Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake.
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 (0.1mg/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.
['Castro-Hernández|Javier|J|', 'Afonso-Oramas|Domingo|D|', 'Cruz-Muros|Ignacio|I|', 'Salas-Hernández|Josmar|J|', 'Barroso-Chinea|Pedro|P|', 'Moratalla|Rosario|R|', 'Millan|Mark J|MJ|', 'González-Hernández|Tomás|T|']
D000818:Animals D000928:Antidepressive Agents D000978:Antiparkinson Agents D017660:Autoreceptors D052160:Benzothiazoles D003342:Corpus Striatum D019281:Dimerization D004298:Dopamine D018491:Dopamine Agonists D050483:Dopamine Plasma Membrane Transport Proteins D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D000077487:Pramipexole D050637:Receptors, Dopamine D3 D051844:alpha-Synuclein
Dopamine transporter Parkinson's disease Depression D(2)R D(3)R Dopamine autoreceptor Multi-protein complex Neuroprotection