The objective of this project is to delineate the role of specific RGS proteins in regulating the timing and sensitivity of G-protein-mediated signal transduction pathways in the mammalian striatum. RGS (Regulators of G-protein Signaling) proteins accelerate the recovery, and in some cases, the activation phases of neuronal responses to stimulation of G-protein-coupled receptors. In the striatum, these include, among others, receptors for dopamine, histamine, serotonin, cannabinoids, and opioids. These receptors and the neurons that use them for signaling play important roles in drug abuse and addiction as well as in human neurological diseases such as Parkinson's and Huntington's diseases. The focus will be on RGS9-2, an RGS protein with highly specific localization in the striatum, whose expression is dramatically reduced by amphetamine treatment. The receptors, G-proteins, and effectors with which it co-localizes will be determined in order to identify the signaling pathways in which it likely functions. Localization within the striatum of another neuronal RGS protein with similar domain structure to RGS9-1, RGS7, will also be examined. The role of RGS9-2 in specific pathways will be tested by assays of signal transduction in wild type and RGS9-knockout mice. Mice with and without the RGS9 gene will also be tested for compensatory changes in other RGS proteins and other signaling proteins, including Gbeta5S, which forms a tight complex with RGS9-2. These studies should reveal the role of RGS9-1 and RGS7 in striatal signal transduction, and should provide insight into the normal functioning of these important signaling pathways and into the mechanisms of their disruption or exploitation in various disease states and in response to drug abuse.
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