The activation of hepatic phosphorylase by catecholamines in the adult male rat is mediated by an Alpha-adrenergic rise in cytosolic calcium while in the female both this mechanism, and a Beta-adrenergic rise in cAMP appear to be important. This proposal is to investigate six aspects of these differences in isolated hepatocytes. They are (1) the influence of the estrous cycle on the adrenergic response in the female; (2) the functional importance of the Beta component in the female; (3) the role of male/female differences in plasma membrane receptors in the response to catecholamines; (4) the ontogeny of the differences; (5) the role of gonadal hormones in modulating the hepatic adrenergic response in adult animals and (6) the importance of neonatal imprinting in determining the adult response. The male and female response to the Alpha and Beta components of epinephrine stimulation will be evaluated at the level of second messenger participation (cAMP content and 45 Ca efflux) and physiological output (phosphorylase activity, glycogen degradation, glucose release). A characterization of the Alpha and Beta receptors of intact cells with respect to the maximum binding and Kd for epinephrine is proposed. Intact animals and adult castrates will be used to evaluate the influence of testosterone and estradiol on the hepatocyte response. Animals castrated at birth will be studied to determine the influence of neonatal exposure to androgen or estrogen on the adult pattern of response to catecholamines. This will be the initial study of a heretofore uncharacterized system of hormonal modulation of adrenergic regulation of hepatic carbohydrate metabolism.
