2.A.23.2.3
Glutamate/aspartate/cysteine:Na⁺ symporter, EAAC1; EAAT3, SLC1A1 (Li⁺ can replace Na⁺; EAAC1 also mediates glutamate-independent anion conductance.) Cotransports glutamic acid with three Na⁺ followed by countertransport of K⁺(Teichman et al., 2009). The 50 residue 4B-4C loop (following TMS4) binds Na⁺ (Koch et al., 2007). (The dicarboxylic aminoaciduria protein in humans; NP_004161; Bröer, 2008a; 2008b). Neutralizing aspartate 83 modifies substrate translocation (Hotzy et al., 2012).  An SLC1A1 deletion segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family (Myles-Worsley et al. 2013).  Thr101 in TMS3 is essential for Na⁺ binding (Tao et al. 2010).  Klotho, a 1012 aa protein with N- and C-terminal TMSs, is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). The 3 Na⁺ binding sites in SLC1A porters have been identified, and both reentrant loops determine cation selectivity (Silverstein et al. 2018).  L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. Using purified human EAAT3, R2-hydroxyglutarate (R-2HG) binding or transport could not be observed. Imaging of EAAT3 bound to L-cysteine revealed several conformational states, including an outward-facing state with a semi-open gate and a disrupted sodium-binding site. These structures demonstrate that the full gate closure, coupled with the binding of the last sodium ion, occurs after substrate binding (Qiu and Boudker 2025). Furthermore, different substrates affect how the transporter distributes between a fully outward-facing conformation and intermediate occluded states on a path to the inward-facing conformation, suggesting that translocation rates are substrate-dependent. Two  SLC1A1-selective BIA derivatives, PBJ1 and PBJ2, with enhanced cytotoxicity, result from the inhibition of SLC1A1-dependent aspartate, glutamate, and cysteine metabolic pathways (Koochaki et al. 2025).