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, 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

Research output: Contribution to journalArticlepeer-review

149 Scopus citations

Abstract

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 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 D 2DR 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.

Original languageEnglish (US)
Pages (from-to)2157-2165
Number of pages9
JournalJournal of Neuroscience
Volume25
Issue number8
DOIs
StatePublished - Feb 23 2005
Externally publishedYes

Keywords

  • Antipsychotic
  • D dopamine receptor
  • DEP domain
  • Dyskinesia
  • RGS9
  • Striatum

ASJC Scopus subject areas

  • General Neuroscience

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