title: PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11beta-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa lutein cells.
abstract: In luteinizing granulosa cells, prostaglandin E(2) (PGE(2)) can exert luteotrophic actions, apparently via the cAMP signalling pathway. In addition to stimulating progesterone synthesis, PGE(2) can also stimulate oxidation of the physiological glucocorticoid, cortisol, to its inactive metabolite, cortisone, by the type 1 11beta-hydroxysteroid dehydrogenase (11betaHSD1) enzyme in human granulosa-lutein cells. Having previously shown these human ovarian cells to express functional G-protein coupled, E-series prostaglandin (PTGER)1, PTGER2 and PTGER4 receptors, the aim of this study was to delineate the roles of PTGER1 and PTGER2 receptors in mediating the effects of PGE(2) on steroidogenesis and cortisol metabolism in human granulosa-lutein cells. PGE(2)-stimulated concentration-dependent increases in both progesterone production and cAMP accumulation (by 1.9 +/- 0.1- and 18.7 +/- 6.8-fold respectively at 3000 nM PGE(2)). While a selective PTGER1 antagonist, SC19220, could partially inhibit the steroidogenic response to PGE(2) (by 55.9 +/- 4.1% at 1000 nM PGE(2)), co-treatment with AH6809, a mixed PTGER1/PTGER2 receptor antagonist, completely abolished the stimulation of progesterone synthesis at all tested concentrations of PGE(2) and suppressed the stimulation of cAMP accumulation. Both PGE(2) and butaprost (a preferential PTGER2 receptor agonist) stimulated concentration-dependent increases in cortisol oxidation by 11betaHSD1 (by 42.5 +/- 3.1 and 40.0 +/- 3.0% respectively, at PGE(2) and butaprost concentrations of 1000 nM). Co-treatment with SC19220 enhanced the ability of both PGE(2) and butaprost to stimulate 11betaHSD1 activity (by 30.2 +/- 0.2 and 30.5 +/- 0.6% respectively), whereas co-treatment with AH6809 completely abolished the 11betaHSD1 responses to PGE(2) and butaprost. These findings implicate the PTGER2 receptor-cAMP signalling pathway in the stimulation of progesterone production and 11betaHSD1 activity by PGE(2) in human granulosa-lutein cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: C
authors.initials: C
authors.lastname: Chandras
authors.forename: T E
authors.initials: TE
authors.lastname: Harris
authors.forename: A López
authors.initials: AL
authors.lastname: Bernal
authors.forename: D R E
authors.initials: DR
authors.lastname: Abayasekara
authors.forename: A E
authors.initials: AE
authors.lastname: Michael
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000527:Alprostadil / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D003348:Cortisone / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D008184:Luteal Cells / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000096:biosynthesis*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011459:Prostaglandins E, Synthetic / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D044004:Xanthones / Q000494:pharmacology
chemical_list: C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; D011448:Prostaglandin Antagonists; D011459:Prostaglandins E, Synthetic; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D044004:Xanthones; D012531:Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D011374:Progesterone; D000242:Cyclic AMP; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000527:Alprostadil; C048491:butaprost; D015232:Dinoprostone; D003348:Cortisone; D006854:Hydrocortisone