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.

Abstract	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.
Authors	Abraham Kovoor, Petra Seyffarth, Jana Ebert, Sami Barghshoon, Ching-Kang Chen, Sigrid Schwarz, Jeffrey D Axelrod, Benjamin N R Cheyette, Melvin I Simon, Henry A Lester, Johannes Schwarz
Journal	The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 25 Issue 8 Pg. 2157-65 (Feb 23 2005) ISSN: 1529-2401 [Electronic] United States
PMID	15728856 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Antiparkinson Agents Antipsychotic Agents Dopamine Agents Dopamine Antagonists RGS Proteins Receptors, Dopamine D1 Receptors, Dopamine D2 Receptors, G-Protein-Coupled Recombinant Fusion Proteins regulator of g-protein signaling 9 Quinpirole 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine Sulpiride Reserpine Haloperidol Apomorphine Dopamine
Topics	2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (pharmacology) Animals Antiparkinson Agents (pharmacology, therapeutic use, toxicity) Antipsychotic Agents (pharmacology, toxicity) Apomorphine (pharmacology) Corpus Striatum (drug effects, physiopathology) Dopamine (physiology) Dopamine Agents (pharmacology, therapeutic use) Dopamine Antagonists (pharmacology, toxicity) Dyskinesia, Drug-Induced (physiopathology) Female Haloperidol (pharmacology, toxicity) Humans Mice Mice, Knockout Movement Disorders (genetics, physiopathology) Parkinson Disease (physiopathology) Patch-Clamp Techniques Protein Interaction Mapping Protein Structure, Tertiary Quinpirole (pharmacology) RGS Proteins (deficiency, genetics, physiology) Receptors, Dopamine D1 (genetics) Receptors, Dopamine D2 (genetics, metabolism) Receptors, G-Protein-Coupled (physiology) Recombinant Fusion Proteins (physiology) Reserpine (pharmacology, toxicity) Subcellular Fractions (chemistry) Sulpiride (pharmacology) Transfection

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