ROLE OF THE STRIATAL-SPECIFIC RGS PROTEIN RGS9-2, IN CELLULAR SIGNALING PATHWAYS

University Of Rhode Island, Kingston RI

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Abstract

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. We have provided data suggesting a role for RGS9-2 in the striatal control of movement and in the movements side-effects of the pharmacotherapy of schizophrenia and Parkinson's disease. For example we showed that RGS9 knockout mice develop abnormal movements that closely resemble drug-induced dyskinesias (DID). DID are unexplained movement side-effects of the pharmacotherapy of Parkinson's disease and schizophrenia, and are thought to result from the chronic actions of the respective drugs on striatal D2-dopamine receptors (D2R). In addition we showed that RGS9-2 targets to D2R and proposed that RGS9-2 either functionally or spatially compartmentalizes D2R in striatal neurons. Thus drug-induced alterations in RGS9-2 mediated striatal D2R cellular compartmentalization may lead to abnormal striatal signal processing and to drug-induced abnormal involuntary movements. Determining how such compartmentalization is altered will require a better understanding of the D2R-RGS9-2 interaction suggested by our previous studies. Thus we will continue with our studies that will test if the targeting RGS9-2 toD2R involves a direct or indirect interaction and map the interacting surfaces. We will also attempt to reconstitute coupling between D2R and ion channels, such as NMDA-receptors that generate and shape striatal signals. We will test if co-expressed RGS9-2 can alter D2R-channel coupling. From a parallel clinical study we have identifed non-synonymous mutations and intronic deletions in the RGS9 gene that are enriched in patients with schizophrenia and Parkinson's disease. Thus we will test the hypothesis that these RGS9 gene variations produce alterations in RGS9-2 cellular functions.