| Project/Area Number |
10557222
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Biological pharmacy
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
ICHIKAWA Atsushi Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Professor, 薬学研究科, 教授 (10025695)
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| Co-Investigator(Kenkyū-buntansha) |
HAMANAKA Nobuyuki Discovery Res. Lab. I, Ono Pharmaceu. Co., Senior Res. Scientist, 創薬第1研, 主席研究員
NEGISHI Manabu Kyoto Univ., Grad. Sch. of Biostudies, Professor, 生命科学研究科, 教授 (60201696)
SUGIMOTO Yukihiko Kyoto Univ., Grad. Sch. of Pharmaceu. Sci., Associate Professor, 薬学研究科, 助教授 (80243038)
MARUYAMA Takayuki Discovery Res. Lab. I, Ono Pharmaceu. Co., Res. Scientist, 創薬第1研, 研究員
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| Project Period (FY) |
1998 – 1999
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| Project Status |
Completed (Fiscal Year 1999)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 1999: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 1998: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | prostaglandin receptor / receptor subtype-selective agonist / G protein / prostaglandin receptor-deficient mice / ligand-receptor interaction / ovulation / fever / ductus arteriosus / EP3サブタイプ受容体 / EP2受容体欠損マウス / 受精 / 卵丘細胞 / プロスタグランジン / PGE受容体欠損マウス / PGF受容体欠損マウス / 情報伝達 / G蛋白質 |
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| Research Abstract |
We established mice deficient in each type of prostanoid receptors, and clarified physiological roles of prostanoids by examining phenotypes in each knockout mice : FP-deficient mice fail to deliver their pups due to persistent production of progesterone in ovaries, indicating that PGF2α plays a role in luteolysis required for normal parturition. IP-deficient mice showed increased tendency of thrombosis, reduced responses of inflammation, and did not show acetic acid-induced writhing responses, indicating that PG12 participates in promotion of inflammation and pain sensation. EP3-deficent mice did not show febrile responses to both endogenous and exogenous pyrogen; PGE2 mediates pyrogen-induced fever generation via EP3. EP4-deficient mice died within three days after birth due to patency of ductus arteriosus. PGE2 plays an essential role in neonatal closure of ductus arteriosus via EP4. EP2-deficent female mice showed reduced fertility due to impaired ovulation and fertilization; PGE2
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contributes to ovulation and fertilization through stimulation of cumulus expansion via EP2 and the resultant increase in cAMP level. Through these studies, we demonstrated importance of receptor subtype-specific activities.
Furthermore, by the analysis of mutant EP3 receptor expressed in CHO cells generated by the method of site-directed mutagenesis, we found that ionic interaction between plus charge of arginine-residue (Arg-306 in mouse EP3 receptor) and minus charge of free carboxyl-residue in ligands is essential for the activation of Gs and Gq proteins, but hydrogen interaction in these residues is enough for the activation of Gi protein. Based on these findings, we developed four agonists for EP receptor subtype (EP1 : ONO-DI-004, EP2 : ONO-AE1-259, EP3 : ONO-EA-248, EP4 : ONO-AE1-329) and an EP1-specific antagonist (ONO-8711) which are excellent in their receptor-specificity. These compounds have potential to be developed as powerful drugs with more specific therapeutic effects and less side effects. Less
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