The dopamine neurotransmitter system serves to regulate neuronal activity and thus plays an important role in movement control and psychological function. A greater understanding of dopamine action will lead to an opportunity for the development of improved treatments for disorders of the dopamine system. These include schizophrenia and Parkinson's disease. The goal of this project will be to elucidate the biochemical basis for dopamine action in the basal for dopamine action in the basal ganglia-a brain region that is a major target for the dopamine system. Previous work has shown that the enzyme protein phosphatase 1 (PP-1) plays an important role in the biochemical integration of signals that are triggered within neurons in response to dopamine. The present study will involved a detailed examination of PP-1 function, and the manner in which that function is regulated. We propose to study the role of PP-1 using animal model systems; the mouse is amenable to genetic manipulation such that the gene encoding PP-1 can be disrupted in a temporal- and tissue-specific manner. Using these animals we will be able to define the contribution made by PP-1 to biochemical, electrophysiological, anatomical and behavioral responses to dopamine. In addition, we have identified several regulatory elements for PP-1 that control the activity of the enzyme in distinct ways. The contribution made by these PP-1 regulatory subunits to the actions of dopamine will be examined, again using animal models in which the genes that code for these proteins have been either disrupted or mutated. Further studies will attempt to identify additional components of the PP-1 regulatory apparatus. With neurons, PP-1 is localized at the synapse, and is therefore ideally placed to regulate neuronal communication. Two of the regulatory subunits under study dictate the synaptic localization of PP-1 by serving as molecular """"""""scaffolds"""""""". We propose to identify additional components that interact with this scaffold with a view to defining the integrated biochemical response to dopamine stimulation.
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