The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment.
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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.
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases
G-Protein-Coupled Receptor Kinases
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Mice, Inbred C57BL
Proto-Oncogene Proteins c-akt
Published Version (Please cite this version)10.1038/srep00301
Publication InfoManagò, Francesca; Espinoza, Stefano; Salahpour, Ali; Sotnikova, Tatyana D; Caron, Marc G; Premont, Richard T; & Gainetdinov, Raul R (2012). The role of GRK6 in animal models of Parkinson's disease and L-DOPA treatment. Sci Rep, 2. pp. 301. 10.1038/srep00301. Retrieved from https://hdl.handle.net/10161/10773.
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James B. Duke Distinguished Professor of Cell Biology
Studies of the mechanisms of action and regulation of hormones and neurotransmitters at the cellular and molecular levels constitute the main goals our of research activities. G protein-coupled receptors (GPCR) mediate the actions of signaling molecules from unicellular organisms to man. We have used adrenergic and dopamine receptors to characterize the structure/function and regulation mechanisms of these prototypes of G protein-coupled receptors. Another approach has been to characterize
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular signals from neurotransmitters and hormones acting on cell surface receptors. Receptors transduce these signals to alter intracellular metabolism and cellular responsiveness through heterotrimeric G protein/second messenger pathways or through small GTP-binding protein/protein kinase cascades. The mechanisms that control the responsiveness of target organ G protein-coupled receptors include receptor ph
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