Katsushige Ono
    • Organizer
      第97回日本生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] N-glycosylation inhibition attenuates heart automaticity by deranging T-type Ca2+ current and HCN current2019

    • Author(s)
      Yangong Liu, Pu Wang, Shinichiro Kume, Tatsuki Kurokawa, Katsushige Ono
    • Organizer
      第29回日本病態生理学会大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] hERGチャネルの細胞内ドメインに関するFRET解析を用いた構造機能連関の研究2019

    • Author(s)
      粂 慎一郎、下村 拓史、立山 充博、久保 義弘
    • Organizer
      第70回西日本生理学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] hERG チャネルの環状ヌクレオチド結合相同ドメインに存在する Phe860 の役割の解析2018

    • Author(s)
      粂 慎一郎、久保 義弘
    • Organizer
      第28回日本病態生理学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] FRET Analyses of the Mechanisms of Accelerated Deactivation by Phe860 Mutations in hERG Channel2018

    • Author(s)
      Shinichiro Kume, Yoshihiro Kubo
    • Organizer
      第65回日本不整脈心電学会学術大会
    • Related Report
      2018 Research-status Report
  • [Presentation] FRET analyses of the effect of Phe860Glu mutation on the interaction between the N- and C- terminal cytoplasmic domains in hERG channel2018

    • Author(s)
      粂 慎一郎
    • Organizer
      第95回日本生理学会大会
    • Related Report
      2017 Research-status Report

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

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