A THERMODYNAMIC ANALYSIS OF ESTROGEN REGULATION OF ALPHA(2)-ADRENOCEPTOR BINDING

We previously demonstrated that in vivo estradiol treatment markedly a ttenuates alpha(2)-adrenoceptor function and coupling to G-proteins in the hypothalamus of female rats. Ligand binding studies indicated tha t 48 h exposure to estradiol decreases the number of alpha(2)-adrenerg ic receptors in the agonist high affinity state. In the present studie s, when [H-3]RX821002 was used to label brain alpha(2)-adrenoceptors, the density of binding sites significantly increased in the hypothalam us and preoptic area 48 h after estrogen treatment. Moreover, the ther modynamics of ligand binding to alpha(2)-adrenergic receptors in membr anes of female rat hypothalamus were modified by the same estradiol tr eatments that reduce alpha(2)-adrenoceptor function. In hypothalamic m embranes from ovariectomized control rats, antagonist (RX821002)-recep tor binding was primarily entropy-driven while agonist (oxymetazoline) binding had a higher enthalpy component. In membranes from estradiol- exposed animals, the entropic contribution to both agonist and antagon ist binding was markedly increased, and the enthalpy component was red uced. Since the thermodynamic characteristics of ligand-receptor bindi ng are strongly correlated with efficacy in activating signal transduc tion [36], these data raise the intriguing possibility that steroids r egulate transmembrane signaling by stabilization of a receptor conform ation with reduced intrinsic efficacy.