The Dopamine Transporter: Involvement in Selective Dopaminergic Neurodegeneration

Summary

The carrier molecule that transports dopamine into dopaminergic neurons by an electrogenic, Na⁺- and Cl^--transport-coupled mechanism is known as the dopamine transporter (DAT). This uptake system is expressed differentially in dopaminergic neurons with significantly greater levels of DAT expression in cells of the substantia nigra pars compacta (SNpc) than those of the ventral tegmental area (VTA) and arcuate hypothalamic neurons. The density of DAT strongly correlates with the extent of dopaminergic cell loss in brains of Parkinson‘s disease (PD) patients. Furthermore, there are DAT gene polymorphisms associated with PD. Though selective for its respective neurotransmitter, the DAT can also transport synthetic or 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-l,2,3,6-tetrahydropyridine (MPTP), which produces selective degeneration of dopaminergic neurons on the SNpc characteristic of PD. The selective dopaminergic toxicity of its active metabolite 1-methyl-4-pyridinium (MPP⁺) is mediated by the DAT through accumulation into dopaminergic neurons, where it inhibits mitochondrial NADH-Q reductase (complex I). Various endogenous and exogenous heterocyclic molecules, which are structurally related to MPTP/MPP⁺, such as pyridine, isoquinoline and ß-carboline derivatives, have been reported to exhibit similar toxic properties on dopaminergic cells, which are conferred by their uptake by the DAT molecule. DAT plays a pivotal role for the selectivity of dopaminergic neurotoxins related to MPP⁺, and that the DAT may be important for selective dopaminergic degeneration in PD.