2001 Fiscal Year Final Research Report Summary
Biopharmaceutical Research on Prostaglandin Receptors
| Project/Area Number |
12470496
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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 | 一般 |
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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) |
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)
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| Project Period (FY) |
2000 – 2001
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| Keywords | prostaglandin / receptor subtypes / cyclic AMP / signal transduction / colitis / platelet aggregation / colon cancer / gene targeting |
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| 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.
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