This R01 application focuses on the role of protein tyrosine phosphatases (PTPs) in signal transduction pathways in the basal ganglia. Compeling evidence suggests that the basal ganglia are involved in a number of neuropsychiatric disorders, including schizophrenia, Tourette's syndrome and obsessive compulsive disorder. In Huntington and Parkinson's disorders, abnormalities of the basal ganglia, or in their efferent and afferent pathways have been found. This collection of nuclei are also the site of action for many of the unwanted side effects of neuroleptic drugs. Disruption of the neural signaling mechanisms within the basal ganglia is a common component of all of these disorders, and further knowledge is needed of the normal signaling pathways that occur in this region of the CNS. The long-term goal of my research are to characterize genes that contribute to neuropsychiatric disorders. Under previous funding mechanisams (a K20 and then a FIRST award from NIMH), my laboratory has isolated a novel family or protein tyrosine phosphatases (PTPs) uniquely present within dopaminoceptive neurons of the basal ganglia and related structures. As the protein is highly enriched within rat striatum, it is termed STEP for Striatal Enriched Phosphatase. The present application is a natural continuation of my FIRST Award in which we isolated four isoforms of the STEP family. The first specific aim proposes to continue to isolate the characterize members of this large and important group of PTPs. The family consists of cytosolic and membrane-associated isoforms, as well as truncated forms that lack on active catalytic siste. One of the most striking features is that some STEPs contain transmembrane domains, PEST sequences, and polyproline-rich sequences. We hypothesize that these provide a mechanism for the subcellular targeting of STEP members, for the regulation of their enzymatic activity, and for their substrate specificity. In addition, we propose that phosphorylation asnd proteolysis of STEP occurs after dopamine D1 signaling. We will identify the physiological substrates of STEP, one of which is proposed to be the NMDA receptor. We will these these hypotheses using biochemical, molecular, and electrophysiological techniques.
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