β1-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 β2-adrenoceptor (AR). We recently showed that gonadotrophs express the β1-AR and that glucocorticoids drastically increase its mRNA expression level. The present investigation explores whether β1-ARs are functionally coupled to adenylate cyclase. In anterior pituitary cell aggregates, the highly selective β1-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 β-AR antagonist carvedilol, but not by other β-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 αT3-1 and LβT2, but not in the somatotroph precursor cell line GHFT and the folliculo-stellate cell line TtT/GF. However, in LβT2 cells CGP 20712A did not inhibit basal cAMP levels by its own. The present data suggest that β1-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 β1-AR significantly contributes to basal adenylate cyclase activity in the pituitary. Copyright © 2008 by The Endocrine Society.