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The Journal of Neuroscience, February 23, 2005, 25(8):2157-2165; doi:10.1523/JNEUROSCI.2840-04.2005
 Previous Article
Neurobiology of Disease
D2 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
Abraham Kovoor,1,6
Petra Seyffarth,2
Jana Ebert,2
Sami Barghshoon,1
Ching-Kang Chen,3
Sigrid Schwarz,1,2
Jeffrey D. Axelrod,4
Benjamin N. R. Cheyette,5
Melvin I. Simon,1
Henry A. Lester,1 and
Johannes Schwarz1,2
1Division of Biology, California Institute of Technology, Pasadena, California 91125, 2Department of Neurology, University of Leipzig, 04103 Leipzig, Germany, 3Departments of Ophthalmology and Visual Sciences and Human Genetics, University of Utah, Salt Lake City, Utah 84112, 4Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, 5Nina Ireland Laboratory of Developmental Neurobiology and Department of Psychiatry and 6The Center for Neurobiology and Psychiatry, University of California, San Francisco, San Francisco, California 94143-0984
Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of G 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 D2-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 D2-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D2DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D2DR 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 D2DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D2DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease.
Key words: antipsychotic; D2 dopamine receptor; dyskinesia; DEP domain; RGS9; striatum
Received Jan 15, 2004;
revised January 4, 2005;
accepted January 4, 2005.
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