D 2 Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

• Published in: The Journal of neuroscience 2005-02, Vol.25 (8), p.2157-2165
• Main Authors: Kovoor, Abraham, Seyffarth, Petra, Ebert, Jana, Barghshoon, Sami, Chen, Ching-Kang, Schwarz, Sigrid, Axelrod, Jeffrey D., Cheyette, Benjamin N. R., Simon, Melvin I., Lester, Henry A., Schwarz, Johannes
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.2840-04.2005

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D 2 -like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D 2 -like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D 2 DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D 2 DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D 2 DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D 2 DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.