MODULATION OF D2-LIKE DOPAMINE RECEPTOR-MEDIATED STRIATAL SIGNALING PATHWAYS BY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This subproject will investigate the functions of a striatal specific protein, RGS9-2, a member of the RGS family of G alpha GTPase accelerating proteins. Our previous data suggest that RGS9-2 is critical in the development of L-DOPA induced dyskinesia (LID) and tardive dyskinesia (TD). LID and TD are irreversible neurological motor toxicities of the pharmacotherapy of Parkinson's disease and psychotic disorders, respectively. While the etiology is unknown we have proposed a preliminary molecular model: D2-dopamine receptors (D2R) are a major target of both antipsychotic drugs and L-DOPA. RGS9-2 targets to D2DR via the RGS9 DEP domain and functionally compartmentalizes D2R in striatal neurons to block D2DR-mediated inhibition of NMDA receptors and Ca2+ channels. Prolonged drug-treatment produces compensatory alterations that disrupt RGS9-2 mediated cellular compartmentalization. These compensatory responses lead to abnormal basal ganglia signal processing and to drug-induced abnormal involuntary movements. Determining how such compartmentalization is disrupted will require a better understanding of the D2DR-RGS9-2 interaction which has been suggested by our colocalization studies. This effort will also be enhanced by a better understanding of the mechanisms by which RGS9-2 can modulate D2R responses. As a member of the RGS family, RGS9-2 can accelerate the deactivation kinetics of D2R responses, as we and others have demonstrated. It is unclear, however; if accelerating G protein turnover is the only mechanism by which RGS9-2 can modulate GPCR signal transduction mechanisms. Thus we will examine the effect of RGS9-2 on multiple signal transduction mechanisms of D2R including agonist dependent internalization and D2R activation the Mitogen Activated Protein Kinase (MAPK) pathways. Though the present proposal is restricted to characterizing the cellular function of RGS9-2, it is my expectation that the effort will provide us with the tools to test, validate, and expand our preliminary model for LID and TD in subsequent studies. Finally, we have identified multiple polymorphisms in the RGS9 gene that are enriched in schizophrenic and Parkinson's patients. We propose investigations of the effect of these polymorphisms on RGS9 function and expression.