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Non-permeation function of TRPM2 channel complexes and its physiological relevance

Research Project

Project/Area Number 19H03417
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionKyoto University

Principal Investigator

Mori Yasuo  京都大学, 工学研究科, 教授 (80212265)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywordsイオンチャネル / TRPチャネル / シグナル伝達 / マクロファージ / 炎症 / カルシウム / 活性酸素種 / STAT3 / 活性酸素 / タンパク質間相互作用 / 免疫応答 / TRP / Ca2+ / STAT / 機能分極 / タンパク質複合体 / 分化 / 細胞シグナル
Outline of Research at the Start

細胞膜のイオンチャネルが化学的・物理学的変化を感知し開口すると、その開いた「穴」を通ってNa+とCa2+等が通過し、様々な電気現象を生体に引き起こす。最近、この旧来から理解されてきたイオンチャネルの働きとは全く異なる、新たな機能が示されつつある。本研究では、生体内外の環境変化のバイオセンサーとして働くTRPタンパク質群が構成するイオンチャネルに着目し、それらがどのような他タンパク質と相互作用することにより、細胞内物質のバランスを変化させ、均質な細胞集団から異なる細胞種を生成していくかを明らかにする。

Outline of Final Research Achievements

TRP proteins form cation-permeable channels activated in response to different environmental cues. To transcend this conventional understanding of so-called channel proteins, we studied mechanistic bases and physiological significance of "non-channel function" of TRPM2 activated by H2O2. STAT3 proteins, which were found to interact directly with TRPM2 through an exhaustive screening of associated proteins, nearly abolished TRPM2 activity when co-expressed, and these two proteins severely suppressed the expression levels of each other. In a tumor-bearing model applied to TRPM2 KO mice, the STAT3 signaling cascade was promoted in tumor-associated macrophages and excessive angiogenesis was elicited, while in the drug-induced inflammation model, inflammatory phenotypes were suppressed in TRPM2 KO mice. Thus, we discovered a novel function of TRPM2 that regulates polarization of macrophages via inhibition of STAT3 signals.

Academic Significance and Societal Importance of the Research Achievements

地球的規模で自然環境や生態の大きな変化が起きようとしている。ヒトがこういった変化にどう適応するべきかの方策を考えていくためには、生物体が備える環境対応能力を理解する必要がある。本研究が対象としたTRPチャネルは、生体内外環境の化学的・物理学的変化のセンサーとして働くことが知られた陽イオンチャネルであることから、このような課題の解明に最もふさわしい題材を提供する。また、生態系の破壊により顕在化する未体験のウイルスや病原微生物も問題になっており、これらからの生体防御の理解にも本研究は重要なきっかけを与える。

Report

(4 results)
  • 2022 Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (15 results)

All 2022 2021 2020 Other

All Int'l Joint Research (4 results) Journal Article (9 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 9 results,  Open Access: 5 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] コーネル大学(米国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] ミュンヘン工科大学(ドイツ)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] オハイオ州立大学(米国)

    • Related Report
      2020 Annual Research Report
  • [Int'l Joint Research] ミュンヘン工科大学(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] TRPM2 deficiency in mice protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages.2022

    • Author(s)
      Zong P, Feng J, Yue Z, Yu AS, Vacher J, Jellison ER, Miller B, Mori Y, Yue L.
    • Journal Title

      Nature Cardiovascular Research

      Volume: 1 Issue: 4 Pages: 344-360

    • DOI

      10.1038/s44161-022-00027-7

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury.2022

    • Author(s)
      Zong PY, Feng JL, Yue ZC, Li YF, Wu GX, Sun BN, He YL, Miller B, Yu AS, Su ZP, Xie, J, Mori Y, Hao B, Yue LX
    • Journal Title

      Neuron

      Volume: 110 Issue: 12 Pages: 1944-1958

    • DOI

      10.1016/j.neuron.2022.03.021

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Striatal TRPV1 activation by acetaminophen ameliorates dopamine D2 receptor antagonists-induced orofacial dyskinesia2021

    • Author(s)
      Nagaoka Koki、Nagashima Takuya、Asaoka Nozomi、Yamamoto Hiroki、Toda Chihiro、Kayanuma Gen、Siswanto Soni、Funahashi Yasuhiro、Kuroda Keisuke、Kaibuchi Kozo、Mori Yasuo、Nagayasu Kazuki、Shirakawa Hisashi、Kaneko Shuji
    • Journal Title

      JCI Insight

      Volume: in press Issue: 10 Pages: 1-16

    • DOI

      10.1172/jci.insight.145632

    • NAID

      120007038817

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] TRPM7 is an essential regulator for volume-sensitive outwardly rectifying anion channel.2021

    • Author(s)
      Numata T, Sato-Numata K, Hermosura MC, Mori Y, Okada Y
    • Journal Title

      Commun. Biol.

      Volume: 4 Issue: 4 Pages: 599-599

    • DOI

      10.1016/j.jphs.2021.04.006

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Activation of Astrocytes in the Persistence of Post-hypoxic Respiratory Augmentation2021

    • Author(s)
      Fukushi Isato、Takeda Kotaro、Pokorski Mieczyslaw、Kono Yosuke、Yoshizawa Masashi、Hasebe Yohei、Nakao Akito、Mori Yasuo、Onimaru Hiroshi、Okada Yasumasa
    • Journal Title

      Frontiers in Physiology

      Volume: 12 Pages: 757731-757731

    • DOI

      10.3389/fphys.2021.757731

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A rapid shift from chronic hyperoxia to normoxia induces systemic anaphylaxis via Transient Receptor Potential Ankyrin 1 channels on mast cells.2021

    • Author(s)
      Matsuda K, Arkwright PD, Mori Y, Oikawa MA, Muko R, Tanaka A , Matsuda, H.
    • Journal Title

      J. Immunol.

      Volume: 205 Issue: 11 Pages: 2959-2959

    • DOI

      10.4049/jimmunol.2000149

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Possible involvement of TRPM2 activation in 5-fluorouracil-induced myelosuppression in mice.2021

    • Author(s)
      Ishibashi M, Ishii M, Yamamoto S, Mori Y, Shimizu S.
    • Journal Title

      Eur. J. Pharmacol. (2021).

      Volume: 89 Pages: 173671-173671

    • DOI

      10.1016/j.ejphar.2020.173671

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Variants That Affect Function of Calcium Channel TRPV6 Are Associated With Early-Onset Chronic Pancreatitis.2020

    • Author(s)
      Masamune A, Kotani H, Sorgel FL, Chen JM, Hamada S, Sakaguchi R, Masson E, Nakano E, et al.
    • Journal Title

      Gastroenterology

      Volume: - Issue: 6 Pages: 1626-1641

    • DOI

      10.1053/j.gastro.2020.01.005

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] O2-Dependent Protein Internalization Underlies Astrocytic Sensing of Acute Hypoxia by Restricting Multimodal TRPA1 Channel Responses2020

    • Author(s)
      Uchiyama Makoto、Nakao Akito、Kurita Yuki、Fukushi Isato、Takeda Kotaro、Numata Tomohiro、Tran Ha Nam、Sawamura Seishiro、Ebert Maximilian、Kurokawa Tatsuki、Sakaguchi Reiko、Stokes Alexander J.、Takahashi Nobuaki、Okada Yasumasa、Mori Yasuo
    • Journal Title

      Current Biology

      Volume: 30 Issue: 17 Pages: 3378-3396

    • DOI

      10.1016/j.cub.2020.06.047

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Remarks] 脳における新しい酸素センシング機構の発見

    • URL

      https://www.kyoto-u.ac.jp/ja/research-news/2020-07-21

    • Related Report
      2019 Annual Research Report
  • [Patent(Industrial Property Rights)] 医薬組成物及びオートファジー活性化剤2022

    • Inventor(s)
      森泰生、植田誉志史、永田龍、濱崎万穂、庄司志咲子、福田かな子
    • Industrial Property Rights Holder
      森泰生、植田誉志史、永田龍、濱崎万穂、庄司志咲子、福田かな子
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2022-088052
    • Filing Date
      2022
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2024-12-25  

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