Dopaminergic supersensitivity in G protein-coupled receptor kinase 6-deficient mice.
Brain dopaminergic transmission is a critical component in numerous vital functions, and its dysfunction is involved in several disorders, including addiction and Parkinson's disease. Responses to dopamine are mediated via G protein-coupled dopamine receptors (D1-D5). Desensitization of G protein-coupled receptors is mediated via phosphorylation by members of the family of G protein-coupled receptor kinases (GRK1-GRK7). Here we show that GRK6-deficient mice are supersensitive to the locomotor-stimulating effect of psychostimulants, including cocaine and amphetamine. In addition, these mice demonstrate an enhanced coupling of striatal D2-like dopamine receptors to G proteins and augmented locomotor response to direct dopamine agonists both in intact and in dopamine-depleted animals. The present study indicates that postsynaptic D2-like dopamine receptors are physiological targets for GRK6 and suggests that this regulatory mechanism contributes to central dopaminergic supersensitivity.
Gainetdinov
Raul R
RR
Howard Hughes Medical Institute Laboratories, Duke University Medical Center, Durham, NC 27710, USA.
Bohn
Laura M
LM
Sotnikova
Tatyana D
TD
Cyr
Michel
M
Laakso
Aki
A
Macrae
Alexander D
AD
Torres
Gonzalo E
GE
Kim
Kyeong Man
KM
Lefkowitz
Robert J
RJ
Caron
Marc G
MG
Premont
Richard T
RT
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000235:genetics; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004305:Dose-Response Relationship, Drug; D054768:G-Protein-Coupled Receptor Kinases; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010627:Phenethylamines / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism
D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D010627:Phenethylamines; D010750:Phosphoproteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C029261:phenethylamine; D000661:Amphetamine; D017346:Protein Serine-Threonine Kinases; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D003042:Cocaine; D004298:Dopamine