Glutamate transporter subfamily

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

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

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

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

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

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

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References

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How to cite this family page

Database page citation:

Glutamate transporter subfamily. Accessed on 23/03/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=163.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA and CGTP Collaborators (2015) The Concise Guide to PHARMACOLOGY 2015/16: Transporters. Br J Pharmacol. 172: 6110-6202.