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Serotonin, L-tryptophan, and tryptamine are effective inhibitors of the amino acid transport system PAT1

Linda Metzner^*, Gabor Kottra, Klaus Neubert, Hannelore Daniel and Matthias Brandsch^*,1

^* Membrane Transport Group, Biozentrum, Martin-Luther-University Halle-Wittenberg, Halle, Germany;
Molecular Nutrition Unit, Center of Life and Food Science, Technical University of Munich, Freising-Weihenstephan, Germany; and the
Institute of Biochemistry, Department of Biochemistry/Biotechnology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

¹Correspondence: Membrane Transport Group, Biozentrum of the Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany. E-mail: matthias.brandsch{at}biozentrum.uni-halle.de

The proton-coupled amino acid transporter PAT1, cloned recently from brain and intestine, mediates the uphill transport of L- and D-proline, L-alanine, glycine, taurine, D-serine, GABA, and many other related compounds and drugs. Here we describe the novel finding that L-tryptophan and its derivatives tryptamine, 5-hydroxy-L-tryptophan, serotonin, and indole-3-propionic acid strongly inhibit H⁺-dependent L-[³H]proline uptake into Caco-2 cells with inhibition constants (K_i) of 0.9 to 6.1 mM. Uptake of L-[³H]tryptophan into Caco-2 cells on the other hand was not inhibited by L-proline. Whereas PAT1 substrates produced significant changes in a membrane potential assay for electrogenic transport in Caco-2 cells, L-tryptophan, tryptamine, and 5-hydroxy-L-tryptophan failed to alter membrane voltage. When PAT1 was expressed in Xenopus laevis oocytes and analyzed by the two-electrode voltage clamp technique, glycine elicited high inward currents that were dependent on membrane potential but no currents were observed with L-tryptophan, tryptamine, 5-hydroxy-L-tryptophan, or serotonin. Although not transported electrogenically by PAT1, L-tryptophan and its derivatives inhibited glycine-evoked currents dose-dependently. We conclude that serotonin, L-tryptophan, and tryptamine bind to PAT1 with potencies similar to the prototype substrates, inhibit transport function but are not transported by this carrier protein. They may be considered as the carriers’ naturally occurring inhibitors that may alter the transport function of PAT1.— Metzner, L., Kottra, G., Neubert, K., Daniel, H., Brandsch, M. Serotonin, L-tryptophan, and tryptamine are effective inhibitors of the amino acid transport system PAT1.

Key Words: membrane transport • proton gradient • nontransported inhibitors • Xenopus laevis oocytes • Caco-2 cells

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