Role of proton-sensing G protein-coupled receptors on microglial activation and neuronal cell survival in a ischemic situation.

• Project/Area Number: 24500435
• 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): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• 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 / 脳内炎症 / 炎症性サイトカイン / 細胞死 / 酸性ストレス / 酸性pH / 神経細胞

Outline of Final Research Achievements

OGR1 family G-protein coupled receptors (GPCR), including OGR1, GPR4, and TDAG8, sense extracellular pH of 8.0-6.0, resulting in the activation of intracellular signaling pathways. Extracellular acidic pH of 6.8-6.1 has been shown to take place with ischemia and neurodegenerative. However, the mechanisms underlying acidic pH-induced actions are poorly understood. This study has especially focused on the roles of proton-sensing GPCR in mouse microglia and neuronal cells in acidic pH cultured medium. Our results suggested that acidic pH inhibits lipopolysaccaride-induced IL-1β production through the TDAG8/cAMP pathway in microglia, and stimulates neuronal NO synthase-mediated cGMP accumulation via OGR1/Ca2+ pathway in N1E115 cells. Thus, the elucidation of the molecular targets for acidic pH actions may provide therapeutic targets of neurodegenerative disorders such as ischemic stroke.

Research Products

• [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/内モンゴル大学(中国)
• [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
• [Journal Article] Extracellular acidification activates ovarian cancer G-protein-coupled receptor 1 and GPR4 homologs of zebra fish. (2015)
  • Author(s): Y. Mochimaru, M. Azuma, N. Oshima, Y. Ichijo, K. Satou, K. Matsuda, Y. Asaoka, H. Nishina, T. Nakakura, C. Mogi, K. Sato, F. Okajima, H. Tomura
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 457 Issue: 4 Pages: 493-499
  • DOI: 10.1016/j.bbrc.2014.12.105
  • Peer Reviewed
• [Journal Article] Inhibition of interleukin-1β production by extracellular acidification through the TDAG8/cAMP pathway in mouse microglia. (2014)
  • Author(s): Ye Jin, Koichi Sato, Ayaka Tobo, Chihiro Mogi, Masayuki Tobo, Naoya Murata, Satoshi Ishii, Dong-Soon Im and Fumikazu Okajima
  • Journal Title: Journal of Neurochemistry Volume: 129(4) Issue: 4 Pages: 683-695
  • DOI: 10.1111/jnc.12661
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine 1-phosphate induced anti-atherogenic and atheroprotective M2 macrophage polarization through IL-4. (2014)
  • Author(s): S.-J. Park, K.-P. Lee, S. Kang, J. Lee, K. Sato, H. Y. Chung, F. Okajima, D.-S. Im
  • Journal Title: Cell. Signal. Volume: 26 Issue: 10 Pages: 2249-2258
  • DOI: 10.1016/j.cellsig.2014.07.009
  • Peer Reviewed
• [Journal Article] Acidic pH increases cGMP accumulation through the OGR1/phospholipase C/Ca2+/neuronal NOS pathway in N1E-115 neuronal cells. (2014)
  • Author(s): M. Kotake, K. Sato, C. Mogi, M. Tobo, H. Aoki, T. Ishizuka, N. Sunaga, H. Imai, K. Kaira, T. Hisada, M. Yamada, F. Okajima
  • Journal Title: Cell. Signal. Volume: 26 Issue: 11 Pages: 2326-2332
  • DOI: 10.1016/j.cellsig.2014.07.010
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lipoprotein-associated lysolipids are differentially involved in high-density lipoprotein- and its oxidized form-induced neurite remodeling in PC12 cells. (2014)
  • Author(s): Koichi Sato, Masayuki Tobo, Chihiro Mogi, Naoya Murata, Mie Kotake, Atsushi Kuwabara, Dong-Soon Im, Fumikazu Okajima
  • Journal Title: Neurochemistry International Volume: 68 Pages: 38-47
  • DOI: 10.1016/j.neuint.2014.02.005
  • Peer Reviewed
• [Journal Article] Proton-sensing ovarian cancer G protein-coupled receptor 1 on dendritic cells is required for airway responses in a murine asthma model (2013)
  • Author(s): Aoki H, Mogi C, Hisada T, Kamide Y, Ichimonji I, Tomura H, Tobo M, Sato K, Tsurumaki H, Dobashi K, Mori T, Harada H, Yamada M, Mori M, Ishizuka T, Okajima F
  • Journal Title: PLoS ONE Volume: 8(11) Issue: 11 Pages: e79985-e79985
  • DOI: 10.1371/journal.pone.0079985
  • Peer Reviewed
• [Journal Article] An orally active lysophosphatidic acid receptor antagonist attenuates panereatic cancer invasion and metastasis in vivo (2012)
  • Author(s): Komachi M
  • Journal Title: Cancer Science Volume: (印刷中) Issue: 6 Pages: 1099-1104
  • DOI: 10.1111/j.1349-7006.2012.02246.x
  • Peer Reviewed
• [Journal Article] Deficiency of proton-sensing ovarian cancer G protein-coupled receptor 1 attenuates glucose stimulated insulin secretion. (2012)
  • Author(s): Nakakura T
  • Journal Title: Endocrinology Volume: 153 Issue: 9 Pages: 4171-4180
  • DOI: 10.1210/en.2012-1164
  • Peer Reviewed
• [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
• [Presentation] マウスミクログリアにおいて酸性pHはTDAG8/PKAを介してMAPK系を抑制することによってIL-1β産生を抑制する (2014)
  • Author(s): 佐藤幸市、金嘩、当房文香、茂木千尋、岡島史和
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ゼブラフィッシュG2Aの機能解析 (2014)
  • Author(s): 一條祐太、東森生、松田恒平、茂木千尋、佐藤幸市、岡島史和、戸村秀明
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] ゼブラフィッシュGPR4、OGR1の分子的特徴 (2014)
  • Author(s): 大嶋菜月、持丸雄太、東森生、松田恒平、中倉敬、茂木千尋、佐藤幸市、岡島史和、戸村秀明
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] N1E115神経細胞における細胞外酸性pHによるcGMP産生機構 (2013)
  • Author(s): 小竹 美絵
  • Organizer: 第86回日本生化学会
  • Place of Presentation: パシフィコ横浜 （神奈川県横浜市）
  • Invited
• [Presentation] N1E115神経細胞における細胞外酸性pHによる細胞内Ca2+動員、Aktリン酸化とプロトン感知性受容体の関与 (2012)
  • Author(s): 佐藤幸市
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場（福岡県）
• [Presentation] Involvement of TDAG8 in extracellular acidification-induced inhibition of interleukin-1β production in microglia. (2012)
  • Author(s): Ye Jin
  • Organizer: 第85回日本生化学会
  • Place of Presentation: 福岡国際会議場（福岡県）
• [Presentation] ヒト膵臓がん細胞の浸潤・転移に対する経口可能なリゾホスファチジン酸受容体アンタゴニストKi16198の抑制作用 (2012)
  • Author(s): 佐藤幸市
  • Organizer: 第54回日本脂質生化学会
  • Place of Presentation: 九州大学医学部百年講堂（福岡県）
• [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
• [Remarks] 群馬大学生体調節研究所
  • URL: http://www.imcr.gunma-u.ac.jp/
• [Remarks] シグナル伝達分野
  • URL: http://signal-transduction.imcr.gunma-u.ac.jp/
• [Remarks] 国立大学法人 群馬大学
  • URL: http://www.gunma-u.ac.jp/
• [Remarks] 国立大学法人 群馬大学
  • URL: http://www.gunma-u.ac.jp/index-j.html
• [Remarks] 群馬大学 生体調節研究所
  • URL: http://www.imcr.gunma-u.ac.jp/
• [Remarks] 国立大学法人 群馬大学
  • URL: http://www.gunma-u.ac.jp/index-j.html
• [Remarks] 群馬大学生体調節研究所
  • URL: http://imcr.showa.gunma-u.ac.jp/
• [Remarks] 群馬大学生体調節研究所シグナル伝達分野
  • URL: http://www.imcr.gunma-u.ac.jp/lab/sigtra/