RT info:eu-repo/semantics/article
T1 Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake
A1 Castro Hernández, Javier Rafael
A1 Afonso-Oramas, Domingo
A1 Cruz-Muros, Ignacio
A1 Salas-Hernández, Josmar
A1 Barroso-Chinea, Pedro
A1 Moratalla, Rosario
A1 Millan, Mark J.
A1 González-Hernández, Tomás
K1 Dopamine transporter
K1 D3R
K1 D2R
K1 Dopamine autoreceptor
K1 Multi-protein complex
K1 Neuroprotection
K1 Parkinson's disease
K1 Depression
AB The dopamine (DA) transporter (DAT), a membrane glycoprotein expressed in dopaminergic neurons, clears DAfrom extracellular space and is regulated by diverse presynaptic proteins like protein kinases, α-synuclein, D2 andD3 autoreceptors. DAT dysfunction is implicated in Parkinson's disease and depression, which are therapeuticallytreated by dopaminergic D2/D3 receptor (D2/D3R) agonists. It is, then, important to improve our understanding ofinteractions between D3R and DAT. We show that prolonged administration of pramipexole (0.1 mg/kg/day, 6 to21 days), a preferential D3R agonist, leads to a decrease in DA uptake in mouse striatum that reflects a reductionin DAT affinity for DA in the absence of any change in DAT density or subcellular distribution. The effect ofpramipexole 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 assessedby co-immunoprecipitation and in situ proximity ligation assay. Furthermore, it promoted the formation of DATdimers 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 ahitherto-unsuspected modification of the DAT interactome. These observations provide novel insights into thelong-term antiparkinson, antidepressant and additional clinical actions of pramipexole and other D3R agonists.
SN 0969-9961
YR 2014
FD 2014
LK http://riull.ull.es/xmlui/handle/915/34747
UL http://riull.ull.es/xmlui/handle/915/34747
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 25-nov-2024