Ionic interactions in the Drosophila serotonin transporter identify it as a serotonin channel

Serotonin transporters (SERTs) are targets for drugs such as Prozac that increase serotonin (5HT) levels by blocking 5HT reuptake. Although SERTs saturate in the micromolar range, synaptic 5HT may exceed 1 mM. To examine SERT's response to high 5HT concentrations, we expressed Drosophila SERT (dSERT) in Xenopus oocytes and found that transport continued to increase with concentration up to 0.3 mM 5HT. As 5HT is a monovalent cation, its entry through an ion channel in SERT might explain uptake at high concentrations. We therefore investigated dSERT using traditional ion channel methods, including mole-fraction experiments under voltage clamp. We propose that SERTs may function as 5HT-permeable channels, and that this mechanism may be important for clearance of the neurotransmitter at high concentrations.