RT info:eu-repo/semantics/article
T1 Prolonged dopamine D3 receptor stimulation promotes dopamine transporter ubiquitination and degradation through a PKC-dependent mechanism
A1 Castro Hernández, Javier Rafael
A1 Luis-Ravelo, Diego
A1 Fumagallo-Reading, Felipe
A1 Barroso-Chinea, Pedro
A1 Afonso-Oramas, Domingo
A1 Febles-Casquero, Alejandro
A1 Cruz-Muros, Ignacio
A1 Salas-Hernández, Josmar
A1 Mesa Infante, Virginia
A1 Rodríguez-Nuñez, Julia
A1 González-Hernández, Tomás
A2 Vulnerabilidad y plasticidad neuronal
K1 Dopaminergic neurons; Autoreceptors; Down-regulation; Parkinson’s disease; Depression
AB The dopamine transporter (DAT) is a membrane glycoprotein in dopaminergic neurons, which modulatesextracellular and intracellular dopamine levels. DAT is regulated by different presynaptic proteins, includingdopamine D2 (D2R) and D3 (D3R) receptors. While D2R signalling enhances DAT activity, some data suggest thatD3R has a biphasic effect. However, despite the extensive therapeutic use of D2R/D3R agonists in neuropsychiatric disorders, this phenomenon has been little studied. In order to shed light on this issue, DAT activity,expression and posttranslational modifications were studied in mice and DAT-D3R-transfected HEK cells.Consistent with previous reports, acute treatment with D2R/D3R agonists promoted DAT recruitment to theplasma membrane and an increase in DA uptake. However, when the treatment was prolonged, DA uptake andtotal striatal DAT protein declined below basal levels. These effects were inhibited in mice by genetic andpharmacological inactivation of D3R, but not D2R, indicating that they are D3R-dependent. No changes weredetected in mesostriatal tyrosine hydroxylase (TH) protein expression and midbrain TH and DAT mRNAs, suggesting that the dopaminergic system is intact and DAT is posttranslationally regulated. The use of immunoprecipitation and cell surface biotinylation revealed that DAT is phosphorylated at serine residues, ubiquitinatedand released into late endosomes through a PKCβ-dependent mechanism. In sum, the results indicate that longterm D3R activation promotes DAT down-regulation, an effect that may underlie neuroprotective and antidepressant actions described for some D2R/D3R agonists
SN 1043-6618
YR 2021
FD 2021
LK http://riull.ull.es/xmlui/handle/915/34743
UL http://riull.ull.es/xmlui/handle/915/34743
LA en
DS Repositorio institucional de la Universidad de La Laguna
RD 16-ago-2024