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プロトンとリゾ脂質をセンスするG蛋白共役型受容体の情報変換機構と生体機能

Publicly Offered Research

Project AreaMolecular interaction and modal shift of cellular sensors
Project/Area Number 21026004
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionGunma University

Principal Investigator

戸村 秀明  群馬大学, 生体調節研究所, 准教授 (70217553)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2010: ¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2009: ¥2,900,000 (Direct Cost: ¥2,900,000)
Keywordsシグナル伝達 / プロトン / G蛋白共役型受容体 / 脂質 / 生理活性 / プロトン感知性GPCR / TDAG8 / マクロファージ / 炎症性サイトカイン / cAMP
Research Abstract

細胞外pHの低下は、周辺の組織や細胞の機能を変化させるが、そのメカニズムの詳細は不明である。OGR1、GPR4、TDGA8、G2Aは細胞外プロトンを感知するユニークなGPCR群であることが我々のものを含め、報告されている(OGR1ファミリー)。我々は細胞外pHの低下に伴う細胞応答のモーダルシフトに、このファミリーが関与するものと考えている。本年は、1.ヒトGPR4の変異体を作成することにより、多様なシグナル系に情報を伝達するGPR4の活性化機構を調べた。GPR4を過剰発現させると、細胞外のpH変化に伴い、cAMP産生(Gs)、SREプロモーターの活性化(G13)、イノシトールリン酸の蓄積(Gq)がおこる。そこで本年度は、各々のシグナル系の活性化につながるGPR4内の細胞外に存在する8個のヒスチジンをそれぞれフェニルアラニンに置換した変異体を用い、各シグナル系を活性化する共通の3個のヒスチジンを同定した。2.ヒト血管平滑筋細胞におけるプロトン感知性GPCRとLPA間のクロストークの解析を行った。ヒト大動脈血管平滑筋細胞では細胞外pH低下に伴い、COX-2の発現上昇と、PGI2の産生増加が観察される。また、LPAが単独ではPGI2の産生をほとんど惹起しないが、pHの低下に伴う,PGI2の産生を大幅に増強するモーダルシフトを示す。本年度はこのモーダルシフトに関与する受容体を同定した(OGR1とLPA1)。またこのLPA作用はpH低下に伴うCOX-2発現以外にもMKP1(MAPK phosphatasel)など、他の遺伝子発現においても観察されることが明らかになった。3.プロトン感知性GPCR欠損マウスの関節、骨組織骨関連細胞の機能解析は継続する予定である。

Report

(2 results)
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (27 results)

All 2010 2009 Other

All Journal Article (13 results) (of which Peer Reviewed: 13 results) Presentation (12 results) Remarks (2 results)

  • [Journal Article] Each one of certain histidine residues in G-protein-coupled receptor GPR4 is critical for extracellular proton-induced stimulation of multiple G-protein-signaling pathways2010

    • Author(s)
      Liu JP
    • Journal Title

      Pharmacol Res

      Volume: 61 Pages: 499-505

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ovarian cancer G protein-coupled receptor 1-dependent and -independent vascular actions to acidic pH in human aortic smooth muscle cells2010

    • Author(s)
      Liu JP
    • Journal Title

      Am J Physiol Heart Circ Phtsiol

      Volume: 299

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Extracellular acidification stimulates IL-6 production and Ca(2+) mobilization through proton-sensing OGR1 receptors in human airway smooth muscle cells2010

    • Author(s)
      Ichimonji I
    • Journal Title

      Am J Physiol Lung Cell Mol Physiol

      Volume: 299

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lysophosphatidic acid inhibits CC chemokine ligand 5/RANTES production by blocking IRF-1-mediated gene transcription in human bronchial epithelial cells2010

    • Author(s)
      Matsuzaki S
    • Journal Title

      J Immunol

      Volume: 185 Pages: 4863-4872

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Constituively active heat shock factor 1 enhances glucose-driven insulin secretion2010

    • Author(s)
      Uchiyama T
    • Journal Title

      Metabolism

      Volume: (In press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cross-talk Between Exogenous Statins and Endogenous High-density Lipoprotein in Anti-inflammatory and Anti-atherogenic Actions2010

    • Author(s)
      Kimura T
    • Journal Title

      Endocrine, Metabolic and Immune Disorder-Drug Targets (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Each one of certain histidine residues in G-protein-coupled receptor GPR4 is critical for extracellular proton-induced stimulation of multiple G-protein-signaling pathways2010

    • Author(s)
      Liu JP
    • Journal Title

      Pharmacol Res (In press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Signaling pathways involved in DNA synthesis and migration in response to lysophosphatidic acid and low-density lipoprotein in coronary artery smooth muscle cells2009

    • Author(s)
      Komachi M
    • Journal Title

      Vasc Pharmacol 50

      Pages: 178-184

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] LPA_1 receptors mediate stimulation, whereas LPA_2 receptors mediate inhibition, of migration of pancreatic cancer cells in response to lysophosphatidic acid and malignant ascites2009

    • Author(s)
      Komachi M
    • Journal Title

      Carcinogenesis 30

      Pages: 457-465

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of Proton-Sensing TDAG8 in Extracellular Acidification-Induced Inhibition of Pro-Inflammatory Cytokine Production In Peritoneal Macrophages2009

    • Author(s)
      Mogi C
    • Journal Title

      J Immunol 182

      Pages: 3243-3251

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of superoxide anion production by extracellular acidification in neutrophils2009

    • Author(s)
      Murata N
    • Journal Title

      Cell Immunol 259

      Pages: 21-26

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of Rap1B and Tumor Suppressor PTEN in the Negative Regulation of Lysophosphatidic Acid-induced Migration by Isoproterenol in Glioma Cells2009

    • Author(s)
      Malchinkhuu E
    • Journal Title

      Mol Biol Cell 20

      Pages: 6156-5165

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mechanism and role of high-density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells2009

    • Author(s)
      Kimura T
    • Journal Title

      J Biol Chem 285

      Pages: 4387-4397

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] インスリン分泌における細胞外pHの影響とOGR1の役割2010

    • Author(s)
      中倉敬
    • Organizer
      BMB 2010
    • Place of Presentation
      兵庫県神戸
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] Each one of specified histidine residues in GPR4 is important for acidic pH-induced stimulation of multiple signaling pathways2010

    • Author(s)
      戸村秀明
    • Organizer
      BMB 2010
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] 糖質コルチコイドの抗炎症作用におけるTDAG8の役割2010

    • Author(s)
      Xiaodong He
    • Organizer
      BMB 2010
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] ヒト膵臓癌細胞のインビボ転移・浸潤に対する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2010

    • Author(s)
      小町麻由美
    • Organizer
      BMB 2010
    • Place of Presentation
      神戸ポートアイランド(兵庫県)
    • Year and Date
      2010-12-07
    • Related Report
      2010 Annual Research Report
  • [Presentation] プロトンをセンスするGタンパク共役型受容体の情報変換機構と生体機能2010

    • Author(s)
      戸村秀明
    • Organizer
      第52回日本脂質生化学会
    • Place of Presentation
      伊香保(群馬県)
    • Year and Date
      2010-06-14
    • Related Report
      2010 Annual Research Report
  • [Presentation] リゾフォスファチジン酸による血管内皮細胞のVEカドヘリンのトランスロケーション制御機構2010

    • Author(s)
      木村孝穂
    • Organizer
      第52回日本脂質生化学会
    • Place of Presentation
      伊香保(群馬県)
    • Year and Date
      2010-06-14
    • Related Report
      2010 Annual Research Report
  • [Presentation] Mechanism and role of high-density lipoprotein-induced cAMP-activated protein kinase activation in endothelial cells2010

    • Author(s)
      Takao Kimura
    • Organizer
      International Symposium on Cardiovascular Endocrinology and Metabolism 2010
    • Place of Presentation
      Nara, Japan
    • Year and Date
      2010-04-01
    • Related Report
      2010 Annual Research Report
  • [Presentation] ヒト大動脈血管平滑筋細胞のCOX-2発現/プロスタサイクリン産生応答におけるプロトン感知性GPCRとLPA受容体のクロストーク2009

    • Author(s)
      劉進朋
    • Organizer
      第51回日本脂質生化学会
    • Place of Presentation
      ウィルあいち(愛知県女性総合センター:名古屋)
    • Related Report
      2009 Annual Research Report
  • [Presentation] LPA1 receptors and LPA2 receptors mediate stimulation and inhibition of migration of pancreatic cancer cells, respectively2009

    • Author(s)
      小町麻由美
    • Organizer
      21st IUBMB & 12th FAOBMB International Congress of Biochemistry and Molecular Biology
    • Place of Presentation
      Shanghai China
    • Related Report
      2009 Annual Research Report
  • [Presentation] ヒト大動脈平滑筋細胞における細胞外プロトン/OGR1受容体を介したシクロゲナーゼー2の発現のリゾホスファチジン酸による増加2009

    • Author(s)
      戸村秀明
    • Organizer
      第82回日本生化学会大会
    • Place of Presentation
      神戸ポートアイランド
    • Related Report
      2009 Annual Research Report
  • [Presentation] ヒト膵臓癌細胞の遊走・浸潤におけるリゾホスファチジン酸受容体LPA2の役割について2009

    • Author(s)
      小町麻由美
    • Organizer
      第82回日本生化学会大会
    • Place of Presentation
      神戸ポートアイランド
    • Related Report
      2009 Annual Research Report
  • [Presentation] マウスマクロファージの酸性下での炎症性サイトカインの産生低下におけるTDAG8の関与2009

    • Author(s)
      戸村秀明
    • Organizer
      第80回日本動物学会大会
    • Place of Presentation
      静岡グランシップ
    • Related Report
      2009 Annual Research Report
  • [Remarks]

    • URL

      http://imcr.showa.gunma-u.ac.jp/lab/signal/index.html

    • Related Report
      2010 Annual Research Report
  • [Remarks]

    • URL

      http://imcr.showa.gunma-u.ac.jp/lab/signal/index.html

    • Related Report
      2009 Annual Research Report

URL: 

Published: 2009-04-01   Modified: 2018-03-28  

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