1998 年度実績報告書

細胞膜情報交換系の構造、機能解析と個体レベルでの役割

研究課題

研究課題/領域番号	09273105
研究機関	京都大学
研究代表者	市川厚京都大学, 薬学研究科, 教授 (10025695)
研究分担者	門松健治名古屋大学, 医学部, 助教授 (80204519) 藤井穂高東京大学, 医学系研究科, 助手 (30302665) 佐藤公道京都大学, 薬学研究科, 教授 (80025709) 芳賀達也東京大学, 医学係研究科, 教授 (30011646) 牛首文隆旭川医科大学, 医学部, 教授 (50243035)
キーワード	情報伝達 / プロスタグランジン受容体 / オピオイド受容体 / G蛋白共役型受容体 / インターロイキン2受容体 / ミッドカイン / ペイシジン / 自己免疫性疾患
研究概要	以下のような研究成果を得た。 (1) 細胞膜受容体のリガンド結合ドメインと機能ドメインの解析:PGE受容体では、EP3のC末端鎖と第7膜貫通領域のそれぞれにG蛋白活性化ドメインを(市川)、また、IP/DPの細胞外領域と第1,3,4膜貫通領域のそれぞれに、PGの5員環構造と側鎖構造を認識するドメインを同定した(牛首)。PGの生体作用を検索するため、7種類のPG受容体の遺伝子欠損マウスを作製し、フェノタイプを解析中である(市川・牛首)。PGI合成酵素の遺伝子欠損マウスは強度の腎障害を起こすことを見出した(田辺)。 (2)orphanの細胞膜受容体に対するリガンドの解析:オピオイド受容体/nociceptin受容体の段階的な点変異キメラ受容体を用いたorphan受容体のリカンド探索系を(佐藤)、また、ムスカリン受容体m1-m5サブタイプの選択的なアゴニスト、及びアゴニスト作用を促進するアロステリックリガンドの評価系を確立した(芳賀)。 (3) インターロイキン2(IL-2)受容体の細胞増殖シグナル:Jak PTKsの下流でのシグナル伝達にStat経路とは別の.Pyk2経路を同定し、それらの情報伝達を介するリンパ球分化、及び増殖シグナルの経路を解明した(藤井・宮崎)。 (4) ミッドカイン・ベイシジンの生理機能:ミッドカインは細胞のトランスフォーム能、海馬歯状回の発達、新生内膜形成に、一方、ベイシジンは両性の生殖生理、特に妊娠の必須因子であることを発見した。また、ベイシジンには記憶学習、匂いに対する反応性等の機能的神経ネットワーク形成作用のあることが判明した(門松)。 (5) 自己免疫性脳脊髄炎の調節:本疾患のモデルマウスを用い、疾患の標的相ではNK細胞が、また、誘導相ではNKT細胞が関与していることを見出し、両細胞の働きを制御する薬物を合成した(田平)。

研究成果
(46件)

すべてその他

すべて文献書誌 (46件)

[文献書誌] Satoh,S., Ichikawa,A.et al.: "The Key Amino Acid Residue of Prostaglandin EP3 Receptor for Governing G Protein Association and Activation Steps." Biochem.Biophys.Res.Commun.255. 164-168 (1999)
[文献書誌] Takahashi,S., Ichikawa,A.et al.: "Localization of a cyclopentenone prostaglandin to the endoplasmic reticulum and induction of BiP mRNA." Biochem.J.335. 35-42 (1998)
[文献書誌] Katsuyama,M., Ichikawa,A.et al.: "Characterization of the gene for the mouse prostaglandin E receptor subtype EP2: tissue-specific initiation of transcription in the macrophage and the uterus." Biochem.J.330. 1115-1121 (1998)
[文献書誌] Segi,E., Ushikubi,F.et al.: "Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice." Biochem.Biophys.Res.Commun.246. 7-12 (1998)
[文献書誌] Suda,M., Ushikubi,F.et al.: "Prostaglandin E_2 (PGE_2) autoamplifies its production through EP1 subtype of PGE receptor in mouse osteoblastic MC3T3-E1 cells." Calcif.Tissue Int.62. 327-331 (1998)
[文献書誌] Ushikubi,F.et al.: "Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3." Nature. 395. 281-284 (1998)
[文献書誌] Ito,K., Haga,T.et al.: "Sequestration of dopamine D2 receptors depends on coexpression of G-protein-coupled receptor kinases 2 and 5." Eur.J.Biochem.(in press). 259. (1999)
[文献書誌] Haga,K., Haga,T.et al.: "GTP-binding-protein-coupled receptor kinase 2 (GRK2) binds and phosphorylates tubulin." Eur.J.Biochem.255. 363-368 (1998)
[文献書誌] Tsuga,H., Haga,T.et al.: "Internalization and down-regulation of human muscarinic acetylcholine receptor m2 subtypes: Role of third intracellular m2 loop and G protein-coupled receptor kinase 2." J.Biol.Chem.273. 5323-5330 (1998)
[文献書誌] Adachi,K., Satoh,M.et al.: "Inhibition of NMDA receptors and nitric oxide synthase reduces ischemic injury of the retina." Eur.J.Pharmacol.350. 53-57 (1998)
[文献書誌] Seki,T., Satoh,M.et al.: "Bremazocine recognizes the difference in four amino acid residues to discriminate between a nociceptin receptor and opioid receptors." Jpn.J.Pharmacol.77. 301-306 (1998)
[文献書誌] Seki,T., Satoh,M.et al.: "DAMGO recognizes four residues in the third extracellular loop to discriminate between μ-and κ-opioid receptors." Eur.J.Pharmacol.350. 301-310 (1998)
[文献書誌] Miyazaki,T., Fujii,H.et al.: "Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway." Genes & Development. 12. 770-775 (1998)
[文献書誌] Fujii,H.et al.: "Functional dissection of the cytoplasmic subregions of the IL-2 receptor βc chain in primary lymphocyte populations." EMBO Journal. 17・22. 6551-6557 (1998)
[文献書誌] Maeda,N., Kadomatsu,K.et al.: "A receptor-like tyrosine phosphataseζ (PTRζ/RPTPβ) binds midkine: involvement of arginine 78 of midkine in the high affinity binding to PTPζ" J.Biol.Chem.(in press). (1999)
[文献書誌] Fan,Q.-W., Kadomatsu,K.et al.: "Expression of basigin, a member of the immunoglobulin superfamily, in the central nervous system." Neurosci.Res.30. 53-63 (1998)
[文献書誌] Yokota,C., Kadomatsu,K.et al.: "Midkine counteracts the activin signal in mesoderm induction and promotes neural formation." J.Biochem.123. 339-346 (1998)
[文献書誌] Illes,Z., Tabira,T.et al.: "Selective loss of invariant Vα24+ T-cells in the peripheral blood of MS patients." Neuroimmunology. 6. 50-51 (1998)
[文献書誌] Tanahashi,H.and Tabira,T.: "Cloning of the cDNA encoding rat presenilin-2." Biochim.Biophys.Acta.1396. 259-262 (1998)
[文献書誌] Inoue,H., Tanabe,T.et al.: "Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial Cells." Biochem.Biophys.Res.Commun.254. 292-298 (1999)
[文献書誌] Subbaramaiah,K., Tanabe,T.et al.: "Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorobol Ester-treated Human Mammary Epithelial Cells." J.Biol.Chem.273. 21875-21882 (1998)
[文献書誌] Takahashi,S., Tanabe,T.et al.: "Localization of cyclooxygenase-2 and regulation of its mRNA expression in gastric ulcers in rats." Am.J.Physiol.275. G1137-G1145 (1998)
[文献書誌] Uehara,T., Nomura,Y.et al.: "Caspase activation accompanying cytochrome c release from mitochondria is possibly involved in nitric oxide-induced neuronal apoptosis in SH-SY5Y cells." J.Neurochem.72 (1). 196-205 (1999)
[文献書誌] Araya,R., Nomura,Y.et al.: "Hypoxia induces apoptosis human neuroblastoma SK-N-MC cells caspase activation accompanying cytochrome C release from mitochondria." FEBS Lett.439. 168-172 (1998)
[文献書誌] Sanchez,J.A., Inagaki,N.et al.: "Modelation of reconstituted ATP-sensitive K+ channels by GTP-binding proteins." J.Physiol.507. 315-324 (1998)
[文献書誌] Nagao,K., Sakamoto,K.et al.: "Characterization of mRNA expression of prostaglandin F2α receptor regulatory protein in the pseudo-pregnant rat ovary." J.Reprod.Fertil.(submitted).
[文献書誌] Hida,A., Seyama,Y.et al.: "Sexual differences in branched chain amino acid metabolism into fatty acids and cholesterol in Harderian gland of golden hamster." J.Biochem.124. 648-653 (1998)
[文献書誌] Igarashi,T., Izumi,T.et al.: "Characterization of the leukotriene B4 receptor in porcine leukocytes. Separation and reconstitution with heterotrimeric GTP-binding proteins." Eur.J.Biochem.259. 419-425 (1999)
[文献書誌] Ishii,I., Izumi,T.et al.: "Agonist-induced sequestration, recycling and resensitization of platelet-activating factor receptor: role of cytoplasmic tail phosphorylation in each process." J.Biol.Chem.273・16. 9878-9885 (1998)
[文献書誌] Hiraoka,Y., Muramatsu,I.et al.: "Binding and functional characterization of α_1-adrenoceptor subtypes in the rat prostate." Eur.J.Pharmacol.366. 119-126 (1999)
[文献書誌] Muramatsu,I.et al.: "α_1-Adrenoceptor subtypes and two receptor systems in vascular tissues." Life Science. 62 (17/18). 1461-1465 (1998)
[文献書誌] Sakai,T., Muramatsu,I.et al.: "Persistent release of noradrenaline caused by anticancer drug 4'-epidoxorubicin in rat tail artery in vitro" Eur.J.Pharmacol.356. 25-30 (1998)
[文献書誌] Hayashi,T., Iguchi,A.et al.: "Physiological concentration of 17β-estradiol inhibits the effect of inducible nitric oxide synthase in macrophage cell line: J774 by receptor mediated system." J.Cardiovascular Pharmacol.31. 292-298 (1998)
[文献書誌] Ramos,M.A., Iguchi,A.et al.: "Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesions." Arteriosclerosis, Thrombosis, and Vascular Biology. 18. 1188-1196 (1998)
[文献書誌] Mukai,T., Saji,H.et al.: "Pharmacokinetic models to evaluate radiolebeling reagents for protein radiopharmaceuticals." Nucl.Med.Biol.25 (1). 31-36 (1998)
[文献書誌] Yamamura,N., Saji,H.et al.: "Evaluation of 〔1-^<11>C〕octanoate as a new radiopharmaceutical for assessing liver function using positron emission tomography." Nucl.Med.Biol.25 (4). 467-472 (1998)
[文献書誌] Nagata,T., Shichida,Y.et al.: "The hydrogen bonding network of water molecules and the peptide backbone in the region connecting Asp83,Gly120 and Glu113 in bovine rhodopsin." Biochemistry. 37. 17216-17222 (1998)
[文献書誌] Terakita,A., Shichida,Y.et al.: "Selective activation of G-protein subtypes by vertebrate and invertebraterhodopsins." FEBS Lett.439. 110-114 (1998)
[文献書誌] Tsukamoto,Y., Miki,N.et al.: "Involvement of gicerin, a cell adhesion molecule, in development and regeneration of oviduct, and metastasis of oviductal adenocarcinomas." Exp.Cell.Res.(in press). (1999)
[文献書誌] Taira,E., Miki,N.et al.: "Neurite promotion from ciliary ganglion neurons by gicerin." Neurochem.Int.32. 23-29 (1998)
[文献書誌] Hashimoto,H., Baba,A.et al.: "Genomic organization and chromosomal location of the mouse vasoactive intestinal polypeptide 1 (VPAC1) receptor." Genomics (in press). (1999)
[文献書誌] Yamamoto,K., Baba,A.et al.: "Cloning and characterization of the mouse pituitary adenylate cyclase-activating polypeptide (PACAP) gene." Gene. 211. 63-69 (1998)
[文献書誌] Sano,H., Ebina,Y.et al.: "Insulin enhances macrophage scavenger receptor-mediated endocytic uptake of advanced glycation end products." J.Biol.Chem.273. 8630-8637 (1998)
[文献書誌] Lauro,D., Ebina,Y.et al.: "Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue." Nature Genetics. 20. 294-298 (1998)
[文献書誌] Eguchi,N., Ito,S.et al.: "Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice." Proc.Natl.Acad.Sci.U.S.A.96. 726-730 (1999)
[文献書誌] Okuda-Ashitake,E., Ito S.et al.: "Nocistatin, a peptide that blocks nociceptin action in pain transmission." Nature. 392. 286-289 (1998)

1998 年度 実績報告書

細胞膜情報交換系の構造、機能解析と個体レベルでの役割

研究代表者

市川 厚 京都大学, 薬学研究科, 教授 (10025695)

研究成果

[文献書誌] Satoh,S., Ichikawa,A.et al.: "The Key Amino Acid Residue of Prostaglandin EP3 Receptor for Governing G Protein Association and Activation Steps." Biochem.Biophys.Res.Commun.255. 164-168 (1999)

[文献書誌] Takahashi,S., Ichikawa,A.et al.: "Localization of a cyclopentenone prostaglandin to the endoplasmic reticulum and induction of BiP mRNA." Biochem.J.335. 35-42 (1998)

[文献書誌] Katsuyama,M., Ichikawa,A.et al.: "Characterization of the gene for the mouse prostaglandin E receptor subtype EP2: tissue-specific initiation of transcription in the macrophage and the uterus." Biochem.J.330. 1115-1121 (1998)

[文献書誌] Segi,E., Ushikubi,F.et al.: "Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice." Biochem.Biophys.Res.Commun.246. 7-12 (1998)

[文献書誌] Suda,M., Ushikubi,F.et al.: "Prostaglandin E_2 (PGE_2) autoamplifies its production through EP1 subtype of PGE receptor in mouse osteoblastic MC3T3-E1 cells." Calcif.Tissue Int.62. 327-331 (1998)

[文献書誌] Ushikubi,F.et al.: "Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3." Nature. 395. 281-284 (1998)

[文献書誌] Ito,K., Haga,T.et al.: "Sequestration of dopamine D2 receptors depends on coexpression of G-protein-coupled receptor kinases 2 and 5." Eur.J.Biochem.(in press). 259. (1999)

[文献書誌] Haga,K., Haga,T.et al.: "GTP-binding-protein-coupled receptor kinase 2 (GRK2) binds and phosphorylates tubulin." Eur.J.Biochem.255. 363-368 (1998)

[文献書誌] Tsuga,H., Haga,T.et al.: "Internalization and down-regulation of human muscarinic acetylcholine receptor m2 subtypes: Role of third intracellular m2 loop and G protein-coupled receptor kinase 2." J.Biol.Chem.273. 5323-5330 (1998)

[文献書誌] Adachi,K., Satoh,M.et al.: "Inhibition of NMDA receptors and nitric oxide synthase reduces ischemic injury of the retina." Eur.J.Pharmacol.350. 53-57 (1998)

[文献書誌] Seki,T., Satoh,M.et al.: "Bremazocine recognizes the difference in four amino acid residues to discriminate between a nociceptin receptor and opioid receptors." Jpn.J.Pharmacol.77. 301-306 (1998)

[文献書誌] Seki,T., Satoh,M.et al.: "DAMGO recognizes four residues in the third extracellular loop to discriminate between μ-and κ-opioid receptors." Eur.J.Pharmacol.350. 301-310 (1998)

[文献書誌] Miyazaki,T., Fujii,H.et al.: "Pyk2 is a downstream mediator of the IL-2 receptor-coupled Jak signaling pathway." Genes & Development. 12. 770-775 (1998)

[文献書誌] Fujii,H.et al.: "Functional dissection of the cytoplasmic subregions of the IL-2 receptor βc chain in primary lymphocyte populations." EMBO Journal. 17・22. 6551-6557 (1998)

[文献書誌] Maeda,N., Kadomatsu,K.et al.: "A receptor-like tyrosine phosphataseζ (PTRζ/RPTPβ) binds midkine: involvement of arginine 78 of midkine in the high affinity binding to PTPζ" J.Biol.Chem.(in press). (1999)

[文献書誌] Fan,Q.-W., Kadomatsu,K.et al.: "Expression of basigin, a member of the immunoglobulin superfamily, in the central nervous system." Neurosci.Res.30. 53-63 (1998)

[文献書誌] Yokota,C., Kadomatsu,K.et al.: "Midkine counteracts the activin signal in mesoderm induction and promotes neural formation." J.Biochem.123. 339-346 (1998)

[文献書誌] Illes,Z., Tabira,T.et al.: "Selective loss of invariant Vα24+ T-cells in the peripheral blood of MS patients." Neuroimmunology. 6. 50-51 (1998)

[文献書誌] Tanahashi,H.and Tabira,T.: "Cloning of the cDNA encoding rat presenilin-2." Biochim.Biophys.Acta.1396. 259-262 (1998)

[文献書誌] Inoue,H., Tanabe,T.et al.: "Glucocorticoid-Mediated Suppression of the Promoter Activity of the Cyclooxygenase-2 Gene Is Modulated by Expression of Its Receptor in Vascular Endothelial Cells." Biochem.Biophys.Res.Commun.254. 292-298 (1999)

[文献書誌] Subbaramaiah,K., Tanabe,T.et al.: "Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorobol Ester-treated Human Mammary Epithelial Cells." J.Biol.Chem.273. 21875-21882 (1998)

[文献書誌] Takahashi,S., Tanabe,T.et al.: "Localization of cyclooxygenase-2 and regulation of its mRNA expression in gastric ulcers in rats." Am.J.Physiol.275. G1137-G1145 (1998)

[文献書誌] Uehara,T., Nomura,Y.et al.: "Caspase activation accompanying cytochrome c release from mitochondria is possibly involved in nitric oxide-induced neuronal apoptosis in SH-SY5Y cells." J.Neurochem.72 (1). 196-205 (1999)

[文献書誌] Araya,R., Nomura,Y.et al.: "Hypoxia induces apoptosis human neuroblastoma SK-N-MC cells caspase activation accompanying cytochrome C release from mitochondria." FEBS Lett.439. 168-172 (1998)

[文献書誌] Sanchez,J.A., Inagaki,N.et al.: "Modelation of reconstituted ATP-sensitive K+ channels by GTP-binding proteins." J.Physiol.507. 315-324 (1998)

[文献書誌] Nagao,K., Sakamoto,K.et al.: "Characterization of mRNA expression of prostaglandin F2α receptor regulatory protein in the pseudo-pregnant rat ovary." J.Reprod.Fertil.(submitted).

[文献書誌] Hida,A., Seyama,Y.et al.: "Sexual differences in branched chain amino acid metabolism into fatty acids and cholesterol in Harderian gland of golden hamster." J.Biochem.124. 648-653 (1998)

[文献書誌] Igarashi,T., Izumi,T.et al.: "Characterization of the leukotriene B4 receptor in porcine leukocytes. Separation and reconstitution with heterotrimeric GTP-binding proteins." Eur.J.Biochem.259. 419-425 (1999)

[文献書誌] Ishii,I., Izumi,T.et al.: "Agonist-induced sequestration, recycling and resensitization of platelet-activating factor receptor: role of cytoplasmic tail phosphorylation in each process." J.Biol.Chem.273・16. 9878-9885 (1998)

[文献書誌] Hiraoka,Y., Muramatsu,I.et al.: "Binding and functional characterization of α_1-adrenoceptor subtypes in the rat prostate." Eur.J.Pharmacol.366. 119-126 (1999)

[文献書誌] Muramatsu,I.et al.: "α_1-Adrenoceptor subtypes and two receptor systems in vascular tissues." Life Science. 62 (17/18). 1461-1465 (1998)

[文献書誌] Sakai,T., Muramatsu,I.et al.: "Persistent release of noradrenaline caused by anticancer drug 4'-epidoxorubicin in rat tail artery in vitro" Eur.J.Pharmacol.356. 25-30 (1998)

[文献書誌] Hayashi,T., Iguchi,A.et al.: "Physiological concentration of 17β-estradiol inhibits the effect of inducible nitric oxide synthase in macrophage cell line: J774 by receptor mediated system." J.Cardiovascular Pharmacol.31. 292-298 (1998)

[文献書誌] Ramos,M.A., Iguchi,A.et al.: "Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesions." Arteriosclerosis, Thrombosis, and Vascular Biology. 18. 1188-1196 (1998)

[文献書誌] Mukai,T., Saji,H.et al.: "Pharmacokinetic models to evaluate radiolebeling reagents for protein radiopharmaceuticals." Nucl.Med.Biol.25 (1). 31-36 (1998)

[文献書誌] Yamamura,N., Saji,H.et al.: "Evaluation of 〔1-^<11>C〕octanoate as a new radiopharmaceutical for assessing liver function using positron emission tomography." Nucl.Med.Biol.25 (4). 467-472 (1998)

[文献書誌] Nagata,T., Shichida,Y.et al.: "The hydrogen bonding network of water molecules and the peptide backbone in the region connecting Asp83,Gly120 and Glu113 in bovine rhodopsin." Biochemistry. 37. 17216-17222 (1998)

[文献書誌] Terakita,A., Shichida,Y.et al.: "Selective activation of G-protein subtypes by vertebrate and invertebraterhodopsins." FEBS Lett.439. 110-114 (1998)

[文献書誌] Tsukamoto,Y., Miki,N.et al.: "Involvement of gicerin, a cell adhesion molecule, in development and regeneration of oviduct, and metastasis of oviductal adenocarcinomas." Exp.Cell.Res.(in press). (1999)

[文献書誌] Taira,E., Miki,N.et al.: "Neurite promotion from ciliary ganglion neurons by gicerin." Neurochem.Int.32. 23-29 (1998)

[文献書誌] Hashimoto,H., Baba,A.et al.: "Genomic organization and chromosomal location of the mouse vasoactive intestinal polypeptide 1 (VPAC1) receptor." Genomics (in press). (1999)

[文献書誌] Yamamoto,K., Baba,A.et al.: "Cloning and characterization of the mouse pituitary adenylate cyclase-activating polypeptide (PACAP) gene." Gene. 211. 63-69 (1998)

[文献書誌] Sano,H., Ebina,Y.et al.: "Insulin enhances macrophage scavenger receptor-mediated endocytic uptake of advanced glycation end products." J.Biol.Chem.273. 8630-8637 (1998)

[文献書誌] Lauro,D., Ebina,Y.et al.: "Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue." Nature Genetics. 20. 294-298 (1998)

[文献書誌] Eguchi,N., Ito,S.et al.: "Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-deficient mice." Proc.Natl.Acad.Sci.U.S.A.96. 726-730 (1999)

[文献書誌] Okuda-Ashitake,E., Ito S.et al.: "Nocistatin, a peptide that blocks nociceptin action in pain transmission." Nature. 392. 286-289 (1998)

1998 年度実績報告書

市川厚京都大学, 薬学研究科, 教授 (10025695)