Action mechanism of pH-sensing OGR1 family receptors and in vivo functions

• Project/Area Number: 15H04641
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Aomori University (2016-2017); Gunma University (2015)
• Principal Investigator: Okajima Fumikazu 青森大学, 薬学部, 教授 (30142748)
• Co-Investigator(Kenkyū-buntansha): 佐藤 幸市 群馬大学, 生体調節研究所, 准教授 (00302498)
• Research Collaborator: MOGI Chihiro ; AOKI Haruka ; HISADA Takeshi
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2016: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2015: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: プロトン / TDAG8 / OGR1 / GPR4 / ミクログリア / 骨代謝 / 内皮細胞 / 樹状細胞 / シグナル伝達 / 神経化学 / 生理学 / T細胞

Outline of Final Research Achievements

It is well known that acidification takes place in the ischemia and inflammatory region. However, how extracellular acidic pH regulates physiological and pathophysiological actions remains uncharacterized yet. In the present study, we investigated the roles of OGR1 family GPCRs, including OGR1, TDAG8, and GPR4, which have been recently identified as extracellular proton-sensing receptors, in bone remodeling, brain ischemia, tumorigenesis, and asthma. The results showed that these receptors play important roles in the physiological cellular functions and the development of ischemic and inflammatory disorders. We further characterized a novel GPR4 antagonist and found that it was effective in the myocardial infarction model.

Research Products

• [Int'l Joint Research] University of Leeds/St. James’s University Hospital/University of Edinburgh(United Kingdom)
• [Int'l Joint Research] Suez Canal University(Egypt)
• [Int'l Joint Research] Gulf Medical University(United Arab Emirates)
• [Int'l Joint Research] university of Michigan(米国)
• [Int'l Joint Research] Istanbul University(Turkey)
• [Int'l Joint Research]
• [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
• [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] 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] 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] 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] 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] Identification of a Potent and Selective GPR4 Antagonist as a Drug Lead for the Treatment of Myocardial Infarction (2016)
  • Author(s): Hayato Fukuda, Saki Ito, Kenji Watari, Chihiro Mogi, Mitsuhiro Arisawa, Fumikazu Okajima, Hitoshi Kurose, Satoshi Shuto
  • Journal Title: ACS Med. Chem. Lett. Volume: 7 Issue: 5 Pages: 493-497
  • DOI: 10.1021/acsmedchemlett.6b00014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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] 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] 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] 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] 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] 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] 17(R)-resolvin D1 ameliorates bleomycin-induced pulmonary fibrosis in mice. (2015)
  • Author(s): Yatomi M, Hisada T, Ishizuka T, Koga Y, Ono A, Kamide Y, Seki K, Aoki-Saito H, Tsurumaki H, Sunaga N, Kaira K, Dobashi K, Yamada M, Okajima F.
  • Journal Title: PHYSIOLOGICAL REPORTS Volume: 3 Issue: 12 Pages: 12628-12628
  • DOI: 10.14814/phy2.12628
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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
• [Presentation] 細胞外pHの低下によるヒト気管支平滑筋細胞からのIL-8産生亢進の転写調節機序とステロイドの抑制作用 (2017)
  • Author(s): 門脇麻衣子、本定千知、梅田幸寛、森川美羽、安斎正樹、山田秀典、齋藤悠、久田剛志、岡島史和、石塚 全
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] TDAG8欠損マウスでは好酸球性炎症は抑制される (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、塚越優介、笠原礼光、澤田友里、村田圭祐、砂長則明、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] OGR1欠損マウスを用いたHDM気管支モデルの解析 (2017)
  • Author(s): 齋藤 悠、茂木千尋、 鶴巻寛朗、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、三浦陽介、塚越優介、澤田友里、中倉敬、前野敏孝、土橋邦生、石塚全、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): Tsurumaki H, Hisada T, Mogi C, Saito-Aoki H, Yatomi M, Kamide Y, Tobo M, Sato K, Koga Y, Ono A, Dobashi K, Ishizuka T, Yamada M, Okajima F.
  • Organizer: ERS（欧州呼吸器学会議）INTERNATIONAL CONGRESS 2016
  • Place of Presentation: LONDON, United Kingdom
  • Year and Date: 2016-09-03
  • Int'l Joint Research
• [Presentation] ヒト気管支平滑筋細胞のプロトン感知性受容体OGR1を介するIL-8産生に対するステロイド薬の作用 (2016)
  • Author(s): 門脇麻衣子、山田秀典、齋藤（青木）悠、森川美羽、梅田幸寛、酒井啓行、飴嶋慎吾、久田剛志、岡島史和、石塚 全
  • Organizer: 第65回日本アレルギー学会学術大会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2016-06-17
• [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回日本呼吸器学会学術講演会
  • Place of Presentation: 京都国際会議場（京都）
  • Year and Date: 2016-04-08
• [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: 第38回日本分子生物学会年会/第88回日本生化学会大会合同大会（BMB2015）
  • Place of Presentation: 神戸ポートアイランド （神戸市中央区港島中町6）
  • Year and Date: 2015-12-01
• [Presentation] 脳虚血再灌流モデルマウスの脳障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: 第38回日本分子生物学会年会/第88回日本生化学会大会合同大会（BMB2015）
  • Place of Presentation: 神戸ポートアイランド （神戸市中央区港島中町6）
  • Year and Date: 2015-12-01
• [Presentation] Proton regulates FcεRI-mediated cytokine production through enhancement of p38MAPK and Akt activation in mouse mast cells (2015)
  • Author(s): Hiroaki Tsurumaki, Youseke Kamide, Tamotsu Ishizuka, Akihiro Ono, Yasuhiko Koga, Takeshi Hisada, Kunio Dobashi, Fumikazu Okajima, Masanobu Yamada, Masami Yaniguchi
  • Organizer: The 25th Congress of Interasma Japan/North Asia
  • Place of Presentation: ホテルニューグランド(横浜市中区山下町10番地)
  • Year and Date: 2015-09-03
  • Int'l Joint Research