2.A.23 The Dicarboxylate/Amino Acid:Cation (Na+ or H+) Symporter (DAACS) Family
The members of the DAACS family catalyze Na+ and/or H+ symport together with (a) a Krebs cycle dicarboxylate (malate, succinate, or fumarate), (b) a dicarboxylic amino acid (glutamate or aspartate), (c) a small, semipolar, neutral amino acid (Ala, Ser, Cys, Thr), (d) both neutral and acidic amino acids or (e) most zwitterionic and dibasic amino acids. The bacterial members are of about 450 (420-491) amino acyl residues while the mammalian proteins are of about 550 (503-574) residues in length. These proteins possess between ten and twelve hydrophobic segments per polypeptide chain. Two of them, human EAAT2 (TC #2.A.23.2.2) and E. coli GltP (TC #2.A.23.1.1) have been shown to be homotrimers (Gendreau et al., 2004). A specific topological model in which 7 α-helical TMSs are followed by a reentrant loop-pore structure followed by one final TMS is presented in Slotboom et al. (1999) and Leighton et al. (2002). Possibly, the transporter consists of eight TMSs, and one or two pore-loop structures that dip into the membrane (one between TMSs 6 and 7, the other between TMSs 7 and 8) in a fashion reminiscent of pore-loop structures found in VIC family ion channels (TC#1.A.1) (Grunewald et al., 2002). This family of transporters has been reviewed (Grewer et al. 2013). Functional up-regulation of GluTs may provide a pharmacotherapeutic approach for the management of chronic pain using pyridazine derivatives and beta-lactams (Gegelashvili and Bjerrum 2019). VGLUTs (TC# 2.A.1.14) and EAATs (TC# 2.A.23.2) may be targets for the treatment of Parkinson's Disease (PD). VGLUTs
and EAATs can be used as clinical drug targets to achieve better
efficacy (Li et al. 2021).
All of the bacterial proteins cluster together on the phylogenetic tree as do the mammalian proteins. The mammalian permeases that transport neutral amino acids cluster separately from those that are specific for the acidic amino acids. Among the mammalian proteins are neuronal excitatory amino acid neurotransmitter permeases. One of these (the GLT-1 L-glutamate/L-aspartate/D-aspartate transporter) has been shown to cotransport the neurotransmitter with 3 Na+ and 1 H+ and to countertransport 1 K+. The EAAT3 carrier (also called the EAAC1 carrier) uses Arg-447 to bind dicarboxylic amino acids in the presence of K+ but not monocarboxylic amino acids (Bendahan et al., 2001). Larsson et al. (2010) have identified the 3rd Na+ binding site and provided evidence for the mechanism of transport. Glutamate and Na+ binding activates an uncoupled chloride conductance in EAAT proteins, showing that they can function both as carriers and channels, and the two functions may arise from separate transmembrane domains (Ryan and Vandenberg 2006).
Some members of the DAACS family from animals, such as EAAT1, EAAT2, EAAT3 and EAAT4, can apparently be induced to function in a 'channel mode' wherein the transporter allows ion passage without being coupled to substrate translocation. This effect may involve a chloride-permeable, anion-selective channel. Some evidence suggests that the N- and C-termini of EAAT3 as well as two histidyl residues (in EAAT4) in the extracellular loop between TMSs 3 and 4 play a role in conversion to the channel mode (Li et al., 2000). The loop between TMSs 3 and 4 functions to allow regulation of this current by Zn2+ (Mitrovic et al., 2001). Distinct conformational states mediate carrier versus channel function, and a dynamic equilibrium exists between the two forms (Borre et al., 2002; Ryan et al., 2002). It is possible to isolate anion permeability mutants in TMS2 that show no change in glutamate transport (Ryan et al., 2004). EAAT4 but not EAAT2 anion channels display voltage-dependent gating that is modified by glutamate (Melzer et al., 2003). Possibly the channel activity is related to their trimeric structures (Gendreau et al., 2004). Torres-Salazar and Fahlke (2007) have reported that neuronal glutamate transporters (EAATs) vary in substrate transport rate but not in unitary anion channel conductance.
The 3-D structure of a member of the DAACS family has been determined (Boudker et al., 2007; Yernool et al., 2004) (see 2.A.23.1.5). The putative transporter is a bowl-shaped trimer with a solvent-filled extracellular basin extending halfway across the membrane bilayer. Each protomer harbors 8 TMSs and two reentrant helical hairpins. At the bottom of the basin are three independent binding sites, each cradled by two helical hairpins, reaching from opposite sides of the membrane. There are 3 independent translocation pathways. The first six transmembrane segments form a distorted 'amino-terminal cylinder' and provide all interprotomer contacts, whereas transmembrane segments TM7 and TM8, together with hairpins HP1 and HP2, coalesce to form a highly conserved core within the amino-terminal cylinder. It is proposed that transport of aspartate or glutamate is achieved by movements of the hairpins that allow alternating access to either side of the membrane. Helical hairpin 2 is the extracellular gate that controls access of aspartate and the ions to the internal binding site (Boudker et al., 2007). Molecular simulations have provided evidence for the substrate translocation pathway (Gu et al., 2009). The central cavity in trimeric glutamate transporters restricts ligand diffusion (Leary et al., 2011).
Excitatory amino acid transporters (EAATs) are essential for terminating
glutamatergic synaptic transmission. They are not only coupled
glutamate/Na+/H+/K+ transporters but also function as
anion-selective channels. EAAT anion channels regulate neuronal
excitability, and gain-of-function mutations in these proteins result in
ataxia and epilepsy. Machtens et al. 2015 examined the prokaryotic homolog GltPh (TC# 2.A.23.1.5) and mammalian EAATs to determine how these
transporters conduct anions. Whereas outward- and inward-facing GltPh
conformations are nonconductive, lateral movement of the glutamate
transport domain from intermediate transporter conformations results in
formation of an anion-selective conduction pathway. Entry of anions
into this pathway, and mutations of homologous pore-forming residues had
analogous effects on GltPh simulations and EAAT2/EAAT4 measurements of
single-channel currents and anion/cation selectivities. These findings
provide a mechanistic framework of how neurotransmitter transporters can
operate as anion-selective and ligand-gated ion channels (Machtens et al. 2015).
As noted above, EAATs
couple the transport of glutamate to the co-transport of three Na+ ions and one H+ ion into the cell, and the counter-transport of one
K+ ion out of the cell. The EAAT Cl- channel is activated by the binding of glutamate and Na+, but
is thermodynamically uncoupled from glutamate transport and involves
molecular determinants distinct from those responsible for glutamate
transport (Qu et al. 2019).
Several O-Benzylated l-threo-beta-hydroxyaspartate derivatives have been developed as highly potent inhibitors of EAATs
with TFB-TBOA ((2S,3S)-2-amino 3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid)
standing out as a low-nanomolar inhibitor (Leuenberger et al. 2016).
The generalized transport reaction catalyzed by members of the DAACS family is:
substrate (dicarboxylate or amino acid) (out) + 4 M+ [M+ =1 H+ and 3 Na+] (out) + K+ (in) →
substrate (in) + 4M+ (in) +K+ (out)
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Glutamate/aspartate:H+ symporter, GltP or GltT; has 8 TMSs with 2 re-entrant loops as for GltPh (TC# 2.A.23.1.5). GltP residues involved in substrate binding and transport have been identified, especially in transmembrane
helices VII and VIII (Rahman et al. 2016).
GltP of E. coli
Organic acid uptake porter, DctA of 444 aas and 8 - 10 putative TMSs. Based on mutant analyses, it may transport succinate, benzoate, acetate, fumarate and malate (Nam et al. 2003). A dctA mutant
colonized tobacco roots to a lesser extent than the wild-type
during early seedling development. Colonization by the dctA mutant, as compared to the wild type, also reduced the level of
systemically induced resistance against the soft rot pathogen Erwinia
carotovora SCC1 (Nam et al. 2006).
DctA of Pseudomonas chlororaphis (Pseudomonas aureofaciens)
Dicarboxylate transporter, DctA of 458 aas and 10 TMSs. Transports L-aspartate, succinate and fumarate. Functions under high oxygen conditions although constitutively synthesized (Wösten et al. 2017).
DctA of Campylobacter jejuni
DAACS family amino acid uptake system, All0342, possibly an acidic amino acid transporter, that also catalyzes amino acid efflux (including γ-amino isobutyrate) by a passive mechanism (Pernil et al. 2015).
All0342 of Anabaena (Nostoc) strain PCC7120
|2.A.23.1.13||Serine/threonine:Na+ symporter, SstT ||Bacteria ||SstT (YgjU) of E. coli (P0AGE4)|
Sodium:glutamate cotransporter (symporter), Glt, of 430 aas and probably 9 TMSs in a 3 + 3 + 3 TMS arrangement. Several 3-d structures are known (Jensen et al. 2013). The binding and transport of L- and D-aspartate have been studied, revealing that both the L- and D-aspartate bound GltTk structures with only minor rearrangements in the structure of the binding site (Arkhipova et al. 2019). A conserved methionine residue plays a role in the ion symport process, apparently by influencing the specific kinetics in the binding reaction, which, while influential for the turnover rate, does not fundamentally explain the ion-coupling mechanism (Zhou et al. 2021). The 3-d structure is available (PDB # 6XWO). It has a covalent trimeric transporter structure with an interconnecting rigid scafford domain (trimerization domain) on the inside. This seems to be a unique structure for a transporter (Colucci et al. 2023). The structure of the P208R mutant is also known (Colucci et al. 2023).
Glt of Thermococcus (Pyrococcus) kodakarensis
|2.A.23.1.2||Glutamate/aspartate:Na+ + H+ symporter ||Bacteria ||GltT of Bacillus stearothermophilus |
C4-dicarboxylate transporter (substrates: fumarate, D- and L-malate, succinate, succinamide, orotate, iticonate, mesaconate). This protein is 85% identical to the Sinorhizobium melitoti ortholog, mutants of which have an alterred substrate specificity and inability to support N2 fixing symbiosis (Yurgel and Kahn 2005).
DctA of Rhizobium leguminosarum
The L-cystine/L-selenocystine:H+ symporter, TcyP (YhcL) (Burguière et al., 2004)
TcyP (YhcL) of Bacillus subtilis (P54596)
Archaeal aspartate transporter, Gltph (GltPh) (3-D structure known; 3V8F and 3V8G) (Boudker et al., 2007; Yernool et al., 2004). Cotransports aspartate with 2 Na+ (Ryan et al., 2009) or 3 Na+ (Groeneveld and Slotboom, 2010) or 1Na+ plus 1 H+ plus 1 K+ (Machtens et al. 2015). Reyes et al. (2009) have solved the structure of the inward facing state by cysteine crosslinking. The loop between TMSs 3 and 4 plays an essential role in transport (Compton et al., 2010). Gltph shows opposite movement of the external gate upon binding cotransported sodium compared with substrate (Focke et al., 2011). The transport pathway and the conformational changes involved have been suggested based on modeling studies (Stolzenberg et al. 2012; Wang et al. 2018). Individual transport domains may alternate between periods of quiescence and
periods of rapid transitions. The switch to the dynamic mode may be due to separation of the transport domain from the trimeric scaffold which precedes domain
movements across the bilayer (Akyuz et al. 2013). This spontaneous dislodging of the substrate-loaded transport domain
is approximately 100-fold slower than subsequent transmembrane movements and may be rate determining
in the transport cycle. Interactions between the transporter and specific lipids in artificial membranes have revealed effects on activity, and mechanisms have been proposed (McIlwain et al. 2015). The system can also function as an anion channel (Machtens et al. 2015). Millisecond dynamics have been described (Matin et al. 2020).
Gltph of Pyrococcus horikoshii (LXFHA)
The dicarboxylate (succinate, fumarate, malate and oxaloacetate):H+ symporter, DctA (probably 3H+ are transported per succinate taken up (Groeneveld et al., 2010).
DctA of Bacillus subtilis (P96603)
Aerobic dicarboxylate transporter, DctA. Interacts with the DcuS sensor kinase (Witan et al., 2012). The interaction of DctA with DcuS has been studied extensively and reviewed (Unden et al. 2016).
DctA of E. coli (P0A830)
Cystine transporter, YdjN, of 463 aas. Also transports L-selenaproline (L-selenazolidine-4-carboxylic acid) and L-selenocystine, both toxic analogues that inhibit growth of urinary tract pathogenic E. coli (Deutch et al. 2014).
YdjN of E. coli
Fumarate:H+ symporter of 442 aas and 14 established TMSs, DctA. Responsible for the transport of dicarboxylates such as succinate, fumarate, and malate. The 3-d structure has been solved (Geertsma et al. 2015). It reveals an inward facing transmembrane domain of two 7 TMS intertwined inverted repeats similar to that of UraA as well as a STAS domain (Geertsma et al. 2015).
Fumarate transporter of Deinococcus geothermalis
Glutamate/aspartate:Na+ symporter, GLAST or EAAT1, Structural rearrangements have been probed by Leighton et al., 2006). EAAT1 interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). CEAT1 couples glutamate uptake to the symport of 3 Na+ and 1 H+ followed by the antiport of 1 K+. It can function as an uncoupled anion, water and/or urea channel (Vandenberg et al., 2011). Large collective motions regulate the functional properties of EAAT1 trimers (Jiang et al., 2011). The reentrant helical
hairpin loop, HP1, functions during the transport cycle as the proposed internal gate.
HP1 is packed against transmembrane domain, TMS 2 and TMS5 in its closed state, and two residues
located in TM2 and HP2 of EAAT1 are in close proximity (Zhang et al. 2014). In EAAT1, R388 is a critical element for the structural
coupling between the substrate translocation and the gating mechanisms of the EAAT-associated anion
channel, and conversion to E or D creates a constitutively open anion channel (Torres-Salazar et al. 2015).
Glutamate/aspartate permease (excitatory amino acid transporter-1, EAAT1) of Rattus norvegicus
Excitatory amino acid transporter (Sodium-dependent glutamate/aspartate transporter), Gkt-1 of 503 aas and 9 - 11 TMSs (Radice and Lustigman 1996).
Glt-1 of Caenorhabditis elegans
EAAT homologue, a glutamate/aspartate preferring transporter of 483 aas. TMS8 includes residues important for substrate and cation binding (Wang et al. 2013).
EAAT homoloue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens)
Dicarboxylic acid over dicarboxylic amino acid preferring EAAT3 homologue of 483 aas (Wang et al. 2013).
EAAT3 homologue of Culex quinquefasciatus (Southern house mosquito) (Culex pungens)
Glutamate/aspartate:Na+ symporter, GLT1; GLUT-R; EAAT2. Interacts directly with the Na+, K+-ATPase (TC #3.A.3.1) (Rose et al., 2009). Cotransports glutamic acid with three Na+ followed by countertransport of K+ (Teichman et al., 2009). The C-terminal 74aa domain regulates transport activity (Leinenweber et al., 2011). Hippocampal glutamate transporter 1 (GLT-1) levels parallel memory training (Heo et al., 2011). GLT-1 is regulated by MAGI-1 (Zou et al., 2011). Venom from the spider Parawixia
bistriata and a purified compound (Parawixin1) stimulate EAAT2 activity and protect retinal tissue
from ischemic damage (Mortensen et al. 2015). Determinants of this stimulation are at the interface of the trimerization and substrate transport domains ((Mortensen et al. 2015). TMS4 of GLT-1 undergoes a complex conformational shift during substrate translocation (Rong et al. 2016). Both reentrant loops determine the cation specificity (Silverstein et al. 2018). A tight spatial and functional relationship between the DAT/GLT-1
transporters and the Kv7.2/7.3 potassium channel immediately readjusts
the membrane potential of the neuron, probably to limit the
neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019).
Glutamate permease (excitatory amino acid transporter-2, EAAT2) of Rattus norvegicus
Glutamate/aspartate/cysteine:Na+ symporter, EAAC1; EAAT3, SLC1A1 (Li+ can replace Na+; EAAC1 also mediates glutamate-independent anion conductance.) Cotransports glutamic acid with three Na+ followed by countertransport of K+(Teichman et al., 2009). The 50 residue 4B-4C loop (following TMS4) binds Na+ (Koch et al., 2007). (The dicarboxylic aminoaciduria protein in humans; NP_004161; Bröer, 2008a; 2008b). Neutralizing aspartate 83 modifies substrate translocation (Hotzy et al., 2012). An SLC1A1 deletion segregates with schizophrenia and bipolar schizoaffective disorder in a 5-generation family (Myles-Worsley et al. 2013). Thr101 in TMS3 is essential for Na+ binding (Tao et al. 2010). Klotho, a 1012 aa protein with N- and C-terminal TMSs,
is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). The 3 Na+ binding sites in SLC1A porters have been identified, and both reentrant loops determine cation selectivity (Silverstein et al. 2018).
SLC1A1 of Homo sapiens
Aspartate/taurine (not glutamate):Na+ symporter, dEAAT2 (mediates both uptake and heteroexchange of its two substrates, both dependent on external Na+ (with taurine outside and Asp inside)); L-glutamate is transported with low affinity and efficiency (Besson et al., 2005).
dEAAT2 of Drosophila melanogaster (E1JHQ6)
|2.A.23.2.5|| solute carrier family 1 (glutamate transporter), member 7||Animals||SLC1A7 of Homo sapiens|
Excitatory amino acid transporter 1 (EAAT1) (Sodium-dependent glutamate/aspartate transporter 1) (GLAST-1) (Solute carrier family 1 member 3). Mutations cause episodic ataxia type 6 (EA6) (Choi et al. 2016; Iwama et al. 2017). EAAT1 regulates the extent and duration of
glutamate-mediated signals by the clearance of glutamate after synaptic release. It
also has an anion channel activity that prevents additional glutamate release. This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Substrate-induced structural rearrangements occur between the TMS4b-4c loop and TMS7 during the transport cycle (Zhang et al. 2019). GLAST serves as a cell surface biomarker for astrocytes (Kumar et al. 2021). It interacts with NHERF1 and NHERF2 (see TC# 8.A.24.1.1) which modify its cell surface expression (Sato et al. 2013). The inhibitor, UCPH-101 slows substrate translocation rather than substrate or Na+ binding, confirming a non-competitive inhibitory mechanism. However, it only
partially inhibits wild-type ASCT2 with relatively low affinity (Dong et al. 2023).
SLC1A3 of Homo sapiens
Excitatory amino acid transporter 2, EAAT2 (Glutamate/aspartate transporter II) (Sodium-dependent glutamate/aspartate transporter 2) (Solute carrier family 1 member 2). This system may be important for the pathophysiology of schizophrenia (Parkin et al. 2018). Amino acids in the TMS2 of EAAT2 are essential for membrane-bound localization, substrate binding, transporter function and anion currents (Mai et al. 2021). The distance between the TMS3-TMS4 loop and TMS7 changes when substrates are transported (Qu et al. 2021). SLC1A2 and SLC1A3 encode the glial glutamate transporters EAAT2 and EAAT1, which are not only the predominant glutamate uptake carriers in the brain, but also function as anion channels. Two homologous mutations, which substitute prolines in the center of the fifth TMS by arginine (P289R EAAT2, P290R EAAT1) cause epileptic encephalopathy (SLC1A2) or with episodic ataxia type 6 (SLC1A3). Both mutations impair glutamate uptake and increase anion conduction (Suslova et al. 2023). Additionally, the P312R mutation generates an anion conducting state that is accessible in the outward facing apo state that is the main determinant of the increased anion conduction of EAAT transporters carrying this mutation.
SLC1A2 (EAAT2) of Homo sapiens
Excitatory amino acid transporter 4, EAAT4 (Sodium-dependent glutamate/aspartate transporter) (Solute carrier family 1 member 6). Klotho, a 1012 aa protein with N- and C-terminal TMSs,
is a regulator of the excitatory amino acid transporters EAAT3 and EAAT4 (Almilaji et al. 2013). Phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, enhanced Cl- currents via EAAT4, but this increased Cl- current was not thermodynamically coupled to glutamate transport. These PMA-enhanced Cl- currents were partially blocked by staurosporine, chelerythrine, and calphostin C, the three PKC inhibitors, implying that PKC-mediated phsophorylation was responsible (Fang et al. 2006).
SLC1A6 of Homo sapiens
|2.A.23.2.9||Putative sodium-dependent excitatory amino acid transporter Glt-3||Worm||Glt-3 of Caenorhabditis elegans|
Neutral amino acid (alanine, serine, cysteine, threonine):Na+ symporter. Also transports homocysteine (Jiang et al., 2007). AscT1 is the Syncytin-1 (Q9UQF0) receptor. Syncytin-1, of 538 aas with 4-7 TMSs, is a viral fusion protein and is involved in the development of multiple sclerosis (Antony et al. 2007). Mutation causes nuerological problems including global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) (Heimer et al. 2015).
SLC1A4 of Homo sapiens
Insulin-activated, Na+-dependet amino acid (serine, alanine, glutamate, glutamine and other neutral amino acids):amino acid antiporter (Ndaru et al. 2019). Also transports homocysteine (Jiang et al., 2007). V-9302 is a selective and potent competitive small molecule antagonist of glutamine uptake via ASCT2. Blockage of ASCT2 activity with V-9302 resulted in attenuated cancer cell growth and proliferation, increased cell death, and increased oxidative stress, which collectively contributed to antitumor responses in vitro and in vivo (Schulte et al. 2018). The glutamine transporter ASCT2 plays a role in antineoplastic therapy (Teixeira et al. 2021).
Insulin-dependent amino acid transporter B of Mus musculus, AscT2
Broad-specificity amino acid:Na+ symporter, LAT1, M7V1, RDR, RDRC, or SLC1A5 (transports most neutral, zwitterionic and dibasic amino acids either uptake or bidirectional transport) (Scalise et al. 2018). Required for intracellular multiplication of Legionella pneumophila (Wieland et al., 2005). SLC7A5 with accessory protein SLC3A2 (the heavy chain; TC# 8.A.9.2.2) mediates bidirectional transport of amino acids and regulates mTOR and autophagy (Nicklin et al., 2009; Estrach et al. 2014). LAT1 is the sole
transport competent subunit of the heterodimer (Napolitano et al. 2015). l-Leucine inhibits uptake of LAT1 substrates as well as cell growth, and it potentiates the efficacy of bestatin and cisplatin, even at low concentrations (25
muM) (Huttunen et al. 2016). Transports certain thyroid hormones and their derivatives (Krause and Hinz 2017). It interacts with scaffold proteins and is glycosylated on two asn residues, N163 and N212. Also serves as the receptor by a group of retroviruses (Scalise et al. 2018). Syncytin-1 interacts with the ASCT2 receptor (Štafl et al. 2021). Discoidin domain receptor 1 promotes hepatocellular carcinoma progression through modulation of the SLC1A5 and the mTORC1 signaling pathway (Pan et al. 2022). LAT1 expression is alterred in patients with pediatric scoliosis (development of skeletal deformities) (Demura et al. 2022). The expression of SLC1A5 is upregulated in glioblastoma
tissues compared with low-grade gliomas. SLC1A5
knockdown inhibits glioma cell proliferation and
invasion, and reduces the sensitivity of ferroptosis via the
GPX4-dependent pathway (Han et al. 2022). It acts as a cell surface receptor for Feline endogenous virus RD114, Baboon M7 endogenous virus, and type D simian retroviruses. LAT1 plays a role in the activation of pathogenic T cell subsets under inflammatory conditions (Ogbechi et al. 2023).
SLC1A5 of Homo sapiens
Uncharaterized protein of 409 aas and 10 TMSs.
UP of Treponema denticola