Role of the Striatal-Specific RGS Protein, RGS9 2, in Cellular Signaling Pathways (2009 - Present)

Investigator:  Abraham Kovoor, University of Rhode Island
Mentor:  Ronald Stanton Duman, Yale University 

Abstract: This proposal describes an extension of the studies funded by a previous grant from the INBRE program to this investigator on the cellular functions of the striatal specific RGS protein, RGS9-2.  The rationale for the proposal is provided by data generated by this investigator and others implicating a role for RGS9-2 in the striatal control of movement and in disorders such as schizophrenia and Parkinson's disease. 

We previously showed that the RGS9 knockout mouse develops 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 and voltage-activated Ca2⁺ channels that generate and shape striatal signals.  The hypothesis that RGS9-2 is involved in functionally compartmentalizing D2R will be tested by determining 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.