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Biopharmaceutical Research on Prostaglandin Receptors

Research Project

Project/Area Number 12470496
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

ICHIKAWA Atsushi  Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Professor, 薬学研究科, 教授 (10025695)

Co-Investigator(Kenkyū-buntansha) TANAKA Satoshi  Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Instructor, 薬学研究科, 助手 (40303846)
SUGIMOTO Yukihiko  Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Associate Professor, 薬学研究科, 助教授 (80243038)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥16,400,000 (Direct Cost: ¥16,400,000)
Fiscal Year 2001: ¥5,900,000 (Direct Cost: ¥5,900,000)
Fiscal Year 2000: ¥10,500,000 (Direct Cost: ¥10,500,000)
Keywordsprostaglandin / receptor subtypes / cyclic AMP / signal transduction / colitis / platelet aggregation / colon cancer / gene targeting / cyclicAMP / プロスタグランジン受容体 / Gタンパク質 / EP3受容体 / EP2受容体 / トロンボキサン受容体 / シクロオキシゲナーゼ
Research Abstract

(1) The new signal transaction pathway exerted by prostanoid receptor EPS : EP3 has been shown to be coupled to Gi activity, inhibition of adenylate cyclase. EP3 has multiple isoforms that are different in their C-terminal structure and in their agonist-dependent Gi activity. We found that EP3 receptors expressed in COS-7 cells showed augmentation of other receptor-stimulated Gs activity in an agonist-dependent manner. The superactivatipn of Gs by EP3 receptors was not affected by the treatment of pertussis toxin, suggesting that the superactivation is not Gi-mediated. The EP3 agonist-dependent supeactivation of Gs is observed in any type of mouse EPS receptor isoforms, irrespective of C-termnal structure of EP3 receptor. This EP3 signaling may reflect some aspects of the physiological function of PGE2, such as pain sensation.
(2) Elucidation of physiological roles of PGE2 by using each receptor subtype-deficient mice : We found that EP2 deficiency attenuated intestinal polyp formation both in number and size in Apc KO mice. We also showed acceleration of COX-2, EP2 and VEGF expression in the intestinal polyps of wild-type mice, but faint expression of COX-2 or VEGF in those of EP2 and Ape double-knockout mice, suggesting that there exists positive feedback regulation between COX-2 and EP2. We introduced dextransulfate (DSS)-induced colitis model into EP-deficient mice. As a result, only EP4-deficient mice showed severe colitis upon 3%DSS treatment that did not induce significant colitisin wild-type mice. EP4 has been shown to promote epithelial regeneration and to inhibit activation ofleukocytes and lymphocytes. We further found that EPS-deficient mice showed increased bleeding tendency and decreased susceptibility to arachidonate-induced thromboembolism compared with wild-type mice. EPS appears to potentiate TP-induced platelet aggregation by increasing intracellular Ca2+ and/or decreasing cAMP level.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Yamane, H., et al.: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-a and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils"Biochem. Biophys. Res. Commun.. 278. 224-228 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuoka, T., et al.: "Prostaglandin D2 as a mediator of allergic asthma"Science. 287. 2013-2017 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikegami, R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages"J. Immunol.. 166. 4689-4696 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita, M., et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice"Nature Medicine. 7. 1048-1051 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kabashima, K., et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J. Clin. Invest.. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, N., et al.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaqlandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yamane, H., et al: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils"Biochem. Biophys. Res. Commun.. 278. 224-228 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Matsuoka, T, et al: "Prostaglandin D2 as a mediator of allergic asthma"Science. 287. 2013-2017 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Ikegami,R.,et al: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages."J. Immunol.. 166. 4689-4696 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita, M., et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice."Nature Medicine. 7. 1048-1051 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kabashima, K., et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J.Clin.Invest. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hatae, N., et al: "Augmentation of Receptor-Mediated Adenpylyl Cyclase Activity by Gi-Coupted Prostaglandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Sonoshita M, Takaku K, Sasaki, Sugimoto Y et al.: "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716"Nature Medicine. 7. 1048-1051 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kabashima Saji T, Murata T et al.: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J.Clin.Invest.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Torii E, Segi E, Sugimoto Y, et al.: "Expression of prostaglandin E2 receptor subtypes in mouse hair follicles"Biochem.Biophys.Res.Commun.. 122. 145-155 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hatae, N., Yamaoka, K., Sugimoto, et al.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaglandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem.Biophys.Res.Commun.. 290. 162-168 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ueno A, Matsumoto H, Naraba H, et al.: "Major roles of prostanoid receptors IP and EP(3) in endotoxin-induced enhancement of pain perception"Biochem.Pharmacol.. 62. 157-160 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ma H, Hara A, Xiao CY, et al.: "Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3"Circulation. 104. 1176-1180 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ikegami,R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages."J.Immunol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamane,H., et al.: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-a and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils."Biochem.Biophys.Res.Commun.. 278. 224-228 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuoka,T., et al.: "Prostaglandin D2 as a mediator of allergic asthma."Science. 287. 2013-2017 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugimoto,Y., et al.: "Distribution and function of prostanoid receptors : studies from knockout mice."Jpn.J.Pharmacol.. 83. 279-285 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Croy,B.A., et al.: "Prolonged gestation does not extend survival of uterine natural killer lymphocytes in mice deleted in the receptor for prostaglandin F_<2α>"J.Reprod.Immunol.. 46. 125-129 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsuboi,K., et al.: "Uterine expression of prostaglandin H_2 synthase in late pregnancy and during parturition in prostaglandin F receptor-deficient mice."Endocrinology. 141. 315-324 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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