Selective deletion of GRK2 alters psychostimulant-induced behaviors and dopamine neurotransmission.
GRK2 is a G protein-coupled receptor kinase (GRK) that is broadly expressed and is known to regulate diverse types of receptors. GRK2 null animals exhibit embryonic lethality due to a severe developmental heart defect, which has precluded the study of this kinase in the adult brain. To elucidate the specific role of GRK2 in the brain dopamine (DA) system, we used a conditional gene knockout approach to selectively delete GRK2 in DA D1 receptor (D1R)-, DA D2 receptor (D2R)-, adenosine 2A receptor (A2AR)-, or DA transporter (DAT)-expressing neurons. Here we show that select GRK2-deficient mice display hyperactivity, hyposensitivity, or hypersensitivity to the psychomotor effects of cocaine, altered striatal signaling, and DA release and uptake. Mice with GRK2 deficiency in D2R-expressing neurons also exhibited increased D2 autoreceptor activity. These findings reveal a cell-type-specific role for GRK2 in the regulation of normal motor behavior, sensitivity to psychostimulants, dopamine neurotransmission, and D2 autoreceptor function.
1] Department of Cell Biology, Duke University Medical Center, Durham, NC, USA [2] Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
Tanya L
TL
Daigle
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Mark J
MJ
Ferris
1] Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy [2] Skolkovo Institute of Science and Technology, Skolkovo, Moscow Region, Russia [3] Faculty of Biology and Soil Science, St Petersburg State University, St Petersburg, Russia.
Raul R
RR
Gainetdinov
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
Tatyana D
TD
Sotnikova
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Nikhil M
NM
Urs
Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Sara R
SR
Jones
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA.
Marc G
MG
Caron
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects
D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D043705:Receptor, Adenosine A2A; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D003042:Cocaine; D004298:Dopamine