RRC ID 43238
Author Janssens K, Boussemaere M, Wagner S, Kopka K, Denef C.
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.
Journal Endocrinology
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.
Volume 149(5)
Pages 2391-402
Published 2008-5
DOI 10.1210/en.2007-1397
PII en.2007-1397
PMID 18202135
MeSH Adenylyl Cyclases / metabolism Adrenergic beta-1 Receptor Antagonists* Adrenergic beta-2 Receptor Antagonists Animals Carbazoles / pharmacology Carvedilol Cell Aggregation / drug effects Cells, Cultured Cyclic AMP / metabolism* Drug Inverse Agonism* Enzyme Activation / drug effects Imidazoles / pharmacology* Isoproterenol / pharmacology Male Pertussis Toxin / pharmacology Pituitary Gland, Anterior / metabolism* Propanolamines / pharmacology Rats Rats, Wistar Receptors, Adrenergic, beta-1 / metabolism Receptors, Adrenergic, beta-1 / physiology* Substrate Specificity
IF 3.961
Times Cited 3
Human and Animal Cells