Role of proton-sensing G protein-coupled receptors on microglial activation and neuronal cell survival in a mouse ischemia reperfusion model.

• Project/Area Number: 15K06767
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• 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): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脳虚血 / 脳内炎症 / ミクログリア / 炎症性サイトカイン / 酸性ストレス / 細胞死 / G蛋白共役型受容体 / pH感知性受容体 / 酸性pH / プロトン感知性受容体

Outline of Final Research Achievements

Extracellular acidic pH of ~6.5 has been shown to take place with ischemia and neurodegenerative. However, the mechanisms underlying acidic pH-induced actions are poorly understood. Proton-sensing OGR1 family G-protein coupled receptors (GPCRs, including OGR1, GPR4, and TDAG8) have been shown to be expressed in brain. This study has focused on the roles of proton-sensing GPCRs in the brain injury in a mouse ischemia reperfusion model. We also analyzed roles of proton-sensing GPCRs in mouse microglia and neuronal cells in acidic pH medium. Our results suggested that acidic pH /TDAG8 functions protectively for cerebral infarction by the mouse ischemia model possibly due to the mechanism involving inhibitory actions against microglia function. And also we showed the involvement of OGR1 and/or GPR4 in the acidic pH regulation of neuronal cell functions. Thus, the elucidation of acidic pH actions may provide therapeutic targets of neurodegenerative disorders such as ischemic stroke.

Research Products

• [Int'l Joint Research] 国立プサン大学(韓国)
• [Int'l Joint Research] リーズ大学(英国)
• [Int'l Joint Research] カリフォルニア大学デービス校/タフツ大学(米国)
• [Int'l Joint Research] 国立ブサン大学(韓国)
• [Int'l Joint Research] 内モンゴル医科大学(中国)
• [Int'l Joint Research] 内モンゴル大学(中国)
• [Journal Article] The proton-sensing G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) shows cardioprotective effects against myocardial infarction. (2017)
  • Author(s): Nagasaka A, Mogi C, Ono H, Nishi T, Horii Y, Ohba Y, Sato K, Nakaya M, Okajima F, Kurose H.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 7812-7812
  • DOI: 10.1038/s41598-017-07573-2
  • Peer Reviewed / Open Access
• [Journal Article] Reactive astrocytes function as phagocytes after brain ischemia via ABCA1-mediated pathway (2017)
  • Author(s): Morizawa Yosuke M.、Hirayama Yuri、Ohno Nobuhiko、Shibata Shinsuke、Shigetomi Eiji、Sui Yang、Nabekura Junichi、Sato Koichi、Okajima Fumikazu、Takebayashi Hirohide、Okano Hideyuki、Koizumi Schuichi
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 28-28
  • DOI: 10.1038/s41467-017-00037-1
  • Peer Reviewed / Open Access
• [Journal Article] Alamandine reduces leptin expression through the c-Src/p38 MAP kinase pathway in adipose tissue. (2017)
  • Author(s): Uchiyama T, Okajima F, Mogi C, Tobo A, Tomono S, S
  • Journal Title: PLoS One. Volume: 12 Issue: 6 Pages: e0178769-e0178769
  • DOI: 10.1371/journal.pone.0178769
  • Peer Reviewed / Open Access
• [Journal Article] Omega-3 polyunsaturated fatty acids accelerate airway repair by activating FFA4 in club cells. (2017)
  • Author(s): K.-P. Lee, S.-J. Park, S. Kang, J.-M. Koh, K. Sato, H.-Y. Chung, F. Okajima, D.-S. Im
  • Journal Title: Am. J. Physiol. Lung Cell. Mol. Physiol. Volume: - Issue: 6 Pages: L835-L844
  • DOI: 10.1152/ajplung.00350.2016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Manganese and cobalt activate zebrafish ovarian cancer G-protein-coupled receptor 1 but not GPR4. (2017)
  • Author(s): J. Negishi, Y. Omori, M. Shindo, H. Takanashi, S. Musha, S. Nagayama, J. Hirayama, H. Nishina, T. Nakakura, C. Mogi, K. Sato, F. Okajima, Y. Mochimaru, H. Tomura
  • Journal Title: J. Recept. Signal Transduct. Res. Volume: - Issue: 4 Pages: 401-408
  • DOI: 10.1080/10799893.2017.1298130
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta. (2016)
  • Author(s): Parry DA, Smith CE, El-Sayed W, Poulter JA, Shore RC, Logan CV, Mogi C, Sato K, Okajima F, Harada A, Zhang H, Koruyucu M, Seymen F, Hu JC, Simmer JP, Ahmed M, Jafri H, Johnson CA, Inglehearn CF, Mighell AJ.
  • Journal Title: Am J Hum Genet. Volume: 99 Issue: 4 Pages: 984-990
  • DOI: 10.1016/j.ajhg.2016.08.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The majority of lipoprotein lipase in plasma is bound to remnant lipoproteins: A new definition of remnant lipoproteins. (2016)
  • Author(s): Sato K, Okajima F, Miyashita K, Imamura S, Kobayashi J, Stanhope KL, Havel PJ, Machida T, Sumino H, Murakami M, Schaefer E, Nakajima K.
  • Journal Title: Clin Chim Acta Volume: 461 Pages: 114-125
  • DOI: 10.1016/j.cca.2016.06.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Two zebrafish G2A homologs activate multiple intracellular signaling pathways in acidic environment. (2016)
  • Author(s): Y. Ichijo, Y. Mochimaru, M. Azuma, K. Satou, J. Negishi, T. Nakakura, N. Oshima, C. Mogi, K. Sato, K. Matsuda, F. Okajima, H. Tomura
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 469 Issue: 1 Pages: 81-86
  • DOI: 10.1016/j.bbrc.2015.11.075
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective role of proton-sensing TDAG8 in lipopolysaccharide-induced acute lung injury. (2015)
  • Author(s): H. Tsurumaki, C. Mogi, H. Aoki-Saito, M. Tobo, Y. Kamide, M. Yatomi, K. Sato, K. Dobashi, T. Ishizuka, T. Hisada, M. Yamada, F. Okajima
  • Journal Title: Int. J. Mol. Sci. Volume: 16 Issue: 12 Pages: 28931-28942
  • DOI: 10.3390/ijms161226145
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Angiotensin II reduces lipoprotein lipase expression in visceral adipose tissue via phospholipase C β4 depending on feeding but increases lipoprotein lipase expression in subcutaneous adipose tissue via c-Src. (2015)
  • Author(s): T. Uchiyama, S. Tomono, K. Sato, T. Nakamura, M. Kurabayashi, F. Okajima
  • Journal Title: PloS One Volume: 10 Issue: 10 Pages: e0139638-e0139638
  • DOI: 10.1371/journal.pone.0139638
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Acidic environment augments FcεRI-mediated production of IL-6 and IL-13 in mast cells. (2015)
  • Author(s): Y. Kamide, T. Ishizuka, M. Tobo, H. Tsurumaki, H. Aoki, C. Mogi, T. Nakakura, M. Yatomi, A. Ono, Y. Koga, K. Sato, T. Hisada, K. Dobashi, M. Yamada, F. Okajima
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 464 Issue: 3 Pages: 949-955
  • DOI: 10.1016/j.bbrc.2015.07.077
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Omega-3 fatty acids induce Ca2+ mobilization responses in human colon epithelial cell lines endogenously expressing FFA4. (2015)
  • Author(s): J.-M. Kim, K.-P. Lee, S.-J. Park, S. Kang, J. Huang, J.-M. Lee, K. Sato, H.-Y. Chung, F. Okajima, D.-S. Im
  • Journal Title: Acta Pharmacol. Sin. Volume: 36 Issue: 7 Pages: 813-820
  • DOI: 10.1038/aps.2015.29
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton- Sensing GPR4 in Extracellular Acidification-Induced Responses (2015)
  • Author(s): Ayaka Tobo, Masayuki Tobo, Takashi Nakakura, Masashi Ebara, Hideaki Tomura, Chihiro Mogi, Dong-Soon Im, Naoya Murata, Atsushi Kuwabara, Saki Ito, Hayato Fukuda, Mitsuhiro Arisawa, Satoshi Shuto, Michio Nakaya, Hitoshi Kurose, Koichi Sato, Fumikazu Okajima
  • Journal Title: PLoS One. Volume: 10 Issue: 6 Pages: e0129334-e0129334
  • DOI: 10.1371/journal.pone.0129334
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Extracellular acidification synergizes with PDGF to stimulate migration of mouse embryo fibroblasts through activation of p38MAPK with a PTX-sensitive manner. (2015)
  • Author(s): C. An, K. Sato, T. Wu, M. Bao, L. Bao, M. Tobo, A. Damirin
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 460 Issue: 2 Pages: 191-197
  • DOI: 10.1016/j.bbrc.2015.03.006
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 脳虚血再灌流モデルマウスの脳病態におけるプロトン感知性受容体TDAG8の役割 (2017)
  • Author(s): 佐藤 幸市、茂木 千尋、岡島 史和
  • Organizer: ConBio2017
• [Presentation] 脳虚血傷害マウスにおけるプロトン感知性受容体TDAG8 の役割 (2017)
  • Author(s): 佐藤 幸市、岡島 史和
  • Organizer: 第56回日本薬学会東北支部大会
• [Presentation] Absence of proton-sensing TDAG8 protects against ovalbumin-induced allergic airway inflammation. (2017)
  • Author(s): Tsurumaki Hiroaki、Mogi Chihiro、Saito-Aoki Haruka、Sato Koichi、Nakakura Takashi、Yatomi Masakiyo、Koga Yasuhiko、Hachisu Yoshimasa、Ono Akihiro、Dobashi Kunio、Okajima Fumikazu、Hisada Takeshi
  • Organizer: Europian Respiratory Society International Congress 2017
  • Int'l Joint Research
• [Presentation] T cell death associated gene 8欠損マウスでは好酸球性気道炎症は抑制される (2017)
  • Author(s): 鶴巻 寛朗、齋藤 悠、茂木 千尋、佐藤 幸市、佐藤 真季子、矢冨 正清、蜂巣 克昌、古賀 康彦、小野 昭浩、澤田 友里、村田 圭祐、前野 敏孝、石塚 全、土橋 邦生、岡島 史和、久田 剛志
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] Proton-sensing TDAG8 exhibits the protective role in lipopolysaccharide-induced acute lung injury. (2016)
  • Author(s): H. Tsurumaki, T. Hisada, C. Mogi, H. Saito-Aoki, M. Yatomi, Y. Kamide, M. Tobo, K. Sato, Y. Koga, A. Ono, K. Dobashi, T. Ishizuka, M. Yamada, F. Okajima
  • Organizer: Europian Respiratory Society International Congress 2016
  • Place of Presentation: London （UK）
  • Year and Date: 2016-09-03
  • Int'l Joint Research
• [Presentation] TDAG8はLPS誘導性急性肺損傷において抑制的に働く (2016)
  • Author(s): 鶴巻 寛朗、齋藤（青木） 悠、茂木 千尋、久田 剛志、石塚 全、上出 庸介、矢冨 正清、古賀 康彦、小野 昭浩、佐藤 幸市、土橋 邦生、山田 正信、岡島 史和
  • Organizer: 第56回呼吸器学会学術講演会
  • Place of Presentation: 国立京都国際会館 （京都府京都市）
  • Year and Date: 2016-04-08
• [Presentation] 脳虚血再灌流モデルマウスの脳傷害におけるプロトン感知性受容体TDAG8の役割 (2015)
  • Author(s): 佐藤幸市、当房文香、当房雅之、茂木千尋、岡島史和
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] プロトン感知性受容体GPR4選択的阻害物質の特性解析：imidazopyridine化合物による負のアロステリック作用 (2015)
  • Author(s): 当房文香、佐藤幸市、当房雅之、茂木千尋、岡島史和
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Acidic pH inhibits interleukin-1β production by down-regulation of mitogen-activated protein kinase activity through the TDAG8/protein kinase A pathway in mouse microglia. (2015)
  • Author(s): K. Sato, Y. Jin, A. Tobo, M. Tobo, C. Mogi, F. Okajima
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 大宮ソニックシティ（埼玉県さいたま市）
  • Year and Date: 2015-09-11
• [Presentation] 血中リポ蛋白リパーゼとレムナント・リポ蛋白の相互関係について (2015)
  • Author(s): 中嶋克行、佐藤幸市、岡島史和、宮下和也、今村茂行、小林淳二、白川尚史、下村洋之助、町田哲男、角野博之、村上正巳
  • Organizer: 第57回日本脂質生化学会
  • Place of Presentation: 一橋大学一橋講堂（東京都千代田区）
  • Year and Date: 2015-05-28
• [Remarks] 群馬大学ホームページ
  • URL: http://www.gunma-u.ac.jp/
• [Remarks] 群馬大学生体調節研究所ホームページ
  • URL: http://www.imcr.gunma-u.ac.jp/
• [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: http://signal-transduction.imcr.gunma-u.ac.jp