The role of GRK6 in animal models of Parkinson's Disease and L-DOPA treatment
Identifieur interne : 001101 ( Main/Exploration ); précédent : 001100; suivant : 001102The role of GRK6 in animal models of Parkinson's Disease and L-DOPA treatment
Auteurs : Francesca Manag [Italie] ; Stefano Espinoza [Italie] ; Ali Salahpour [Canada] ; Tatyana D. Sotnikova [Italie] ; Marc G. Caron [États-Unis] ; Richard T. Premont [États-Unis] ; Raul R. Gainetdinov [Italie, États-Unis]Source :
- Scientific Reports [ 2045-2322 ] ; 2012.
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 D2 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.
Url:
DOI: 10.1038/srep00301
PubMed: 22393477
PubMed Central: 3293148
Affiliations:
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Sotnikova</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Neuroscience and Brain Technologies</institution>, Istituto Italiano di Tecnologia, Genoa,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Caron, Marc G" sort="Caron, Marc G" uniqKey="Caron M" first="Marc G." last="Caron">Marc G. Caron</name><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Cell Biology, Duke University</institution>, Durham (NC),<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Premont, Richard T" sort="Premont, Richard T" uniqKey="Premont R" first="Richard T." last="Premont">Richard T. Premont</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Department of Medicine, Duke University</institution>, Durham (NC),<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Neuroscience and Brain Technologies</institution>, Istituto Italiano di Tecnologia, Genoa,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Department of Cell Biology, Duke University</institution>, Durham (NC),<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>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<sub>2</sub> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fearnley, J M" uniqKey="Fearnley J">J. M. Fearnley</name></author><author><name sortKey="Lees, A J" uniqKey="Lees A">A. J. Lees</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kish, S J" uniqKey="Kish S">S. J. Kish</name></author><author><name sortKey="Shannak, K" uniqKey="Shannak K">K. Shannak</name></author><author><name sortKey="Hornykiewicz, O" uniqKey="Hornykiewicz O">O. Hornykiewicz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bezard, E" uniqKey="Bezard E">E. Bezard</name></author><author><name sortKey="Brotchie, J M" uniqKey="Brotchie J">J. M. Brotchie</name></author><author><name sortKey="Gross, C E" uniqKey="Gross C">C. E. 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Lundblad</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li><li>Italie</li><li>États-Unis</li></country></list><tree><country name="Italie"><noRegion><name sortKey="Manag, Francesca" sort="Manag, Francesca" uniqKey="Manag F" first="Francesca" last="Manag">Francesca Manag</name></noRegion><name sortKey="Espinoza, Stefano" sort="Espinoza, Stefano" uniqKey="Espinoza S" first="Stefano" last="Espinoza">Stefano Espinoza</name><name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name><name sortKey="Sotnikova, Tatyana D" sort="Sotnikova, Tatyana D" uniqKey="Sotnikova T" first="Tatyana D." last="Sotnikova">Tatyana D. Sotnikova</name></country><country name="Canada"><noRegion><name sortKey="Salahpour, Ali" sort="Salahpour, Ali" uniqKey="Salahpour A" first="Ali" last="Salahpour">Ali Salahpour</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Caron, Marc G" sort="Caron, Marc G" uniqKey="Caron M" first="Marc G." last="Caron">Marc G. Caron</name></noRegion><name sortKey="Gainetdinov, Raul R" sort="Gainetdinov, Raul R" uniqKey="Gainetdinov R" first="Raul R." last="Gainetdinov">Raul R. Gainetdinov</name><name sortKey="Premont, Richard T" sort="Premont, Richard T" uniqKey="Premont R" first="Richard T." last="Premont">Richard T. Premont</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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