Dopamine transporter: involvement in selective dopaminergic neurotoxicity and degeneration

The carrier molecule that transports dopamine (DA) into dopamine neurons by an electrogenic, Na(+)- and Cl(-)-transport-coupled mechanism is known as the dopamine transporter (DAT). This uptake system is exclusively expressed in DA neurons with significantly higher levels of DAT expression in cells of the substantia nigra pars compacta than those of the ventral tegmental area and arcuate hypothalamic neurons. The expression density of DAT strongly correlates with the extent of DA cell loss in Parkinson's disease (PD). There are also DAT gene polymorphisms associated with PD. These data suggest a role of the DAT in the pathogenesis of PD. Though selective for its respective neurotransmitter, the DAT can also transport synthetic/natural analogues of the transmitter. Should such compounds interact with vital intracellular structures, their penetration into the neuron might have significant consequences. This sequence of toxic events could indeed demonstrated for the synthetic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces selective degeneration of DA neurons characteristic of PD. Dopaminergic toxicity of its active metabolite 1-methyl-4-pyridinium (MPP(+)) is mediated by the DAT through accumulation into DA neurons, where it inhibits mitochondrial complex I activity. Various endogenous and exogenous heterocyclic molecules, which are structurally related to MPTP/MPP(+), such as isoquinolines and beta-carbolines, have been reported to exhibit similar toxic properties on DA cells, which are conferred by their uptake by the DAT. Taken together, there is large body of evidence from morphological, molecular biological and toxicological studies indicating that the DAT might be responsible for the selectivity of DA cell death in PD.