Insight into the Structure of the Neutral Amino Acid Transporter B⁰AT2 Enabled the Discovery of Tiagabine as an Inhibitor

Abstract

The sodium-dependent membrane transporter SLC6A15 (B0AT2) belongs to the SLC6 family, which comprises carriers of amino acids and monoamines. B0AT2 is expressed in the central nervous system (CNS), including the glutaminergic and GABAergic system. SLC6A15 supplies neurons with neutral amino acids. Its main substrates, branched-chain amino acids, and proline serve for glutamate biosynthesis, whereas silencing of B0AT2 leads to lower levels of neuronal glutamate. Recent research revealed that polymorphisms in the vicinity of slc6a15 are associated with major depressive disorder and anxiety. Mouse B0AT2 knockouts, by contrast, showed an antianxiety feature. Applying computational tools, we constructed models of B0AT2. Their structure was discussed extensively, enabling insight into the determinants of transport mechanism and substrate selectivity. Understanding the molecular basis of the B0AT2 inhibition by loratadine led to the discovery of a new inhibitor that is tiagabine, an anticonvulsant drug prescribed off-label in the treatment of anxiety and possessing antidepressant features. The results showed that tiagabine appears to have a higher affinity to the transporter than loratadine, which is the most potent inhibitor to date. Our findings support the development of new B0AT2 inhibitors that could be useful for investigating their therapeutic relevance, while the identification of tiagabine as a novel SLC6A15 inhibitor adds a new dimension to the pharmacological complexity of this drug.