• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Molecular Mechanisms of Potassium Channel Facilitation by Blockers and its Impact on Arrhythmias

Research Project

Project/Area Number 21K06812
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 48030:Pharmacology-related
Research InstitutionTokushima Bunri University

Principal Investigator

Furutani Kazuharu  徳島文理大学, 薬学部, 准教授 (40452437)

Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsイオンチャネル / 薬物 / 不整脈 / 薬理学 / 心臓電気生理学 / 構造生物学 / コンピューターシミュレーション / 創薬 / 電位依存性カリウムチャネル / 構造モデル / 電気生理学 / 心臓 / カリウムチャネル / 遮断薬
Outline of Research at the Start

心室不整脈誘発の副作用リスクのある薬剤が、心室筋細胞の活動電位後の再分極を担う電位依存性カリウムチャネルのhERGチャネルを遮断することが知られている。しかしその作用の詳細や不整脈との関連は十分理解されていない。本研究の目的は、薬物-hERGチャネル相互作用の分子機構を理解し、薬物のhERGチャネル遮断活性に起因する不整脈誘発機構をより正しく理解することである。そのために、実験と理論の両面から解析を行う。この研究は、薬物によるイオンチャネル機能制御の理解を深め、hERG遮断薬の不整脈誘発リスクを再評価し、医薬品開発にも貢献する成果が期待される。

Outline of Final Research Achievements

A major cause of drug-induced arrhythmias is drug-induced blockade of voltage-gated potassium channels (hERG channels) in cardiomyocytes. In recent years, it has become known that many drugs known as hERG blockers not only block the channels but also facilitate their voltage-dependent activation. In the present study, we have advanced our understanding of the molecular mechanisms blocking agents that facilitate hERG channel activation. We also developed a pipeline to quantitatively predict the effects of drugs on hERG channels based on their structures and to assess how they affect ventricular myocyte and cardiac tissue function and risk of arrhythmogenesis. The results of this study may lead to the development of methods to predict and avoid drug-induced arrhythmias.

Academic Significance and Societal Importance of the Research Achievements

電位依存性カリウムチャネルの一種であるhERGチャネルは、様々な薬物によって遮断され、QT延長症候群の原因となる。この機構は、長年、世界的な研究テーマである。本研究は、活性化を促進する作用を併せ持つ遮断薬に着目し、薬物によるhERGチャネル機能制御の分子機構を明らかにした。この成果は、分子薬理学領域の未解明な問題を解決し、学術的な意義があった。さらに、本研究の成果は、疾患の治療薬の開発段階で必要な心毒性の予測・評価・回避に関して示唆を与え社会的な意義もあった。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (26 results)

All 2024 2023 2022 2021 Other

All Int'l Joint Research (3 results) Journal Article (6 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 6 results) Presentation (15 results) (of which Invited: 4 results) Book (1 results) Remarks (1 results)

  • [Int'l Joint Research] University of California, Davis(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of California, Davis(米国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] University of California, Davis(米国)

    • Related Report
      2021 Research-status Report
  • [Journal Article] Structural modeling of hERG channel-drug interactions using Rosetta2023

    • Author(s)
      Emigh Cortez Aiyana M.、DeMarco Kevin R.、Furutani Kazuharu、Bekker Slava、Sack Jon T.、Wulff Heike、Clancy Colleen E.、Vorobyov Igor、Yarov-Yarovoy Vladimir
    • Journal Title

      Frontiers in Pharmacology

      Volume: 14 Pages: 1244166-1244166

    • DOI

      10.3389/fphar.2023.1244166

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk2023

    • Author(s)
      Furutani Kazuharu
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 22 Pages: 16261-16261

    • DOI

      10.3390/ijms242216261

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pore Opening, Not Voltage Sensor Movement, Underpins the Voltage-Dependence of Facilitation by a hERG Blocker2022

    • Author(s)
      Furutani Kazuharu、Kawano Ryotaro、Ichiwara Minami、Adachi Ryo、Clancy Colleen E.、Sack Jon T.、Kita Satomi
    • Journal Title

      Molecular Pharmacology

      Volume: 102 Issue: 5 Pages: 223-233

    • DOI

      10.1124/molpharm.122.000569

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural modeling of the hERG potassium channel and associated drug interactions2022

    • Author(s)
      Maly Jan、Emigh Aiyana M.、DeMarco Kevin R.、Furutani Kazuharu、Sack Jon T.、Clancy Colleen E.、Vorobyov Igor、Yarov-Yarovoy Vladimir
    • Journal Title

      Frontiers in Pharmacology

      Volume: 13 Pages: 966463-966463

    • DOI

      10.3389/fphar.2022.966463

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Molecular determinants of pro-arrhythmia proclivity of d- and l-sotalol via a multi-scale modeling pipeline2021

    • Author(s)
      DeMarco Kevin R.、Yang Pei-Chi、Singh Vikrant、Furutani Kazuharu、Dawson John R.D.、Jeng Mao-Tsuen、Fettinger James C.、Bekker Slava、Ngo Van A.、Noskov Sergei Y.、Yarov-Yarovoy Vladimir、Sack Jon T.、Wulff Heike、Clancy Colleen E.、Vorobyov Igor
    • Journal Title

      Journal of Molecular and Cellular Cardiology

      Volume: 158 Pages: 163-177

    • DOI

      10.1016/j.yjmcc.2021.05.015

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural modeling of the hERG potassium channel and associated drug interactions2021

    • Author(s)
      Maly Jan、Emigh Aiyana M.、DeMarco Kevin R.、Furutani Kazuharu、Sack Jon T.、Clancy Colleen E.、Vorobyov Igor、Yarov-Yarovoy Vladimir
    • Journal Title

      bioRxiv

      Volume: -

    • DOI

      10.1101/2021.07.08.451699

    • Related Report
      2021 Research-status Report
    • Open Access / Int'l Joint Research
  • [Presentation] hERGの阻害剤による促進作用の機能的・構造的基盤2024

    • Author(s)
      古谷 和春, Cortez Aiyana, Vorobyov Igor, Yarov-Yarovoy Vladimir, 喜多 紗斗美
    • Organizer
      第101回日本生理学会大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] hERGチャネル遮断薬は開状態にあるhERGチャネルと相互作用し促進作用を発揮する2023

    • Author(s)
      古谷和春, 河野諒太朗, 一藁南, 足立亮, Colleen E. Clancy, Jon T. Sack, 喜多紗斗美
    • Organizer
      第143回日本薬理学会近畿部会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 薬物によるhERGチャネル遮断と活性化促進の構造基盤,2023

    • Author(s)
      和田友睦, 古谷和春, Aiyana M. Emigh Cortez, Igor Vorobyov, Vladimir Yarov-Yarovoy, 喜多紗斗美
    • Organizer
      第13回トランスポーター研究会九州部会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 薬物によるhERGチャネル遮断と活性化促進の構造基盤2023

    • Author(s)
      古谷和春, 和田友睦, Aiyana M. Emigh Cortez, Igor Vorobyov, Vladimir Yarov-Yarovoy, 喜多紗斗美
    • Organizer
      生体機能と創薬シンポジウム2023
    • Related Report
      2023 Annual Research Report
  • [Presentation] hERGチャネル遮断薬が活性化促進作用を発揮する構造的機構2023

    • Author(s)
      和田友睦, 古谷和春, Aiyana M. Emigh Cortez, Igor Vorobyov, Vladimir Yarov-Yarovoy, 喜多紗斗美
    • Organizer
      第62回日本薬学会中国四国支部学術大会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 薬理学実験から示唆される電位依存性カリウムチャネルのゲーティングに伴う構造変化2023

    • Author(s)
      古谷和春
    • Organizer
      第97回日本薬理学会年会シンポジウム「イオンチャネル研究の最前線: 新規イオン電流の評価から活性制御の動的構造基盤の解析まで」
    • Related Report
      2023 Annual Research Report
  • [Presentation] 薬物誘発性不整脈リスクの予測への応用を目指した心筋細胞イオンチャネルの薬理学研究2022

    • Author(s)
      古谷和春
    • Organizer
      第16回徳島文理大学薬学部学術講演会
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] コロナ禍で実施した薬理学実習から教員が学んだこと2022

    • Author(s)
      古谷和春、喜多紗斗美
    • Organizer
      生体機能と創薬シンポジウム2022
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] hERG Kv チャネル制御の機能構造的理解2022

    • Author(s)
      古谷和春
    • Organizer
      生理研研究会2022 「構造情報を基盤とした膜機能分子の生理機能理解に向けて」
    • Related Report
      2022 Research-status Report
    • Invited
  • [Presentation] Functional and structural basis of hERG facilitation by its blockers2022

    • Author(s)
      Kazuharu Furutani, Ryotaro Kawano, Satomi Kita
    • Organizer
      第96回日本薬理学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Pore opening, not voltage sensor movement, underpins the voltage-dependence of facilitation by a hERG blocker2022

    • Author(s)
      Ryotaro Kawano, Kazuharu Furutani, Minami Ichiwara, Ryo Adachi, Colleen E. Clancy, Jon T. Sack, Satomi Kita
    • Organizer
      第96回日本薬理学会年会
    • Related Report
      2022 Research-status Report
  • [Presentation] Pore opening, not voltage sensor movement, underpins the voltage-dependence of facilitation by a hERG blocker2022

    • Author(s)
      Kazuharu Furutani, Ryotaro Kawano, Minami Ichiwara, Ryo Adachi, Colleen E. Clancy, Jon T. Sack, Satomi Kita
    • Organizer
      日本生理学会 第100回記念大会
    • Related Report
      2022 Research-status Report
  • [Presentation] hERG channel inactivation and drug binding2022

    • Author(s)
      Kazuharu Furutani, Jan Maly, Vladimir Yarov-Yarovoy
    • Organizer
      第95回日本薬理学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] 薬物相互作用に影響するhERGチャネルの不活性化機構2022

    • Author(s)
      古谷和春、マリー ヤン、ヴラディミール ヨロフヨロボイ
    • Organizer
      第99回日本生理学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] hERGチャネルの不活性化機構と薬物相互作用2021

    • Author(s)
      古谷和春
    • Organizer
      2021年度 生理研研究会「比較統合生理学的観点からの循環生理の解析」
    • Related Report
      2021 Research-status Report
    • Invited
  • [Book] ギャノング生理学 原書26版2022

    • Author(s)
      岡田 泰伸、佐久間 康夫、岡村 康司(古谷 和春 分担翻訳)
    • Total Pages
      910
    • Publisher
      丸善出版
    • ISBN
      4621307088
    • Related Report
      2022 Research-status Report
  • [Remarks] 徳島文理大学薬学部薬理学講座ホームページ

    • URL

      http://p.bunri-u.ac.jp/lab12/

    • Related Report
      2023 Annual Research Report 2022 Research-status Report 2021 Research-status Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi