PT  - JOURNAL ARTICLE
AU  - Shreyas Bhat
AU  - Marco Niello
AU  - Klaus Schicker
AU  - Christian Pifl
AU  - Harald H. Sitte
AU  - Michael Freissmuth
AU  - Walter Sandtner
TI  - Solving the trade-off by differences in handling of intracellular K<sup>+</sup>: why substrate translocation by the dopamine transporter but not by the serotonin transporter is voltage-dependent
AID  - 10.1101/2020.07.09.196642
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.09.196642
4099  - http://biorxiv.org/content/early/2020/07/11/2020.07.09.196642.short
4100  - http://biorxiv.org/content/early/2020/07/11/2020.07.09.196642.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.