REGULATION OF BIOSYNTHESIS OF DOPAMINE-BETA-HYDROXYLASE

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Elucidating the mechanisms involved in the regulation of biosynthesis of dopamine-Beta-hydroxylase (DBH) is central in understanding factors controlling the development and expression of the noradrenergic neuronal system. The proposed research will: 1. Characterize the biochemical differences between the subunit forms of DBH (one of which is soluble and the other membrane-bound) which I have recently succeeded in differentiating in the PC12 pheochromocytoma cell line. The relationship between these 2 forms will be studied and if they are interconverted, alterations in specific proteolytic cleavage glycosylation and phosphorylation will be considered. 2. Study the mechanism by which nerve growth factor, dexamethasone and dibutyryl cyclic AMP alter the distribution of the DBH subunits. 3. Examine the functional significance of alterations in the DBH forms and determine whether this phenomenon is specific for pheochromocytoma or also can be related to regulation of DBH in vivo in the peripheral and central nervous system, or to serum DBH. 4. Determine the subcellular site of synthesis of dopamine-Beta-hydroxylase and the mechanism by which it obtains its subcellular localization in the soluble and membrane components of chromaffin and synaptic vesicles.