In striatal neurons, one important step in dopaminergic signal transduction involves the activation of the protein phosphatase 1 inhibitors, DARPP-32 and inhibitor 1. In response to dopamine, these proteins are phosphorylated by cAMP-dependent protein kinase and block dephosphorylation of downstream effectors which regulate the physiological state of the neurons. An objective of this proposal is to identify and characterize new first messenger pathways occurring in medium spiny neurons of the basal ganglia which regulate the phosphorylation state of DARPP-32 and inhibitor 1 and understand the molecular mechanisms by which they achieve their effects.
The specific aims of this proposal are (1) to identify novel protein phosphorylation events in which DARPP-32 and inhibitor 1 serve as substrates and characterize these phosphorylation events in vitro, (2) to demonstrate that the novel phosphorylation events occur in vivo and to study their role in signal transduction pathways in the basal ganglia. Enzymatic phosphorylation of DARPP32 and inhibitor 1 will be studied in vitro with the resulting data being applied to studies of brain tissue. Novel phosphorylation sites will be identified and these sites will be examined for phosphorylation state in neostriatal tissue under basal conditions, during developmental, and after pharmacological treatments. It is possible that new targets for antipsychotic drugs may be developed on the basis of this research.
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