Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops [25]. The crystal structure of a glutamate transporter homologue (GltPh) from Pyrococcus horikoshii supports this topology and indicates that the transporter assembles as a trimer, where each monomer is a functional unit capable of substrate permeation [6,40,54] reviewed by [28]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [21] and several functional studies that propose the monomer is the functional unit [23,31,34,45]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [39]. The activity of glutamate transporters located upon both neurones (predominantly EAAT3, 4 and 5) and glia (predominantly EAAT 1 and 2) serves, dependent upon their location, to regulate excitatory neurotransmission, maintain low ambient extracellular concentrations of glutamate (protecting against excitotoxicity) and provide glutamate for metabolism including the glutamate-glutamine cycle. The Na⁺/K⁺-ATPase that maintains the ion gradients that drive transport has been demonstrated to co-assemble with EAAT1 and EAAT2 [42]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [20,35]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [5]. DA is characterized by excessive excretion of the acidic amino acids glutamate and aspartate and EAAT3 is the predominant glutamate/aspartate transporter in the kidney. Enhanced expression of EAAT2 resulting from administration of β-lactam antibacterials (e.g. ceftriaxone) is neuroprotective and occurs through NF-κB-mediated EAAT2 promoter activation [19,36,43] reviewed by [30]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [41]. In addition, several translational activators of EAAT2 have recently been described [8] along with treatments that increase the surface expression of EAAT2 (e.g. [33,58]), or prevent its down-regulation (e.g. [22]). A thermodynamically uncoupled Cl^- flux, activated by Na⁺ and glutamate [24,29,38] (Na⁺ and aspartate in the case of GltPh [44]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [50,53]. Indeed, it has recently been suggested that the primary function of EAAT5 is as a slow anion channel gated by glutamate, rather than a glutamate transporter [18].

The K_B (or K_i) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage-clamped Xenopus laevis oocytes [14,46-47,52]. K_B (or K_i) values derived in uptake assays are generally higher (e.g. [47]). In addition to acting as a poorly transportable inhibitor of EAAT2, (2S,4R)-4-methylglutamate, also known as SYM2081, is a competitive substrate for EAAT1 (K_M = 54µM; [26,52]) and additionally is a potent kainate receptor agonist [57] which renders the compound unsuitable for autoradiographic localisation of EAATs [3]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [47]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [12-13]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) [9-10]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [15]. [³H]SYM2081 demonstrates low affinity binding (K_D ≅ 6.0 µM) to EAAT1 and EAAT2 in rat brain homogenates [4] and EAAT1 in murine astrocyte membranes [2], whereas [³H]ETB-TBOA binds with high affinity to all EAATs other than EAAT3 [48]. The novel isoxazole derivative (-)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [7]. Threo-3-methylglutamate induces substrate-like currents at EAAT4, but does not elicit heteroexchange of [³H]-aspartate in synaptosome preparations, inconsistent with the behaviour of a substrate inhibitor [14]. Parawixin 1, a compound isolated from the venom from the spider Parawixia bistriata is a selective enhancer of the glutamate uptake through EAAT2 but not through EAAT1 or EAAT3 [16-17]. In addition to the agents listed in the table, DL-threo-β-hydroxyaspartate and L-trans-2,4-pyrolidine dicarboxylate act as non-selective competitive substrate inhibitors of all EAATs. Zn²⁺ and arachidonic acid are putative endogenous modulators of EAATs with actions that differ across transporter subtypes (reviewed by [51]).

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