The dopamine transporter antiports potassium to increase the uptake of dopamine

Abstract

The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na⁺ gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K⁺, but investigations of K⁺-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the Drosophila- and human dopamine transporters are inhibited by K⁺, and the conformational dynamics of the Drosophila dopamine transporter in K⁺ are divergent from the apo- and Na⁺-states. Furthermore, we find that K⁺ increases dopamine uptake by the Drosophila dopamine transporter in liposomes, and visualize Na⁺ and K⁺ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K⁺ on other transporters in this pharmacologically important family.