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

Nature Neuroscience volume 2, pages 605–610 (1999)Cite this article

Abstract

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.

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Figure 1: Currents from dSERT-injected and uninjected oocytes in Na+ or Li+ Ringer's.
Figure 2: 5HT has opposing effects on current in Na+ or Li+ Ringer's.
Figure 3: Current in a mixture of Na+ and Li+ Ringer's is not additive.
Figure 4: 5HT restores additivity to a mixture of Na+ and Li+ Ringer's.
Figure 5: Uptake plateaus but concentration gradient collapses at 300 μM 5HT.
Figure 6: Rate of uptake increases but current decreases at 300 μM 5HT.

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Acknowledgements

A NARSAD Distinguished Investigator Award to L.J.D. and NINDS Grant NS-34075 and NIDA Grant DA-07390 supported this work. We wish to thank Gary Rudnick, Randy Blakely and Christoph Fahlke for discussion, Jeff Balser for the μ1 clone, Hyeon-Gyu Shin for assistance with μ1 characterization and Dawn Borromeo for help in harvesting oocytes, preparing solutions and other technical assistance.

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  1. Department of Pharmacology and Center for Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, 37232-6600, Tennessee, USA

    Christina I. Petersen & Louis J. DeFelice

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  1. Christina I. Petersen
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  2. Louis J. DeFelice
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Correspondence to Louis J. DeFelice.

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Petersen, C., DeFelice, L. Ionic interactions in the Drosophila serotonin transporter identify it as a serotonin channel. Nat Neurosci 2, 605–610 (1999). https://doi.org/10.1038/10158

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