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The Journal of Neuroscience, February 23, 2005, 25(8):2157-2165; doi:10.1523/JNEUROSCI.2840-04.2005

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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 Schwarz^1,2

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

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Received Jan 15, 2004; revised January 4, 2005; accepted January 4, 2005.

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