title: Elucidation of mechanisms of the reciprocal cross talk between gonadotropin-releasing hormone and prostaglandin receptors.
abstract: We recently described a novel GnRH receptor signaling pathway mediated by the prostaglandins (PGs) F(2alpha) and PGI(2), which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and inhibit LH but not FSH release. Here we further explore the cross talk between GnRH and the PG receptors. GnRH stimulates arachidonic acid (AA) release from LbetaT2 gonadotrope cells via the Ca(2+)-independent phospholipase A(2) (iPLA(2)) and not via the more common Ca(2+)-dependent cytosolic phospholipase A(2)alpha (cPLA(2)alpha). AA release was followed by a marked induction of cyclooxygenase (COX)-1 and COX-2 by GnRH via the protein kinase C/c-Src/phosphatidylinositol 3-kinase/MAPK pathway. COX-2 transcription by GnRH is mediated by the two nuclear factor-kappaB sites and the CCAAT/enhancer-binding protein site within its promoter. Indeed, GnRH stimulates p65/RelA phosphorylation (22-fold) in LbetaT2 cells and the two nuclear factor-kappaB sites apparently act as a composite response element. Although GnRH stimulates cAMP formation in LbetaT2 cells, we found no role for cAMP acting via the cAMP response element site in the COX-2 promoter. PGF(2alpha), PGI(2), or PGE(2) had no effect on GnRH-stimulated ERK, c-Jun N-terminal kinase, and p38MAPK activation or on GnRH- and high K(+)-stimulated intracellular Ca(2+) elevation in LbetaT2 and gonadotropes in primary culture. Although, PGF(2alpha), PGI(2), and PGE(2) reduced GnRH-stimulated cAMP formation, we could not correlate it to the inhibition of GnRH receptor expression, which is exerted only by PGF(2alpha) and PGI(2.) Hence, the inhibition by PGF(2alpha) and PGI(2) of the autoregulation of GnRH receptor expression is most likely mediated via inhibition of GnRH-stimulated phosphoinositide turnover and not by inhibition of Ca(2+) elevation and MAPK activation.
authors.affiliation: Department of Biochemistry, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Naidich
authors.forename: Boris
authors.initials: B
authors.lastname: Shterntal
authors.forename: Ran
authors.initials: R
authors.lastname: Furman
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Pawson
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.forename: Robert P
authors.initials: RP
authors.lastname: Millar
authors.forename: Jingjing
authors.initials: J
authors.lastname: Jia
authors.forename: Melanija
authors.initials: M
authors.lastname: Tomic
authors.forename: Stanko
authors.initials: S
authors.lastname: Stojilkovic
authors.forename: Naftali
authors.initials: N
authors.lastname: Stern
authors.forename: Zvi
authors.initials: Z
authors.lastname: Naor
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D011464:Epoprostenol / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D054522:Group VI Phospholipases A2 / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011966:Receptors, LHRH / Q000378:metabolism*; D011982:Receptors, Prostaglandin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D016718:Arachidonic Acid; D002118:Calcium; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015237:Dinoprost; D015232:Dinoprostone; D011464:Epoprostenol; D007987:Gonadotropin-Releasing Hormone; D054513:Group IV Phospholipases A2; D054522:Group VI Phospholipases A2; D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011966:Receptors, LHRH; D011982:Receptors, Prostaglandin; D000097782:NF-kappaB-Inducing Kinase