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.
Type
Journal articleSubject
AnimalsCyclic AMP
Disease Models, Animal
Extracellular Signal-Regulated MAP Kinases
G-Protein-Coupled Receptor Kinases
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
Levodopa
Locomotion
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutation
Parkinson Disease
Proto-Oncogene Proteins c-akt
Signal Transduction
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https://hdl.handle.net/10161/10773Published Version (Please cite this version)
10.1038/srep00301Publication Info
Managò, 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.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Marc G. Caron
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
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Richard Thomas Premont
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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