This project will seek to examine protein phosphorylation pathways in the basal ganglia which mediate the actions of dopamine in normal and abnormal brain function. The pharmacological regulation of phosphoproteins enriched in the basal ganglia will be studied using intact cell preparations derived from basal ganglia structures of normal animals (e.g., neostriatal slices, primary neostriatal cell cultures, synaptosomes) or in immortalized cells which mimic various physiological properties of basal ganglia neurons. In addition, the regulation of these phosphoproteins under physiological conditions will be studied by administration of drugs to normal, intact animals and the subsequent analysis of the phosphorylated proteins in the brains of these animals. The goal of these studies is to identify first messenger and signal transduction pathways which play a significant role in regulating the function of basal ganglia phosphoproteins in the intact animal. Some of these studies will seek to identify signaling pathways which regulate phosphoproteins by using transgenic animals, which express mutagenized phosphoproteins, or genetically-altered animals, which are deficient in cell signaling molecules. Finally, the levels of phosphoproteins and associated signaling molecules will be measured in post-mortem brain tissue from normal individuals and patients with schizophrenia, in order to assess the possible involvement of phosphoproteins and their regulatory pathways in this dopamine-associated brain disorder. It is anticipated that these studies will provide an essential understanding of dopamine-mediated protein phosphorylation in the normal brain and the possible role of this process in dopamine-mediated motor and psychiatric disease.
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