2.A.22.3.2
γ-Aminobutyric acid (GABA):Na⁺:Cl^- symporter, GAT-1 (Stoichiometry, GABA:Na⁺ = 1:2 where both Na⁺ binding sites, Na1 and Na2, have been identified. Na2 but not Na1 can accommodate Li⁺ (Zhou et al., 2006)). Cai et al. 2005 have reported that N-glycosylation increases the stability, trafficking and GABA-uptake of GABA transporter 1. Glutamine 291 is essential for Cl^- binding (Ben-Yona et al., 2011). Four human isoforms have been identified, GAT-1, GAT-2, GAT-3, and GAT-4, all about 70% identical to each other (Borden et al., 1992). GAT-2 transports γ-aminobutyric acid and β-alanine (Christiansen et al, 2007) It also concentratively takes up β-alanine and α-fluoro-β-alanine (Liu et al., 1999). GAT1 is capable of intracellular Na⁺-, Cl^-- and GABA-induced outward currents (reverse GABA transport; GABA efflux) (Bertram et al., 2011). An acidic amino acid residue in transmembrane helix 10 conserved in the Neurotransmitter:Sodium:Symporters is essential for the formation of the extracellular gate of GAT-1 (Ben-Yona and Kanner, 2012). It is required for stringent gating and tight coupling of ion- and substrate-fluxes in the GABA transporter family (Dayan et al. 2017). GAT-1 is the target of the antiepileptic drug, tiagabine (Kardos et al. 2010). The monomeric protein has been purified fused to GFP (Hu et al. 2017). The methodology involving the reconstitution of GABA, glycine and glutamate transporters has been described (Danbolt et al. 2021). Neurodevelopmental phenotypes have been associated with pathogenic variants of SLC6A1 (Kahen et al. 2021). 4-Phenylbutyrate restores GABA uptake and reduced seizures in SLC6A1 patient variants (Nwosu et al. 2022). The cryo-EM structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor, tiagabine, has appeared (Motiwala et al. 2022).