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The Sodium-Coupled Neutral Amino Acid Transporter SNAT2 Mediates an Anion Leak Conductance that Is Differentially Inhibited by Transported Substrates

University of Miami School of Medicine, Miami, Florida 33136

Correspondence: Address reprint requests to Christof Grewer, PhD, Dept. of Physiology and Biophysics, University of Miami School of Medicine, 1600 NW 10th Avenue, Miami, FL 33136. Tel.: 305-243-1021; Fax: 305-243-5931; E-mail: cgrewer{at}med.miami.edu.

The sodium-coupled neutral amino acid transporter SNAT2 mediates cellular uptake of glutamine and other small, neutral amino acids. Here, we report the existence of a leak anion pathway associated with SNAT2. The leak anion conductance was increased by, but did not require the presence of, extracellular sodium. The transported substrates L-alanine, L-glutamine, and -(methylamino)isobutyrate inhibited the anion leak conductance, each with different potency. A transporter with the mutation H-304A did not catalyze alanine transport but still catalyzed anion leak current, demonstrating that substrate transport is not required for anion current inhibition. Both the substrate and Na⁺ were able to bind to the SNAT2_H-304A transporter normally. The selectivity sequence of the SNAT2_H-304A anion conductance was SCN^– >> > I^– > Br^– > Cl^– > Mes^–. Anion flux mediated by the more hydrophobic anion SCN^– was not saturable, whereas nitrate flux demonstrated saturation kinetics with an apparent K_m of 29 mM. SNAT2, which belongs to the SLC38 family of transporters, has to be added to the growing number of secondary, Na⁺-coupled transporters catalyzing substrate-gated or leak anion conductances. Therefore, we can speculate that such anion-conducting pathways are general features of Na⁺-transporting systems.

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