The dopamine transporter is differentially regulated after dopaminergic lesion.
The dopamine transporter (DAT) is a transmembrane glycoprotein responsible for dopamine (DA) uptake, which has been shown to be involved in DA-cell degeneration in Parkinson's disease (PD). At the same time, some studies suggest that DAT may be regulated in response to dopaminergic injury. We have investigated the mechanisms underlying DAT regulation after different degrees of dopaminergic lesion. DAT is persistently down-regulated in surviving midbrain DA-neurons after substantial (62%) loss of striatal DA-terminals, and transiently after slight (11%) loss of DA-terminals in rats. Transient DAT down-regulation consisted of a decrease of glycosylated (mature) DAT in the plasma membrane with accumulation of non-glycosylated (immature) DAT in the endoplasmic reticulum-Golgi (ERG) compartment, and recovery of the normal expression pattern 5 days after lesion. DAT redistribution to the ERG was also observed in HEK cells expressing rat DAT exposed to MPP(+), but not after exposure to DAT-unrelated neurotoxins. In contrast to other midbrain DA-cells, those in the ventrolateral region of the substantia nigra do not regulate DAT and degenerate shortly after slight DA-lesion. These data suggest that DAT down-regulation is a post-translational event induced by DA-analogue toxins, consisting of a stop in its glycosylation and trafficking to the plasma membrane. Its persistence after substantial DA-lesion may act as a compensatory mechanism helping maintain striatal DA levels. The fact that neurons which do not regulate DAT die shortly after lesion suggests a relationship between DAT down-regulation and neuroprotection.
Afonso-Oramas
Domingo
D
Departamento de Anatomía, Facultad de Medicina, Universidad de La Laguna, Tenerife, Spain.
Cruz-Muros
Ignacio
I
Barroso-Chinea
Pedro
P
Álvarez de la Rosa
Diego
D
Castro-Hernández
Javier
J
Salas-Hernández
Josmar
J
Giráldez
Teresa
T
González-Hernández
Tomás
T
D018663:Adrenergic Agents / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D015536:Down-Regulation; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D016627:Oxidopamine / Q000008:administration & dosage / Q000633:toxicity*; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D018663:Adrenergic Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D016627:Oxidopamine