Dopamine d3 receptor induces autophagy and downregulation of the dopamine transporter

Resumo

Autophagy disruption leads to the accumulation of cytotoxic misfolded proteins that play a pivotal role in the pathogenesis of neurodegenerative diseases (NDD). Parkinson's disease is a NDD characterized by the degeneration of midbrain dopaminergic (DA-) neurons. The vulnerability of DA-cells in Parkinson's disease has been associated with dopamine (DA) metabolism because it is an important source of oxidative stress. Cytosolic levels of DA mostly depend on the uptake of DA through the dopamine transporter (DAT), a membrane glycoprotein selectively expressed in DA-cells. Recent studies indicate that DA D2 (DRD2) and D3 (DRD3) receptor agonists and antagonists may modulate autophagy. In addition, DAT activity is regulated by DRD2 and DRD3 autoreceptors. Results from our group indicate that prolonged treatment with the DRD2/DRD3 agonist pramipexole induces DAT oligomerization and a decrease of DA uptake through DRD3. Our hypothesis is that DRD2/DRD3 agonists can modulate DAT activity and induce autophagy. The aim of this work is to give further light on the regulation of DAT by DRD3 and to elucidate whether DRD2/DRD3 agonists induce autophagy, if this effect is mediated by DRD2, by DRD3 or by both receptors. Experiments were performed in DRD2-, DRD3- and DAT-transfected HEK293 cells, rat and mouse striatal cells, and drd2-KO and drd3-RKO mice.