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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
-
Animals
-
Antiparkinson Agents / pharmacology
-
Antiparkinson Agents / therapeutic use
-
Antiparkinson Agents / toxicity
-
Antipsychotic Agents / pharmacology
-
Antipsychotic Agents / toxicity*
-
Apomorphine / pharmacology
-
Corpus Striatum / drug effects
-
Corpus Striatum / physiopathology
-
Dopamine / physiology*
-
Dopamine Agents / pharmacology
-
Dopamine Agents / therapeutic use
-
Dopamine Antagonists / pharmacology
-
Dopamine Antagonists / toxicity
-
Dyskinesia, Drug-Induced / physiopathology
-
Female
-
Haloperidol / pharmacology
-
Haloperidol / toxicity
-
Humans
-
Mice
-
Mice, Knockout
-
Movement Disorders / genetics*
-
Movement Disorders / physiopathology
-
Parkinson Disease / physiopathology
-
Patch-Clamp Techniques
-
Protein Interaction Mapping
-
Protein Structure, Tertiary
-
Quinpirole / pharmacology
-
RGS Proteins / deficiency
-
RGS Proteins / genetics
-
RGS Proteins / physiology*
-
Receptors, Dopamine D1 / genetics
-
Receptors, Dopamine D2 / genetics
-
Receptors, Dopamine D2 / metabolism*
-
Receptors, G-Protein-Coupled / physiology
-
Recombinant Fusion Proteins / physiology
-
Reserpine / pharmacology
-
Reserpine / toxicity
-
Subcellular Fractions / chemistry
-
Sulpiride / pharmacology
-
Transfection
Substances
-
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