Role of proton-sensing G-protein-coupled receptors in the regulation of microglia and microvessel endothelial cell function in the brain stroke in a mouse ischemia reperfusion model.

• Project/Area Number: 18K07362
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Gunma University
• Principal Investigator: Sato Koichi 群馬大学, 生体調節研究所, 准教授 (00302498)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: プロトン感知性受容体 / G蛋白共役型受容体 / 脳虚血 / ミクログリア / 微小血管内皮細胞 / 脳内炎症 / 細胞死 / 酸性pH / 脳神経疾患 / 炎症 / 血液脳関門 / シグナル伝達

Outline of Final Research Achievements

Extracellular acidic pH of ~6.0 has been shown to take place with brain ischemia. However, their mechanisms for signaling an acidic pH in a cerebral injury during ischemia have been poorly elucidated. Proton-sensing OGR1 family G-protein coupled receptors (GPCRs, including OGR1, GPR4, and TDAG8) have been shown to be expressed in central nervous system. This study has focused on the roles of proton-sensing GPCRs in the brain injury in a mouse ischemia reperfusion model. Our results suggested that acidic pH/TDAG8 functions protectively for cerebral infarction by the ischemia model possibly due to the mechanism involving inhibitory actions against microglia function. We also found the involvement of acidic pH/GPR4 in the expression of adhesion molecules in endothelial cells. Thus, although further studies are necessary to clarify the roles of proton-sensing GPCRs in ischemic brain functions, they may help to identify the therapeutic targets for a brain injury accompanied by acidosis.

Academic Significance and Societal Importance of the Research Achievements

本研究では虚血性神経性疾患で報告されている低pH環境変動が中枢神経系細胞群の活性制御を介して神経機能に何らかの作用を及ぼし、脳内恒常性の破綻に関わっているのではないかという仮説を実証しようとしたものである。微小環境因子としてのpH変動は中枢神経系を含む様々な炎症性疾患で生じていると想定されており、このような環境変化を感知する受容体分子の究明は炎症性疾患の新しい治療戦略の構築に寄与すると期待される。また、本研究の成果は細胞外pH変化による多彩な生物作用の分子基盤となる。

Research Products

• [Int'l Joint Research] Kyung Hee University(韓国)
• [Int'l Joint Research] University of Leeds(英国)
• [Journal Article] The protective role of proton-sensing TDAG8 in the brain injury in a mouse ischemia reperfusion model. (2020)
  • Author(s): Sato K, Tobo A, Mogi C, Tobo M, Yamane N, Tosaka M, Tomura H, Im DS, Okajima F.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 17193-17193
  • DOI: 10.1038/s41598-020-74372-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A missense mutation of Leu74Pro of OGR1 found in familial amelogenesis imperfecta actually causes the loss of the pH-sensing mechanism. (2020)
  • Author(s): Sato K, Mogi C, Mighell AJ, Okajima F.
  • Journal Title: Biochem Biophys Res Commun. Volume: 526 Issue: 4 Pages: 920-926
  • DOI: 10.1016/j.bbrc.2020.04.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Involvement of GPR4 in increased <i>growth hormone</i> and <i>prolactin</i> expressions by extracellular acidification in MtT/S cells (2020)
  • Author(s): Musha S, Yoshida S, Murakami S, Kojima R, Deai M, Saso N, Mogi C, Sato K, Okajima F, Tomura H.
  • Journal Title: Journal of Reproduction and Development Volume: 66 Issue: 2 Pages: 175-180
  • DOI: 10.1262/jrd.2019-159
  • NAID: 130007830039
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access
• [Journal Article] Species-Dependent Enhancement of Ovarian Cancer G Protein-Coupled Receptor 1 Activation by Ogerin. (2020)
  • Author(s): Murakami S, Mochimaru Y, Musha S, Kojima R, Deai M, Mogi C, Sato K, Okajima F, Tomura H.
  • Journal Title: Zoolog Sci. Volume: 37 Issue: 2 Pages: 103-108
  • DOI: 10.2108/zs190106
  • NAID: 210000171197
  • Peer Reviewed
• [Journal Article] Characterization of Molecular Mechanisms of Extracellular Acidification-Induced Intracellular Ca 2+ Increase in LβT2 Cells (2019)
  • Author(s): Kojima R, Horiguchi K, Mochimaru Y, Musha S, Murakami S, Deai M, Mogi C, Sato K, Okajima F, Tomura H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 517 Issue: 4 Pages: 636-641
  • DOI: 10.1016/j.bbrc.2019.07.083
  • Peer Reviewed
• [Journal Article] Protons Differentially Activate TDAG8 Homologs from Various Species. (2019)
  • Author(s): S. Musha, S. Nagayama, S. Murakami, R. Kojima, M. Deai, K. Sato, F. Okajima, H. Ueharu, H. Tomura
  • Journal Title: Zoolog. Sci. Volume: 36 Issue: 2 Pages: 105-111
  • DOI: 10.2108/zs180128
  • NAID: 40021868137
  • Peer Reviewed
• [Journal Article] Extracellular acidification-induced CXCL8 production through a proton-sensing receptor OGR1 in human airway smooth muscle cells: a response inhibited by dexamethasone. (2019)
  • Author(s): M. Kadowaki, H. Yamada, K. Sato, H. Shigemi, Y. Umeda, M. Morikawa, Y. Waseda, M. Anzai, Y. Kamide, H. Aoki-Saito, T. Hisada, F. Okajima, T. Ishizuka
  • Journal Title: J. Inflamm. (Lond.) Volume: 16 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12950-019-0207-1
  • Peer Reviewed / Open Access
• [Journal Article] Metals differentially activate ovarian cancer G protein-coupled receptor 1 in various species. (2018)
  • Author(s): 6.Mochimaru Y, Negishi J, Murakami S, Musha S, Sato K, Okajima F, Tomura H.
  • Journal Title: Zoolog Sci. Volume: 35 Issue: 2 Pages: 109-114
  • DOI: 10.2108/zs170145
  • NAID: 40021514985
  • Peer Reviewed
• [Presentation] エナメル質形成不全症の家系から発見されたプロトン感知性受容体OGR1変異体Leu74Proの機能解析 (2020)
  • Author(s): 佐藤幸市、茂木千尋、Mighell A.J.、岡島史和
  • Organizer: 第93回日本生化学会大会
• [Presentation] 金属刺激によるヒト気道平滑筋細胞のIL-6産生とステロイドの抑制効果 (2020)
  • Author(s): 門脇麻衣子、佐藤幸市、神尾尚志、熊谷信、梅田幸寛、早稲田優子、安斎正樹、重見博子、齋藤悠、久田剛志、岡島史和、石塚全
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] T cell death associated gene 8 mediates MUC5AC expression in acidic conditions. (2019)
  • Author(s): H. Tsurumaki, H. Saito-Aoki, C. Mogi, K. Sato, T. Nakakura, Y. Koga, M. Yatomi, M. Sato, K. Dobashi, F. Okajima, T. Hisada
  • Organizer: Europian Respiratory Society International Congress 2019
  • Int'l Joint Research
• [Presentation] 金属刺激によるヒト気道平滑筋細胞のIL-6産生 (2019)
  • Author(s): 門脇麻衣子、佐藤幸市、熊谷信、神尾尚志、本定千知、重見博子、梅田幸寛、森川美羽、早稲田優子、安斎正樹、齋藤悠、久田剛志、岡島史和、石塚全
  • Organizer: 第50回日本職業・環境アレルギー学会総会・学術大会
• [Presentation] T cell death associated gene 8はOvalbumin誘導喘息モデルにおいてMUC5ACを制御する (2019)
  • Author(s): 鶴巻寛朗、齋藤悠、茂木千尋、佐藤幸市、中倉敬、古賀康彦、矢冨正清、佐藤真季子、石塚全、土橋邦生、岡島史和、久田剛志
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] T cell death associated gene 8 mediates MUC5AC expressions in the ovalbumin-induced asthma model. (2018)
  • Author(s): H. Tsurumaki, H. Saito-Aoki, C. Mogi, K. Sato, T. Nakakura, Y. Koga, M. Yatomi, M. Sato, K. Dobashi, F. Okajima, T. Hisada
  • Organizer: XXIV World Congress of Asthma 2018
  • Int'l Joint Research
• [Presentation] 固相化リポ蛋白リパーゼ（LPL）抗体を用いた血中レムナントリポ蛋白の単離の試み (2018)
  • Author(s): 長澤拓海、佐藤幸市、宮下かずや、深町勇、中嶋克行、町田哲男、村上正巳、安部由美子
  • Organizer: 第58回日本臨床化学会年次学術集会
• [Remarks] 生体調節研究所シグナル伝達グループホームページ
  • URL: https://signal-transduction.imcr.gunma-u.ac.jp/index.html
• [Remarks] 群馬大学生体調節研究所ホームページ
  • URL: https://www.imcr.gunma-u.ac.jp
• [Remarks] 群馬大学ホームページ
  • URL: http://www.gunma-u.ac.jp
• [Remarks] 群馬大学ホームページ
  • URL: https://www.imcr.gunma-u.ac.jp