dc.contributor.author | Castro Hernández, Javier Rafael | |
dc.contributor.author | Afonso-Oramas, Domingo | |
dc.contributor.author | Cruz-Muros, Ignacio | |
dc.contributor.author | Salas-Hernández, Josmar | |
dc.contributor.author | Barroso-Chinea, Pedro | |
dc.contributor.author | Moratalla, Rosario | |
dc.contributor.author | Millan, Mark J. | |
dc.contributor.author | González-Hernández, Tomás | |
dc.date.accessioned | 2023-12-13T21:06:44Z | |
dc.date.available | 2023-12-13T21:06:44Z | |
dc.date.issued | 2014 | |
dc.identifier.issn | 0969-9961 | |
dc.identifier.uri | http://riull.ull.es/xmlui/handle/915/34747 | |
dc.description.abstract | The 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.mimetype | application/pdf | |
dc.language.iso | en | |
dc.relation.ispartofseries | Neurobiology of Disease,
Volume 74, 2015. | |
dc.rights | Licencia Creative Commons (Reconocimiento-No comercial-Sin obras derivadas 4.0 Internacional) | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es_ES | |
dc.title | Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake | |
dc.type | info:eu-repo/semantics/article | |
dc.identifier.doi | 10.1016/j.nbd.2014.12.007 | |
dc.subject.keyword | Dopamine transporter | en |
dc.subject.keyword | D3R | en |
dc.subject.keyword | D2R | en |
dc.subject.keyword | Dopamine autoreceptor | en |
dc.subject.keyword | Multi-protein complex | en |
dc.subject.keyword | Neuroprotection | en |
dc.subject.keyword | Parkinson's disease | en |
dc.subject.keyword | Depression | en |