Modulation of D2-Like Dopamine Receptor-Mediated Striatal Signaling Pathways by RGS9-2 (2007 - Present)

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

Abstract:  This proposal will investigate the cellular functions of the striatally enriched RGS protein, RGS9-2, a member of the RGS family of Gα GTPase accelerating proteins.  The rationale for this investigation is provided by data recently published by this principal investigator and others which suggest that alterations in RGS9-2 are key factors in the development of L-DOPA induced dyskinesia (LID) and tardive dyskinesia (TD).  LID and TD are devastating and irreversible neurological motor toxicities of the pharmacotherapy of Parkinson's disease and psychotic disorders such as schizophrenia, respectively. 

While the molecular mechanisms underlying LID and TID have not been established, we have recently published a preliminary model.  In this model, RGS9-2 targets to D2-like dopamine receptors (D2-like DR) via the RGS9 DEP domain and either functionally or spatially compartmentalizes D2-like DR in striatal neurons so as 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 compensatory striatal responses including alterations in the function of RGS9-2 that disrupt 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 D2-dopamine receptor (D2DR)-RGS9-2 interaction that has been suggested by our previously published colocalization studies.  Hence we will investigate if the subcellular targeting of RGS9-2 to 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 and 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.