Insight into\nthe Structure of the Neutral Amino Acid\nTransporter B<sup>0</sup>AT2 Enabled the Discovery of Tiagabine as\nan Inhibitor

The sodium-dependent membrane transporter SLC6A15 (B<sup>0</sup>AT2) belongs to the SLC6 family, which comprises carriers\nof amino\nacids and monoamines. B<sup>0</sup>AT2 is expressed in the central\nnervous system (CNS), including the glutaminergic and GABAergic system.\nSLC6A15 supplies neurons with neutral amino acids. Its main substrates,\nbranched-chain amino acids, and proline serve for glutamate biosynthesis,\nwhereas silencing of B<sup>0</sup>AT2 leads to lower levels of neuronal\nglutamate. Recent research revealed that polymorphisms in the vicinity\nof <i>slc6a15</i> are associated with major depressive disorder\nand anxiety. Mouse B<sup>0</sup>AT2 knockouts, by contrast, showed\nan antianxiety feature. Applying computational tools, we constructed\nmodels of B<sup>0</sup>AT2. Their structure was discussed extensively,\nenabling insight into the determinants of transport mechanism and\nsubstrate selectivity. Understanding the molecular basis of the B<sup>0</sup>AT2 inhibition by loratadine led to the discovery of a new\ninhibitor that is tiagabine, an anticonvulsant drug prescribed off-label\nin the treatment of anxiety and possessing antidepressant features.\nThe results showed that tiagabine appears to have a higher affinity\nto the transporter than loratadine, which is the most potent inhibitor\nto date. Our findings support the development of new B<sup>0</sup>AT2 inhibitors that could be useful for investigating their therapeutic\nrelevance, while the identification of tiagabine as a novel SLC6A15\ninhibitor adds a new dimension to the pharmacological complexity of\nthis drug.