ESTROGEN UNCOUPLES BETA-ADRENERGIC-RECEPTOR FROM THE STIMULATORY GUANINE-NUCLEOTIDE-BINDING PROTEIN IN FEMALE RAT HYPOTHALAMUS

The responsiveness of adenylyl cyclase to beta-adrenergic receptor sti mulation was investigated in membranes prepared from hypothalamus-preo ptic area and cortex of ovariectomized female rats injected with oil v ehicle or estradiol benzoate 24 or 48 h before death. Membranes from t he hypothalamus-Preoptic area of ovariectomized animals displayed a co ncentration-dependent stimulation of adenylyl cyclase when incubated w ith the beta-adrenergic receptor agonist, isoproterenol (10(-7)-10(-5) M). This response was suppressed in membranes from estrogen-treated a nimals. The effect of estrogen was observed 48 h, but not 24 h, after hormone administration. In addition, estrogen had no measurable effect on hypothalamic adenylyl cyclase activation by either GTP (10(-8)-10( -5) m) or forskolin (10(-8)-10(-6) m), on beta-adrenergic receptor den sity, or on antagonist binding affinity measured with the beta-adrener gic antagonist [I-125]iodocyanopindolol. Analysis of isoproterenol dis placement of iodocyanopindolol binding revealed that estrogen reduced agonist binding affinity in hypothalamus-preoptic area membranes. In m embranes from ovariectomized controls, high affinity agonist binding t o the beta-adrenergic receptor was apparent and was abolished by guani ne nucleotides. However, membranes from estradiol-treated rats demonst rated only low affinity agonist binding that was unaffected by guanine nucleotides. Estradiol did not detectably alter concentrations of eit her cholera or pertussis toxin substrates in hypothalamus-preoptic are a membranes. These data indicate that estrogen promotes a stable time- dependent desensitization of beta-adrenergic receptor activation of ad enylyl cyclase in hypothalamus and preoptic area by uncoupling the rec eptor from the guanine nucleotide-binding protein, G(s).