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Truncations in the amino terminus reveal a region key to supporting amphetamine-induced efflux by the human serotonin transporter


The serotonin transporter (SERT) terminates neurotransmission via reuptake of serotonin from the synaptic cleft. Upon stimulation with amphetamines, SERT switches into an outward transport mode to rapidly release serotonin. We have previously shown that truncation of the first 64 residues of SERT amino terminus leads to loss of amphetamine-induced efflux [1]. This was comparable to the effects of a single point mutation of a juxtamembrane threonine residue at position 81 [1].


Truncation mutants of SERT amino terminus were generated by removing 22 (Δ22-SERT), 32 (Δ32-SERT) or 42 (Δ42-SERT) amino terminal residues. In addition, alanine scanning mutagenesis was performed along a segment of amino acid residues 32–42. All mutants were pharmacologically characterised in uptake, binding and efflux studies.


Cellular localisation of the mutants examined by confocal microscopy, revealed no differences compared to the wild-type SERT. Functional analysis showed only modest changes in their substrate uptake properties (no significant changes in the Km values and a moderate decrease in the Vmax value of Δ42-SERT). Similarly, there were no marked alterations in the KD and Bmax values of imipramine or in the Ki values of p-chloroamphetamine and ibogaine, determined in radiolabelled imipramine binding assays. However, while amphetamine-induced efflux was unimpaired for Δ22-SERT and to a slight extent decreased for Δ32-SERT, it was completely abolished for Δ42-SERT.


Our results shed new light on the functional role of the amino terminus and point to the segment encompassing residues 32–42 as a region of key importance to supporting amphetamine-induced efflux by SERT.


  1. Sucic S, Dallinger S, Zdrazil B, Weissensteiner R, Jørgensen TN, Holy M, Kudlacek O, Seidel S, Cha JH, Gether U, Newman AH, Ecker GF, Freissmuth M, Sitte HH: The N terminus of monoamine transporters is a lever required for the action of amphetamines. J Biol Chem. 2010, 285: 10924-10938. 10.1074/jbc.M109.083154.

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This work was supported by SFB35.

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Correspondence to Michael Freissmuth.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Sucic, S., Kern, C., Vidovic, D. et al. Truncations in the amino terminus reveal a region key to supporting amphetamine-induced efflux by the human serotonin transporter. BMC Pharmacol 11 (Suppl 2), A20 (2011).

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