The objective of the proposed project is to elucidate the mechanisms by which glucocorticoids exert their permissive action on glucagon and catecholamine control of hepatic carbohydrate metabolism. Findings from this project in the past several years indicate that adrenalectomy in the male rate resulted in (i) a decrease in hepatic Alpha1-adrenergic receptor, and increases in Alpha2- and Beta-adrenergic receptors, (ii) decreased hepatic phosphorylase b kinase and an increase in phosphorylase phosphatase activities which may be important contributors to the blunted glucagon activation of phosphorylase, and (ii) a less active state of 6-phosphofructo-1-kinase which is not further influenced by glucagon and might account in part for the inability of glucagon to activate gluconeogenesis. It is planned to study systematically the physiological important of the observed changes in Alpha1-, Alpha2-, and Beta-adrenergic receptors. Fractionated and partially purified plasma membrane subfractions will be used to further characterize the changes in radioligand binding to the various adrenergic receptor subtypes, and their possible interaction in altering adenylate cyclase activity. The role of the alter phophorylase kinase and phosphatase activation in glucagon and adrenergic activation of glycogenolysis will be further examined using the isolated hepatocytes, liver subfractions and purified enzymes. Emphasis will be focused on the relationship between phosphorylation and activation of these enzymes. The investigation of the glucocorticoids on gluconeogenic stimulation by glucagon and catecholamine will be focused on the apparently altered 6-phosphofructo-1-kinase activity and purified enzymes.
