title: Beta1-adrenoceptors in rat anterior pituitary may be constitutively active. Inverse agonism of CGP 20712A on basal 3',5'-cyclic adenosine 5'-monophosphate levels.
abstract: Catecholamines directly stimulate GH, ACTH, and prolactin secretion from rat anterior pituitary through the beta(2)-adrenoceptor (AR). We recently showed that gonadotrophs express the beta(1)-AR and that glucocorticoids drastically increase its mRNA expression level. The present investigation explores whether beta(1)-ARs are functionally coupled to adenylate cyclase. In anterior pituitary cell aggregates, the highly selective beta(1)-AR antagonists CGP 20712A and ICI 89,406-8a attenuated isoproterenol-stimulated cAMP accumulation, but no agonist action of norepinephrine could be detected. Remarkably, CGP 20712A inhibited basal cAMP levels by its own for at least 50%, an action that tended to be more effective in dexamethasone-supplemented medium. The latter effect was abolished by the beta-AR antagonist carvedilol, but not by other beta-AR antagonists. Pretreatment with pertussis toxin abolished the action of CGP 20712A on basal cAMP. CGP 20712A also attenuated isoproterenol-induced cAMP accumulation in the gonadotroph cell lines alphaT3-1 and LbetaT2, but not in the somatotroph precursor cell line GHFT and the folliculo-stellate cell line TtT/GF. However, in LbetaT2 cells CGP 20712A did not inhibit basal cAMP levels by its own. The present data suggest that beta(1)-AR in the anterior pituitary is positively coupled to adenylyl cyclase but is constitutively active in a pertussis toxin-sensitive manner. CGP 20712A may act as an inverse agonist with approximately 50% negative intrinsic activity, suggesting that the beta(1)-AR significantly contributes to basal adenylate cyclase activity in the pituitary.
authors.affiliation: Laboratory of Cell Pharmacology, University of Leuven, Medical School, Campus Gasthuisberg (O & N), B-3000 Leuven, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Janssens
authors.forename: Magaly
authors.initials: M
authors.lastname: Boussemaere
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Carl
authors.initials: C
authors.lastname: Denef
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D000077261:Carvedilol; D002449:Cell Aggregation / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D054314:Drug Inverse Agonism; D004789:Enzyme Activation / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D037342:Pertussis Toxin / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000378:metabolism*; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism / Q000502:physiology*; D013379:Substrate Specificity
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D002227:Carbazoles; D007093:Imidazoles; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000077261:Carvedilol; C049763:CGP 20712A; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases; D007545:Isoproterenol