Recent advances in pharmacology of plasma membrane Gaba transporters
Plasma membrane transporters for γ‑aminobutyric acid (GABA) belong to the solute carrier 6 (SLC6) family of proteins able to perform transport of amino acids and their derivatives into cells. These molecules use cotransport of extracellular sodium ions as a driving force for substrate transport against chemical gradient. The four cloned plasma membrane GABA transporters (GAT1-4) have distinct localization in the central nervous system (CNS) and in peripheral tissues being an essential part of the GABAergic system able to control neuronal excitability by counterbalancing the effects of excitatory neurotransmitters. The use of a selective GAT1 inhibitor – tiagabine is a therapeutic strategy to abolish seizures but recent studies utilizing GAT1-knockout animals or GAT1 inhibitors (tiagabine, NO-711, DDPM-2571) have shown that the inhibition of GAT1 could provide therapeutic benefits related to improvement of mood disorders (anxiety, depression), cognitive decline, acute or neuropathic pain, sleep disorders and others. Strong efforts of medicinal chemistry focused on the discovery of non-GAT1-selective tools to study the biological role of GAT2-4 and to establish potential therapeutic use of their inhibitors. However in this area little progress has been achieved as these compounds were not able to discriminate between GAT1-4 subtype. Hence, the functional role of GAT2-4 and their therapeutic potential remains not fully understood and so far only few compounds, such as EF1502 – a GAT1/GAT2 inhibitor and (S)-SNAP-5114, a semiselective GAT4 inhibitor proved their anticonvulsant activity in animal models. The results of these studies confirmed that GAT2 and GAT4 might be also a promising antiepileptic drug target for compounds administered either alone, or in combination with tiagabine. Taken together, although most of the current research is focused on GAT1 inhibition and seizure control, also non-GAT1 transporters are interesting drug targets in various CNS disorders. FINANCIAL SUPPORT: Supported by Jagiellonian University grant K/ZDS/005546 .