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β₁-Adrenoceptors in Rat Anterior Pituitary May Be Constitutively Active. Inverse Agonism of CGP 20712A on Basal 3',5'-Cyclic Adenosine 5'-Monophosphate Levels

Laboratory of Cell Pharmacology (K.J., M.B., C.D.), University of Leuven, Medical School, Gasthuisberg, B-3000 Leuven, Belgium; Department of Nuclear Medicine (S.W., K.K.), University Hospital of the University of Münster, D-48129 Münster, Germany; and European Institute of Molecular Imaging (S.W., K.K.), D-48149 Münster, Germany

Address all correspondence and requests for reprints to: Professor Carl Denef, Laboratory of Cell Pharmacology, University of Leuven, Medical School, Campus Gasthuisberg (O & N), B-3000 Leuven, Belgium. E-mail: Carl.Denef{at}med.kuleuven.be.

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 T3–1 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.

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				K. Janssens, O. Krylyshkina, N. Hersmus, H. Vankelecom, and C. Denef {beta}1-Adrenoceptor Expression in Rat Anterior Pituitary Gonadotrophs and in Mouse {alpha}T3-1 and L{beta}T2 Gonadotrophic Cell Lines Endocrinology, May 1, 2008; 149(5): 2313 - 2324. [Abstract] [Full Text] [PDF]