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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015189-03
Application #
6743780
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Pollock, Jonathan D
Project Start
2002-07-15
Project End
2007-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
3
Fiscal Year
2004
Total Cost
$263,375
Indirect Cost
Name
Baylor College of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Mancuso, James J; Larson, Adam M; Wensel, Theodore G et al. (2009) Multiphoton adaptation of a commercial low-cost confocal microscope for live tissue imaging. J Biomed Opt 14:034048
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Wensel, Theodore G (2008) Signal transducing membrane complexes of photoreceptor outer segments. Vision Res 48:2052-61