BPS/IUPHAR Guide to Pharmacology | GRAC TRANSPORTER FAMILIES | SLC1 family of amino acid transporters

SLC1 family of amino acid transporters

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Glutamate transporter subfamily
Alanine/serine/cysteine transporter subfamily

The SLC1 family of sodium dependent transporters includes the plasma membrane located glutamate transporters and the neutral amino acid transporters ASCT1 and ASCT2 [1,7,34-35,46].

Glutamate transporter subfamily

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Glutamate transporters present the unusual structural motif of 8TM segments and 2 re-entrant loops [30]. 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 [8,48,63] reviewed by [33]). This structural data is in agreement with the proposed quaternary structure for EAAT2 [25] and several functional studies that propose the monomer is the functional unit [27,37,39,53]. Recent evidence suggests that EAAT3 and EAAT4 may assemble as heterotrimers [44]. 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 [50]. Recent evidence supports altered glutamate transport and novel roles in brain for splice variants of EAAT1 and EAAT2 [24,40]. Three patients with dicarboxylic aminoaciduria (DA) were recently found to have loss-of-function mutations in EAAT3 [6]. 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 [23,41,51] reviewed by [36]). PPARγ activation (e.g. by rosiglitazone) also leads to enhanced expression of EAAT though promoter activation [49]. In addition, several translational activators of EAAT2 have recently been described [12] along with treatments that increase the surface expression of EAAT2 (e.g. [38]; [68]), or prevent its down-regulation (e.g. [26]). A thermodynamically uncoupled Cl^- flux, activated by Na⁺ and glutamate [29,34,43] (Na⁺ and aspartate in the case of GltPh [52]), is sufficiently large, in the instances of EAAT4 and EAAT5, to influence neuronal excitability [58,62]. 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 [22].

Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Transporters

Excitatory amino acid transporter 1 (SLC1A3) Show »« Hide

Excitatory amino acid transporter 2 (SLC1A2) Show »« Hide

Excitatory amino acid transporter 3 (SLC1A1) Show »« Hide

Excitatory amino acid transporter 4 (SLC1A6) Show »« Hide

Excitatory amino acid transporter 5 (SLC1A7) Show »« Hide

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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 [17,54-55,61]. K_B (or K_i) values derived in uptake assays are generally higher (e.g. [55]). 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; [31,61]) and additionally is a potent kainate receptor agonist [67] which renders the compound unsuitable for autoradiographic localisation of EAATs [3]. Similarly, at concentrations that inhibit EAAT2, dihydrokainate binds to kainate receptors [55]. WAY-855 and WAY-213613 are both non-substrate inhibitors with a preference for EAAT2 over EAAT3 and EAAT1 [15-16]. NBI-59159 is a non-substrate inhibitor with modest selectivity for EAAT3 over EAAT1 (>10-fold) and EAAT2 (5-fold) [13-14]. Analogously, L-β-threo-benzyl-aspartate (L-β-BA) is a competitive non-substrate inhibitor that preferentially blocks EAAT3 versus EAAT1, or EAAT2 [18]. [³H](2S,4R)-4-methylglutamate 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 [56]. The novel isoxazole derivative (–)-HIP-A may interact at the same site as TBOA and preferentially inhibit reverse transport of glutamate [11]. 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 [17]. 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 [20-21]. 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 [60]).

Alanine/serine/cysteine transporter subfamily

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ASC transporters mediate Na⁺-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr and their structure is predicted to be similar to that of the glutamate transporters [5,59]. ASCT1 and ASCT2 also exhibit thermodynamically uncoupled chloride channel activity associated with substrate transport [10,66]. Whereas EAATs counter-transport K⁺ (see above) ASCTs do not and their function is independent of the intracellular concentration of K⁺ [66].

Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Transporters

Alanine/serine/cysteine transporter 1 (SLC1A4) Show »« Hide

Nomenclature	Alanine/serine/cysteine transporter 1
Systematic nomenclature	SLC1A4
Common abbreviation	ASCT1
Other names	Neutral amino acid transporter A, SATT, SATT, ASCT1, alanine/serine/cysteine/threonine transporter, neutral amino acid transporter ASCT1, solute carrier family 1 (glutamate/neutral amino acid transporter), member 4
Genes	SLC1A4 (Hs), Slc1a4 (Mm), Slc1a4 (Rn)
Ensembl ID	ENSG00000115902 (Hs), ENSMUSG00000020142 (Mm), ENSRNOG00000005248 (Rn)
Endogenous substrates	L-cysteine > L-alanine = L-serine > L-threonine
Stoichiometry	1 Na⁺: 1 amino acid (in): 1 Na⁺: 1 amino acid (out); (homo-, or hetero-exchange; [65])

Alanine/serine/cysteine transporter 2 (SLC1A5) Show »« Hide

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