Catecholamines released from the adrenal medulla and from sympathetic nerves play an important role in the regulation of blood pressure, cardiac contractility, and heart rate. The long-term goal of this research is to understand the mechanisms that regulate catecholamine synthesis and secretion in adrenal chromaffin cells and sympathetic neurons. The studies proposed in this application will investigate protein phosphorylation and phospholipid metabolism in PC12 pheochromocytoma cells and in the superior cervical ganglion of the rat. Electrical stimulation of the preganglionic cervical sympathetic trunk increases the phosphorylation and the activity of tyrosine hydroxylase in the superior cervical ganglion. The proposed experiments will analyze the sites on tyrosine hydroxylase that are phosphorylated in response to electrical and chemical stimuli, and will attempt to clarify the roles of specific protein kinases in regulating tyrosine hydroxylase phosphorylation and catecholamine synthesis in the ganglion. Preganglionic stimulation also increases the hydrolysis of inositol-containing phospholipids in the superior cervical ganglion. The proposed experiments will identify the products of phospholipid hydrolysis and will evaluate the role of phospholipid metabolism in mediating the activation of protein kinases in the ganglion. Muscarinic cholinergic agonists increase phospholipid hydrolysis and inhibit the accumulation of cyclic adenosine 3':5'-monophosphate in PC12 cells. The proposed experiments will focus on the relationship between these two actions of muscarine and on the interactions between the phospholipase C pathway and the adenylate cyclase pathway in the regulation of catecholamine synthesis and secretion.
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