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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

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Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops [24]. 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 [5,39,53] reviewed by [27]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [20] and several functional studies that propose the monomer is the functional unit [22,30,33,44]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [38]. 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 [41]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [19,34]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [4]. 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 antibiotics (e.g. ceftriaxone) is neuroprotective and occurs through NF-κB-mediated EAAT2 promoter activation [18,35,42] reviewed by [29]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [40]. In addition, several translational activators of EAAT2 have recently been described [7] along with treatments that increase the surface expression of EAAT2 (e.g. [32,57]), or prevent its down-regulation (e.g. [21]). A thermodynamically uncoupled Cl- flux, activated by Na+ and glutamate [23,28,37] (Na+ and aspartate in the case of GltPh [43]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [49,52]. 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 [17].

Transporters

871
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EAAT1 (Excitatory amino acid transporter 1 / SLC1A3) C Show summary »

EAAT2 (Excitatory amino acid transporter 2 / SLC1A2) C Show summary »

EAAT3 (Excitatory amino acid transporter 3 / SLC1A1) C Show summary »

EAAT4 (Excitatory amino acid transporter 4 / SLC1A6) C Show summary »


Target Id 871
Nomenclature Excitatory amino acid transporter 4
Systematic nomenclature SLC1A6
Common abbreviation EAAT4
Previous and unofficial names EAAT4 | excitatory amino acid transporter 4 | high affinity aspartate/glutamate transporter | sodium-dependent glutamate/aspartate transporter | solute carrier family 1 member 6 | solute carrier family 1 (high affinity aspartate/glutamate transporter), member 6 | solute carrier family 1 (high affinity aspartate/glutamate transporter)
Genes SLC1A6 (Hs), Slc1a6 (Mm), Slc1a6 (Rn)
Ensembl ID ENSG00000105143 (Hs), ENSMUSG00000005357 (Mm), ENSRNOG00000007509 (Rn)
UniProtKB AC P48664 (Hs), O35544 (Mm), O35921 (Rn)
Bioparadigms SLC Tables SLC1A6 (Hs)
Endogenous substrates
L-glutamic acid
L-aspartic acid
Substrates
DL-threo-β-hydroxyaspartate
L-trans-2,4-pyrolidine dicarboxylate
D-aspartic acid
Inhibitors
DL-TBOA pKi 5.4 [45]
threo-3-methylglutamate pKi 4.3 [13]
Labelled ligands
[3H]ETB-TBOA (Binding) pKd 7.9 [47] - Rat
[3H]L-aspartic acid
[3H]D-aspartic acid
Stoichiometry Probably 3 Na+: 1 H+ : 1 glutamate (in): 1 K+(out)

EAAT5 (Excitatory amino acid transporter 5 / SLC1A7) C Show summary »

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How to cite this family page

Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol. 176 Issue S1: S397-S493.