A thermodynamic analysis of estrogen regulation of alpha 2-adrenoceptor binding.
We previously demonstrated that in vivo estradiol treatment markedly attenuates alpha 2-adrenoceptor function and coupling to G-proteins in the hypothalamus of female rats. Ligand binding studies indicated that 48 h exposure to estradiol decreases the number of alpha 2-adrenergic receptors in the agonist high affinity state. In the present studies, when [3H]RX821002 was used to label brain alpha 2-adrenoceptors, the density of binding sites significantly increased in the hypothalamus and preoptic area 48 h after estrogen treatment. Moreover, the thermodynamics of ligand binding to alpha 2-adrenergic receptors in membranes of female rat hypothalamus were modified by the same estradiol treatments that reduce alpha 2-adrenoceptor function. In hypothalamic membranes from ovariectomized control rats, antagonist (RX821002)-receptor 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 antagonist bindings was markedly increased, and the enthalpy component was reduced. Since the thermodynamic characteristics of ligand-receptor binding are strongly correlated with efficacy in activating signal transduction [36], these data raise the intriguing possibility that steroids regulate transmembrane signaling by stabilization of a receptor conformation with reduced intrinsic efficacy.
Karkanias
G B
GB
Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Etgen
A M
AM
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004146:Dioxanes / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D019329:Idazoxan / Q000031:analogs & derivatives; D008024:Ligands; D010052:Ovariectomy; D010109:Oxymetazoline / Q000378:metabolism; D011301:Preoptic Area / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D013696:Temperature; D013816:Thermodynamics
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D008024:Ligands; D011942:Receptors, Adrenergic, alpha; D006165:Guanylyl Imidodiphosphate; D004958:Estradiol; D010109:Oxymetazoline; C058525:2-methoxyidazoxan; D019329:Idazoxan