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dc.contributor.authorCastro Hernández, Javier Rafael
dc.contributor.authorAfonso-Oramas, Domingo
dc.contributor.authorCruz-Muros, Ignacio
dc.contributor.authorSalas-Hernández, Josmar
dc.contributor.authorBarroso-Chinea, Pedro
dc.contributor.authorMoratalla, Rosario
dc.contributor.authorMillan, Mark J.
dc.contributor.authorGonzález-Hernández, Tomás
dc.date.accessioned2023-12-13T21:06:44Z
dc.date.available2023-12-13T21:06:44Z
dc.date.issued2014
dc.identifier.issn0969-9961
dc.identifier.urihttp://riull.ull.es/xmlui/handle/915/34747
dc.description.abstractThe dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DA from extracellular space and is regulated by diverse presynaptic proteins like protein kinases, α-synuclein, D2 and D3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeutically treated by dopaminergic D2/D3 receptor (D2/D3R) agonists. It is, then, important to improve our understanding of interactions between D3R and DAT. We show that prolonged administration of pramipexole (0.1 mg/kg/day, 6 to 21 days), a preferential D3R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reduction in DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect of pramipexole was absent in mice with genetically-deleted D3R (D3R−/−), yet unaffected in mice genetically deprived of D2R (D2R−/−). Pramipexole treatment induced a physical interaction between D3R and DAT, as assessed by co-immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DAT dimers and DAT association with both D2R and α-synuclein, effects that were abolished in D3R−/− mice, yet unaffected in D2R−/− mice, indicating dependence upon D3R. Collectively, these data suggest that prolonged treatment with dopaminergic D3 agonists provokes a reduction in DA reuptake by dopaminergic neurons related to a hitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into the long-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists.en
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.relation.ispartofseriesNeurobiology of Disease, Volume 74, 2015.
dc.rightsLicencia Creative Commons (Reconocimiento-No comercial-Sin obras derivadas 4.0 Internacional)
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/deed.es_ES
dc.titleProlonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1016/j.nbd.2014.12.007
dc.subject.keywordDopamine transporteren
dc.subject.keywordD3Ren
dc.subject.keywordD2Ren
dc.subject.keywordDopamine autoreceptoren
dc.subject.keywordMulti-protein complexen
dc.subject.keywordNeuroprotectionen
dc.subject.keywordParkinson's diseaseen
dc.subject.keywordDepressionen


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