Currents in neurotransmitter transporters.

Traditionally, substrate translocation by neurotransmitter transporters has been described by the alternate access model. Recent structural data obtained with three distantly related transporters have also been interpreted as supportive of this model, because conformational correlates were visualized (inward-facing conformation, occluded state). However, the experimental evidence is overwhelmingly in favour of a more complex mode of operation: Transporters also exist in conformations that do not seal the permeation pathway. These conformations support a channel-like activity, including random permeation of substrate and co-substrate ions in a single-file mode. It is likely that the channel-like activity is modified by the interaction of the transporters with accessory proteins and regulatory kinases. Finally, channel-like activity is instrumental to understand the mechanism of action of amphetamines.