This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.RGS9-2 is a member of the RGS family of G GTPase accelerating proteins that is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement. Our recent data suggest that RGS9 2 is critical in the development of L-DOPA induced dyskinesia (LID) and tardive dyskinesia (TD), the devastating and irreversible neurological motor toxicities of the pharmacotherapy of Parkinson's disease and psychoses, respectively. Our data suggests a preliminary model for TD and LID: RGS9-2 targets to D2-like dopamine receptors (D2-like DR) via the RGS9 DEP domain and compartmentalizes D2-like DR in striatal neurons to block D2-like DR-mediated inhibition of NMDA-type glutamate receptors and voltage-activated Ca2+ channels. Prolonged drug-treatment (antipsychotic drugs or L-DOPA) produces alterations in the function of RGS9-2 that disrupt compartmentalization leading to abnormal basal ganglia signaling and to 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. Hence we will determine if the targeting of RGS9-2 to D2 dopamine receptors (D2DR) involves either a direct or indirect physical interaction. We will map and characterize the interacting surfaces and evaluate the effect of covalent modifications such as protein phosphorylation on the molecular interaction. We will in addition investigate the molecular mechanism for abnormal signaling between D2-like DR and NMDA-receptors observed in the absence of RGS9. We will test the hypothesis that coexpressed RGS9-2 can inhibit D2DR-NMDA-receptor coupling reconstituted in vitro. Parallel approaches will examine the role for RGS9-2 in the coupling between striatal D2DR and voltage-activated Ca2+ channels. 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.
Showing the most recent 10 out of 376 publications
