title: The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.
abstract: G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D(2) dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Managò
authors.forename: Stefano
authors.initials: S
authors.lastname: Espinoza
authors.forename: Ali
authors.initials: A
authors.lastname: Salahpour
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Richard T
authors.initials: RT
authors.lastname: Premont
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007980:Levodopa / Q000627:therapeutic use*; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007980:Levodopa; D000242:Cyclic AMP; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3