Glutamate transporter subfamily C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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].
Transporters
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Targets of relevance to immunopharmacology are highlighted in blue
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EAAT1 (Excitatory amino acid transporter 1 / SLC1A3) C Show summary » |
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EAAT2 (Excitatory amino acid transporter 2 / SLC1A2) C Show summary » |
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EAAT3 (Excitatory amino acid transporter 3 / SLC1A1) C Show summary »
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EAAT4 (Excitatory amino acid transporter 4 / SLC1A6) C Show summary » |
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EAAT5 (Excitatory amino acid transporter 5 / SLC1A7) C Show summary » |
Comments
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Transporters. Br J Pharmacol. 180 Suppl 2:S374-469.
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The KB (or Ki) values reported, unless indicated otherwise, are derived from transporter currents mediated by EAATs expressed in voltage-clamped Xenopus laevis oocytes [14,46-47,52]. KB (or Ki) 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 (KM = 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 (KD ≅ 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]).