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Review
. 2012 Sep;167(2):256-78.
doi: 10.1111/j.1476-5381.2012.01975.x.

The solute carrier 6 family of transporters

Stefan Bröer  1 , Ulrik Gether
Affiliations
Review

The solute carrier 6 family of transporters

Stefan Bröer et al. Br J Pharmacol. 2012 Sep.

Abstract

The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters.

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Figures

Figure 1
Figure 1
Sequence similarity of SLC6 transporters. Peptide sequences of all human SLC6 members were aligned using T-coffee (Notredame et al., 2000), and similarities were visualized using Treeview (Page, 1996). The main substrate for each transporter is shown next to the name. Subfamilies are indicated.
Figure 2
Figure 2
Regulation of SLC6 transporters. Major mechanisms regulating transporter activity and localization are illustrated. In (1), in order to be trafficked to the cell surface, transporters (shown in green) often need to dimerize or associate with a trafficking subunit (orange). At (2), fusion of vesicles with the plasma membranes occurs through interaction of t-SNARE and v-SNARE proteins, shown as helices. Once in the cell membrane (3), a variety of neurotransmitter transporters interact with the t-SNARE protein syntaxin1A (helix) or with the trafficking subunit (orange). To stabilise localisation in the cell membrane (4), transporters can interact with scaffolding proteins, such as PDZ domain-binding proteins (shown as brown globular structures). These can anchor transporters to the cytoskeleton, shown as orange filaments. Internalization of transporters frequently starts with phosphorylation of the N-terminus or C-terminus of transporters and this phosphorylated form is recognized by adapter proteins (5), causing internalization and subsequent removal of the transporter to endosomal compartments (6). Internalization often occurs in specialized lipid domains, such as lipid rafts.
Figure 3
Figure 3
Structure of SLC6 family transporters. The structure of the prokaryotic leucine transporter LeuT is used as a template to generate homology structures of SLC6 transporters. In (A) the structure of LeuT is shown in the open-outside conformation (Protein database 3TT1) and in (B) as the open-inside conformation (Protein database 3TT3). Its structure is characterized by an inverted repeat of a group of five helices. Helices 1–5 are shown in blue and helices 6–10 in orange. Extracellular loop 4 is shown in magenta. Helices 11 and 12 are omitted for clarity. Note the significant movement of helix 1b to allow substrate access on the inside. Extracellular loop 4 blocks access from the outside in the open-inside conformation.
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