It is proposed to study the role of cyclic AMP-dependent protein phosphorylation in mediating the physiological actions of dopamine in the basal ganglia. Specific substrates for cyclic AMP-dependent protein kinase which have previously been found to be highly enriched in the basal ganglia will be purified and their biochemical properties characterized. Previous studies had identified nine such proteins, of which three termed DARPP-32, ARPP-21 and ARPP-16 have been purified and the function of one, DARPP-32, has been elucidated. The remaining five proteins will be purified and their biochemical properties, including the elucidation of their primary structure, will be determined. Antibodies to each protein will be prepared and immunological techniques developed for their quantitative determination. In addition, site-directed antibodies will be prepared which specifically recognize either the dephosphorylated or phosphorylated form of each protein. These antibodies will be used for the quantitative determination of the state of phosphorylation of each protein. Previously uncharacterized protein kinases which phosphorylate DARPP-32 and ARPP-16 will be purified and characterized. Phosphoprotein phosphatase in the basal ganglia will also be purified and characterized. The characterization of basal-ganglia specific phosphoproteins will permit the development of procedures to study the role of these proteins in certain mental and neurological illnesses.

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