Heading in the Wrong Direction?

Abstract

The neurotransmitter dopamine is cleared from synapses by presynaptic dopamine transporters, which thus play a key role in regulating dopaminergic signaling. Mazei-Robison et al ., who previously identified a mutant form of the dopamine transporter in two brothers with attention deficit hyperactivity disorder (ADHD), investigated the effects of this mutation on transporter function. When transfected into human embryonic kidney (HEK) 293T cells, the total and surface abundance of the mutant transporter [in which an alanine at residue 559 is substituted with valine (hDAT A559V)] was similar to that of the transfected wild-type human dopamine transporter (hDAT), as was dopamine uptake. Amperometric recordings of cells preloaded with dopamine, however, revealed that, whereas cells expressing hDAT showed little dopamine efflux, hDAT A559V cells exhibited pronounced dopamine efflux currents. Whole-cell patch clamp analysis combined with experiments in which the intracellular concentrations of Na + or dopamine were varied indicated that hDAT A559V showed an exaggerated increase in dopamine efflux in response to depolarization compared with hDAT and an increased sensitivity to intracellular Na + . Intriguingly, amphetamine, which is used to treat ADHD, enhanced hDAT-mediated dopamine efflux (as it typically does) but inhibited hDAT A559V–mediated efflux. The authors thus propose that alterations in dopamine efflux through hDAT may play a role in ADHD and perhaps other brain disorders associated with altered dopamine signaling. M. S. Mazei-Robison, E. Bowton, M. Holy, M. Schmudermaier, M. Freissmuth, H. H. Sitte, A. Galli, R. D. Blakely, Anomalous dopamine release associated with a human dopamine transporter coding variant. J. Neurosci . 28 , 7040-7046 (2008). [Abstract] [Full Text]