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.
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.
Kovoor
Abraham
A
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Seyffarth
Petra
P
Ebert
Jana
J
Barghshoon
Sami
S
Chen
Ching-Kang
CK
Schwarz
Sigrid
S
Axelrod
Jeffrey D
JD
Cheyette
Benjamin N R
BN
Simon
Melvin I
MI
Lester
Henry A
HA
Schwarz
Johannes
J
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000633:toxicity*; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D018492:Dopamine Antagonists / Q000494:pharmacology / Q000633:toxicity; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009069:Movement Disorders / Q000235:genetics* / Q000503:physiopathology; D010300:Parkinson Disease / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D019257:Quinpirole / Q000494:pharmacology; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012110:Reserpine / Q000494:pharmacology / Q000633:toxicity; D013347:Subcellular Fractions / Q000737:chemistry; D013469:Sulpiride / Q000494:pharmacology; D014162:Transfection
D000978:Antiparkinson Agents; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D020710:RGS Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C116925:regulator of g-protein signaling 9; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D013469:Sulpiride; D012110:Reserpine; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine
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