title: Oestradiol-17beta inhibits tamoxifen-induced LHRH self-priming blocking hormone-dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat.
abstract: In the rat, administration of tamoxifen (TX) in the absence of oestrogen (E) induces LHRH self-priming, the progesterone receptor (PR)-dependent property of LHRH that increases gonadotrope responsiveness to itself. The oestrogen-dependent PR can be phosphorylated/activated by progesterone (P4) and, in the absence of the cognate ligand, by intracellular LHRH signals, particularly cAMP/protein kinase A. We have recently found that oestradiol-17beta (E2), acting on a putative membrane estrogen receptor-alpha in the gonadotrope, inhibits this agonist action of TX. This study investigated the mechanism by which E2 inhibits TX-elicited LHRH self-priming using both incubated pituitaries from TX-treated ovariectomized (OVX) rats and anterior pituitary cells from OVX rats cultured with TX. It was found that (1) in addition to the inhibitory effect on TX-elicited LHRH self-priming, E2 blocked P4 and adenylyl cyclase activator forskolin augmentation of LHRH-stimulated LH secretion, and (2) E2 did not affect the increasing action of TX on gonadotrope PR expression or pituitary cAMP content. Furthermore, inhibition of protein phosphatases with okadaic acid suppressed E2 inhibition of TX-elicited LHRH-induced LH secretion, while stimulation of protein phosphatases with ceramide blocked TX-induced LHRH self-priming. Together, these results indicated that membrane ER-mediated E2 inhibition of the TX-stimulated LHRH self-priming pathway involves a blockade of gonadotrope PR phosphorylation/activation, but not a deficient response of PR to phosphorylases. Results also suggested that the inhibitory effect of E2 on TX-induced LHRH self-priming is exerted through modulation of cellular protein phosphatase activity in the gonadotrope.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, University of Córdoba, Avda. Menendez Pidal s/n, 14004 Córdoba, Spain. fi1sacrj@uco.es
authors.forename: José E
authors.initials: JE
authors.lastname: Sánchez-Criado
authors.forename: José C
authors.initials: JC
authors.lastname: Garrido-Gracia
authors.forename: Carmina
authors.initials: C
authors.lastname: Bellido
authors.forename: Rafaela
authors.initials: R
authors.lastname: Aguilar
authors.forename: Pedro
authors.initials: P
authors.lastname: Guelmes
authors.forename: Pedro
authors.initials: P
authors.lastname: Abreu
authors.forename: Rafael
authors.initials: R
authors.lastname: Alonso
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Barranco
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Millán
authors.forename: Juana Martín
authors.initials: JM
authors.lastname: de Las Mulas
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D002518:Ceramides / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003864:Depression, Chemical; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D009924:Organ Culture Techniques; D010052:Ovariectomy; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism*; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011980:Receptors, Progesterone / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D011980:Receptors, Progesterone; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D005576:Colforsin; D019319:Okadaic Acid; D007987:Gonadotropin-Releasing Hormone; D011374:Progesterone; D004958:Estradiol; D010749:Phosphoprotein Phosphatases; D000262:Adenylyl Cyclases