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Evidence that Oestradiol Attenuates β‐Adrenoceptor Function in the Hypothalamus of Female Rats by Altering Receptor Phosphorylation and Sequestration

Activation of β‐adrenoceptors in the hypothalamus (HYP) and preoptic area (POA) inhibits both gonadotropin release and reproductive behaviour in female rats. Exposure of female rats for 48 h to physiologically relevant doses of oestrogen attenuates β‐adrenoceptor function in the HYP and POA as indicated by reduced isoproterenol (β‐adrenoceptor agonist) stimulation of adenylyl cyclase activity. Reduced β‐adrenoceptor coupling to G protein in the HYP‐POA from oestrogen‐exposed female rats correlates with attenuation of β‐adrenoceptor function. To examine potential mechanisms underlying receptor‐G protein uncoupling, initial experiments tested the hypothesis that oestrogen attenuation of β‐adrenoceptor function in the HYP and POA involves receptor phosphorylation. Activation of endogenous serine/threonine phosphatases with protamine restores agonist‐stimulated cAMP accumulation in HYP slices from oestrogen‐exposed female rats to control levels. Additional experiments examined whether oestrogen‐induced changes in β‐adrenoceptor binding density and/or subcellular localization correlate with the attenuation of β‐adrenoceptor function in the HYP and POA. Oestrogen treatment does not alter total β‐adrenoceptor binding density in the HYP or POA. However, oestrogen significantly reduces cell surface binding of the hydrophilic β‐adrenoceptor antagonist [3H] CGP 12177 to intact HYP and POA slices. At the same time, oestrogen decreases the fraction of β‐adrenoceptors localized in a light vesicle fraction following sucrose density gradient centrifugation. Therefore, oestrogen attenuates β‐adrenoceptor signalling in the HYP‐POA by uncoupling the β‐adrenoceptor from G protein, perhaps by promoting receptor phosphorylation. Furthermore, a significant fraction of β‐adrenoceptors in the HYP and POA are no longer accessible to hydrophilic ligands, but are not internalized. Thus, physiological doses of oestrogen may facilitate reproductive behaviour and gonadotropin release, in part, by stabilizing β‐adrenoceptor phosphorylation in the HYP and POA, thereby uncoupling the receptors from G protein.