Solving the trade-off by differences in handling of intracellular K+: why substrate translocation by the dopamine transporter but not by the serotonin transporter is voltage-dependent

The dopamine transporter (DAT) retrieves dopamine into presynaptic terminals after synaptic release. The concentrative power of DAT is thought to be fueled by the transmembrane Na+ gradient, but it is conceivable that DAT can also rely on other energy sources, e.g. membrane voltage and/or the K+ gradient. Here, we recorded uptake of dopamine or the fluorescent substrate APP+ ((4-(4-dimethylamino)phenyl-1-methylpyridinium) in DAT-expressing cells under voltage control. We show that DAT differs substantially from the closely related serotonin transporter (SERT): substrate uptake by DAT was voltage-dependent, intracellular K+ binding to DAT was electrogenic but transient in nature thus precluding antiport of K+ by DAT. There is a trade-off between maintaining constant uptake and harvesting membrane potential for concentrative power. Based on our observations, we conclude that subtle differences in the kinetics of co-substrate ion binding allow closely related transporters to select between voltage-independent uptake and high concentrative power.