Tyrosine kinase effects on adrenoceptor-stimulated cyclic AMP accumulationin preoptic area and hypothalamus of female rats: modulation by estradiol

These studies examined the functional interactions between adrenergic G-pro tein coupled receptors and protein tyrosine kinases in the preoptic area an d hypothalamus, brain regions that regulate reproductive function in female rats, and evaluated whether in vivo treatment with estradiol for 2 days mo dulates the cross-talk between these two signaling pathways. In hypothalami c slices genistein, a general tyrosine kinase inhibitor, enhances norepinep hrine-stimulated cAMP synthesis independent of estradiol treatment. Geniste in appears to act by increasing beta-adrenoceptor signaling. At high norepi nephrine concentrations, estradiol potentiates genistein enhancement of the cAMP response in hypothalamic slices. This interaction between estradiol a nd genistein appears to involve modification of alpha(2)-adrenoceptor signa ling mechanisms. In preoptic area slices, genistein enhancement of norepine phrine-stimulated cAMP synthesis is only observed in estradiol-treated rats . In this brain region, genistein enhances cAMP accumulation by modifying a lpha(1)- and/or alpha(2)-adrenoceptor rather than beta-adrenoceptor signali ng. Genistein amplification of norepinephrine-stimulated cAMP synthesis is not mediated by interactions with estrogen receptors, or by regulation of a denylyl cyclase or phosphodiesterase activities. At the concentration used, genistein inhibits tyrosine phosphorylation in slices from both brain regi ons. Daidzein, an inactive analogue of genistein, fails to enhance the nore pinephrine-stimulated cAMP response in either brain region independent of h ormone treatment. These results suggest that protein tyrosine kinases regul ate adrenergic responses in the hypothalamus and preoptic area. Moreover, t he functional interaction between adrenergic G-protein coupled receptor sig naling and protein tyrosine kinases is modified in a brain region and recep tor subtype specific manner by estradiol. (C) 2000 Elsevier Science B.V. Al l rights reserved.