Elimination of GRK2 from cholinergic neurons reduces behavioral sensitivity to muscarinic receptor activation.
Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChAT(IRES-cre)Grk2(f/f) KO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated function in vivo.
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. t.daigle@cellbio.duke.edu
Tanya L
TL
Daigle
Marc G
MG
Caron
D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000166:cytology; D002795:Choline O-Acetyltransferase / Q000235:genetics; D059329:Cholinergic Neurons / Q000187:drug effects / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000172:deficiency*; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D018721:Muscarinic Agonists / Q000494:pharmacology; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012472:Salivation / Q000187:drug effects / Q000235:genetics
D018765:Dopamine Uptake Inhibitors; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D010095:Oxotremorine; C042743:oxotremorine M; D002795:Choline O-Acetyltransferase; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D003042:Cocaine