| TCID | Name | Domain | Kingdom/Phylum | Protein(s) |
|---|---|---|---|---|
|
2.A.22.1.1 | Serotonin (5-hydroxytryptamine; 5 HT):Na+:Cl- symporter, SERT-A It also transports amphetamines; blocked by cocaine and tricyclic antidepressants such as Prozac; interacts directly with the secretory carrier-associated membrane protein-2 (SCAMP2; O15127) to regulate the subcellular distribution (Muller et al., 2006). The 3 D structure is known ()PDB 5I6X), and it uses an alternating sites mechanism with all 3 substrates bound (Zhang and Rudnick, 2006). Molecular determinants for antidepressants in the human serotonin and norepinephrine A transporters have been identified (Andersen et al., 2011). A conserved asparagine residue in transmembrane segment 1 (TMS1) of the serotonin transporter dictates chloride-coupled neurotransmitter transport (Henry et al., 2011). The formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation (Gabrielsen et al., 2012). Methylation of the SLC6A4 gene promoter controls depression in men by an epigenetic mechanism (Devlin et al., 2010). The 5HT Km is 0.4 micromolar (Banovic et al. 2010). Regulated allosterically by ATM7 which stabilizes the outward-facing conformation of SERT (Kortagere et al. 2013). Functional and regulatory mechanisms involving the N- and C-terminal hydrophilic domains have been considered (Fenollar-Ferrer et al. 2014). The range of substrates bound and transported has been predicted (Kaufmann et al. 2009). TMS3 may function in substrate and antagonist recognition (Walline et al. 2008). The 3-d x-ray structures with antidepressants bound have been solved, leading to mechanistic predictions; antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between TMSs 1, 3, 6, 8 and 10, directly blocking serotonin binding (Coleman et al. 2016). Na+ and cocaine stabilize outward-open conformations of SERT and decrease phosphorylation while agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increase phosphorylation. The opposing effects of the inhibitors, cocaine and ibogaine, were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na+ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively (Zhang et al. 2016). SERT is regulated by multiple molecular mechanisms including its physical interaction with intracellular proteins including the ASCT2 (alanine-serine-cysteine-threonine 2; TC# 2.A.23.3.2), co-expressed with SERT in serotonergic neurons and involved in the transport of small neutral amino acids across the plasma membrane (Seyer et al. 2016). SERT transports substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) (Sealover et al. 2016). A naturally occurring mutation, I425V, associated with obsessive-compulsive disorder and other neuropsychiatric disorders, activates hSERT and eliminates stimulation via the cyclicGMP-dependent pathway (Zhang et al. 2007). The substituted amphetamine, 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy), is a widely used drug of abuse that induces non-exocytotic release of serotonin, dopamine, and norepinephrine through their cognate transporters as well as blocking the reuptake of neurotransmitter by the same transporters. In SERT, Glu394 plays a role in MDMA recognition (Sealover et al. 2016). Intestinal dysbiosis may upregulate SERT expression and contribute to the development of chronic constipation (Cao et al. 2017). Cryo-EM structures of SERT-ibogaine complexes captured in outward-open, occluded and inward-open conformations have been solved (Coleman et al. 2019). Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMSs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TMS 1a and the partial unwinding of TMS 5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm, thus defining the structural rearrangements that occur from the outward-open to inward-open conformations. SERT and cholecytokinin (CCK) seem to be involved in the pathogenesis of Irrritable Bowl Syndrome (IBS-D) by regulating the brain-gut axis and affecting visceral sensitivity (Qin et al. 2020). Altered SERT function leads to several neurological diseases including depression, anxiety, mood disorders, and attention deficit hyperactivity disorders (ADHD) (Szöllősi and Stockner 2021). The structure and dynamics of the two sodium binding sites indicate that sodium binding is accompanied by an induced-fit mechanism that leads to new conformations (Szöllősi and Stockner 2021). Occlusion of the serotonin transporter is mediated by serotonin-induced conformational changes in the bundle domain (Gradisch et al. 2022). A structural rearrangement of the SERT intracellular gate is induced by Thr276 phosphorylation (Chan et al. 2022). Na+/Cl--dependent neurotransmitter transporters form oligomers. A leucine heptad repeat in TMS2 and a glycophorin-like motif in TMS6 may stabilize the oligomer (Just et al. 2004). Oligomerization of hSERT involves at least two discontinuous interfaces to form an array-like structure containing multimers of dimers (Just et al. 2004). Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. A decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR; decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation (Castillero et al. 2023). Cocaine-regulated trafficking of dopamine transporters in cultured neurons has been revealed using a pH sensitive reporter (Saenz et al. 2023). Two SERT ligands, fluoxetine and escitalopram, enter neurons within minutes, while simultaneously accumulating in many membranes (Nichols et al. 2023). Berberine and evodiamine influence serotonin transporter (5-HTT) expression via the 5-HTT-linked polymorphic region (Hu et al. 2012). Dehydroevodiamine has a dihedral angle of 3.71 degrees compared to 82.34 degrees for evodiamine. Dehydroevodiamine can more easily pass through a phospholipid bilayer than evodiamine because it has a more planar stereo-structure (Luo et al. 2023). SLC6A4 gene variants moderate associations between childhood food insecurity and adolescent mental health (Pilkay et al. 2024). | Eukaryota |
Metazoa, Chordata | SERT or SLC6A4 of Homo sapiens |
|
2.A.22.1.2 | Noradrenaline (norepinephrine):Na+ symporter (NET1, NAT1, SLC6A2) (also transports 1-methyl-4-tetrahydropyridinium and amphetamines; it is a target of cocaine and amphetamines as well as of therapetics for depression, obsessive-compulsive disorders, and post-traumatic stress disorder. This homooligomeric transporter binds one substrate molecule per transporter subunit (Schwartz et al., 2005; Schlessinger et al., 2011; Andersen et al., 2011). Extracellular loop 3 contributes to substrate and inhibitor selectivity (Lynagh et al. 2013). The highly conserved MELAL and GQXXRXG motifs, located in the second transmembrane domain and the first intracellular loop of hNET, respectively, are determinants of NET cell surface expression, and substrate and inhibitor binding (Sucic and Bryan-Lluka 2007). Based on modeling, the high affinity substrate binding site (S1) of the human norepinephrine transporter has been predicted and then verified by mutational studies (Jha et al. 2020). Proline residues play roles in the expression and function of the human noradrenaline transporter (Paczkowski and Bryan-Lluka 2004). Phosphatidylinositol 4,5-bisphosphate (PIP2) facilitates norepinephrine transporter dimerization and modulates substrate efflux (Luethi et al. 2022).
| Eukaryota |
Metazoa, Chordata | SLC6A2 of Homo sapiens |
|
2.A.22.1.3 | Dopamine:Na+ symporter, DAT (also takes up amphetamines in symport with Na+ which promotes intracellular Na+-dependent dopamine efflux (Khoshbouei et al., 2003)). It is inhibited by cocaine, amphetamines, neurotoxins, antidepressants and ethanol (Chen et al., 2004)]. Zn2+ potentiates uncoupled Cl- conductance (Meinild et al., 2004). A conserved salt bridge between TMSs 1 and 10 constitutes an extracellular gate (Pedersen et al. 2014). The 3-D structure of DAT is known (PDB 4M48; 4XPA). P101 of DAT plays an essential role in DA translocation (Lin and Uhl 2005). DAT is regulated by D3 dopamine receptors (Zapata et al., 2007). P25α (tubulin polymerization-promoting protein, TPPP (UniProt acc # O94811) increases dopamine transporter localization to the plasma membrane (Fjorback et al., 2011). DAT mediates paraquat (an herbicide) neurotoxicity (Rappold et al., 2011). Membrane cholesterol modulates the outward facing conformation and alters cocaine binding (Hong and Amara 2010). Threonine-53 phosphorylation in the rat orthologue (P23977) (Serine 53 in the human transporter) regulates substrate reuptake and amphetamine-stimulated efflux (Foster et al. 2012). DAT is enriched in filopodia and induces filopodia formation (Caltagarone et al. 2015). Dasotraline is an inhibitor of dopamine and norepinephrine reuptake, used for the treatment of attention-deficit/hyperactivity disorder (ADHD) (Hopkins et al. 2015). When in complex with 1-(1-benzofuran-5-yl)-N-methylpropan-2-amine (5-MAPB), a psychoactive adictive agonists, DAT can exhibit conformational transitions that spontaneously isomerize the transporter into the inward-facing state, similarly to that observed in dopamine-bound DAT (Sahai et al. 2016). The cytoplasmic N- and C-terminal domains contribute to substrate and inhibitor binding (Sweeney et al. 2016). DAT can exist as a monomer, a cooperative dimer subject to allosteric regulation (Cheng et al. 2017) or an oligomer involving the scaffold domain but not the bundle domain (Jayaraman et al. 2018). Cocaine binds in the S1 site to stabilize an inactive form of DAT (Krout et al. 2017). Dopamine efflux is caused by 3,4-methylenedioxypyrovalerone (MDPV) (Shekar et al. 2017). The cholesterol binding sites observed in the DAT crystal structures may be preserved in all human monoamine transporters (dopamine, serotonin and norepinephrine) and when cholesterol is bound, transport is inhibited (Zeppelin et al. 2018). The cell permeable furopyrimidine, AIM-100, augments DAT oligomerization through an allosteric mechanism associated with the DAT conformational state, and oligomerization-triggered clustering leads to a coat-independent endocytosis and subsequent endosomal retention of DAT (Sorkina et al. 2018). Dysfunction of this transporter leads to disease states, such as Parkinson's disease, bipolar disorder and/or depression (Jayaraman et al. 2018). DAT dysfunction is linked to neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BPD), and autism spectrum disorder (ASD). The DAT Val559 mutation changes the transporter localization and lateral mobility that contributes to ADE and alterations in dopamine signaling underlying multiple neuropsychiatric disorders (Thal 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). Evidence for the association of polymorphisms of DAT1 (SLC6A3) with heroin dependence has been presented (Koijam et al. 2020). A direct coupling between conformational dynamics of DAT, functional activity of the transporter and its oligomerization leading to endocytosis has been documented (Sorkina et al. 2021). Association of the sigma-1 receptor with the dopamine transporter attenuates the binding of methamphetamine via helix-helix interactions (Xu and Chen 2021). Potential partners for DAT, include the transmembrane chaperone 4F2hc (TC# 8.A.9.2.2), the proteolipid M6a (TC# 9.B.38.1.1) and a potential membrane receptor for progesterone (PGRMC2) (TC# 9.B.433.1.1) (Piniella et al. 2021). Two cytoplasmic proteins: a component of the Cullin1-dependent ubiquitination machinery termed F-box/LRR-repeat protein 2 (FBXL2; Q9UKC9), and the enzyme inositol 5-phosphatase 2 (SHIP2; O15357) were also associated. M6a, SHIP2 and Cullin1 were shown to increase DAT activity in coexpression experiments. M6a, enriched in neuronal protrusions (filopodia or dendritic spines), colocalized with DAT in these structures. In addition, the product of SHIP2 enzymatic activity (phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]) was tightly associated with DAT. PI(3,4)P2 strongly stimulated transport activity in electrophysiological recordings, and conversely, inhibition of SHIP2 reduced DA uptake (Piniella et al. 2021). There are weak associations between DAT mRNA expression and DAT availability in human brains (Pak et al. 2022). Gender differences in cocaine-induced hyperactivity and dopamine transporter trafficking to the plasma membrane have been reported (Deng et al. 2022). The dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson's disease (Vidyadhara et al. 2023). DAT may play a role in Parkinson's disease (Zhou et al. 2023). Dopamine transporter (DAT) deficient rodents have been characterized suggesting perspectives and limitations for neuroscience (Savchenko et al. 2023). Epigenetic analyses of the dopamine transporter gene DAT1 through methylation have reveaed the basis for certain personality traits in athletes (Humińska-Lisowska et al. 2023). Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release (Keighron et al. 2023). Known data on the consequences of changes in DAT expression in experimental animals, and results of pharmacological studies in these animals have been reviewed (Savchenko et al. 2023). DAT knockout rats display epigenetic alterations in response to cocaine exposure, and targeting epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4)may be therapeutic in treating addiction-related behaviors in a sex-dependent manner (Vilca et al. 2023). An overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are considered (Mercer et al. 2024). The structure of the human dopamine transporter (hDAT) and the mechanisms of inhibition by several agents have beeBartolomé-Martín et al. 2019). Evidence for the association of polymorphisms of DAT1 (SLC6A3) with heroin dependence has been presented (Koijam et al. 2020). A direct coupling between conformational dynamics of DAT, functional activity of the transporter and its oligomerization leading to endocytosis has been documented (Sorkina et al. 2021). Association of the sigma-1 receptor with the dopamine transporter attenuates the binding of methamphetamine via helix-helix interactions (Xu and Chen 2021). Potential partners for DAT, include the transmembrane chaperone 4F2hc (TC# 8.A.9.2.2), the proteolipid M6a (TC# 9.B.38.1.1) and a potential membrane receptor for progesterone (PGRMC2) (TC# 9.B.433.1.1) (Piniella et al. 2021). Two cytoplasmic proteins: a component of the Cullin1-dependent ubiquitination machinery termed F-box/LRR-repeat protein 2 (FBXL2; Q9UKC9), and the enzyme inositol 5-phosphatase 2 (SHIP2; O15357) were also associated. M6a, SHIP2 and Cullin1 were shown to increase DAT activity in coexpression experiments. M6a, enriched in neuronal protrusions (filopodia or dendritic spines), colocalized with DAT in these structures. In addition, the product of SHIP2 enzymatic activity (phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2]) was tightly associated with DAT. PI(3,4)P2 strongly stimulated transport activity in electrophysiological recordings, and conversely, inhibition of SHIP2 reduced DA uptake (Piniella et al. 2021). There are weak associations between DAT mRNA expression and DAT availability in human brains (Pak et al. 2022). Gender differences in cocaine-induced hyperactivity and dopamine transporter trafficking to the plasma membrane have been reported (Deng et al. 2022). The dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson's disease (Vidyadhara et al. 2023). DAT may play a role in Parkinson's disease (Zhou et al. 2023). Dopamine transporter (DAT) deficient rodents have been characterized suggesting perspectives and limitations for neuroscience (Savchenko et al. 2023). Epigenetic analyses of the dopamine transporter gene DAT1 through methylation have reveaed the basis for certain personality traits in athletes (Humińska-Lisowska et al. 2023). Interactions of calmodulin kinase II with the dopamine transporter facilitate cocaine-induced enhancement of evoked dopamine release (Keighron et al. 2023). Known data on the consequences of changes in DAT expression in experimental animals, and results of pharmacological studies in these animals have been reviewed (Savchenko et al. 2023). DAT knockout rats display epigenetic alterations in response to cocaine exposure, and targeting epigenetic modulators, Lysine Demethylase 6B (KDM6B) and Bromodomain-containing protein 4 (BRD4)may be therapeutic in treating addiction-related behaviors in a sex-dependent manner (Vilca et al. 2023). An overview of patient preparation, common imaging findings, and potential pitfalls that radiologists and nuclear medicine physicians should know when performing and interpreting dopamine transporter examinations. Alternatives to 123I-ioflupane imaging for the evaluation of nigrostriatal degeneration are considered (Mercer et al. 2024). The structure of the human dopamine transporter (hDAT) and the mechanisms of inhibition by several agents have been determined (Srivastava et al. 2024). | Eukaryota |
Metazoa, Chordata | DAT (SLC6A3) of Homo sapiens |
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2.A.22.1.4 | Antidepressant- and cocaine-sensitive dopamine transporter, T23G5.5 (Km for dopamine, 1.2 µM; dependent on extracellular Na+ and Cl-; blocked by cocaine and D-amphetamine) (Jayanthi et al. 1998) (interacts with syntaxin 1A to regulate channel activity and dopaminergic synaptic transmission; Carvelli et al., 2008). It is blocked by the neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium ion, and neuron-specific toxin suppressor mutants have been isolated (Nass et al. 2005). | Eukaryota |
Metazoa, Nematoda | T23G5.5 of Caenorhabditis elegans (Q03614) |
|
2.A.22.1.5 | High affinity octopamine transporter, OAT (also transports tyramine and dopamine in the 0.4-3.0 μM range (Donly et al., 2007)). | Eukaryota |
Metazoa, Arthropoda | OAT of Trichoplusia ni (Q95VZ4) |
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2.A.22.1.6 | The dopamine/norepinephrine transporter (SmDAT) (Larsen et al. 2011). | Eukaryota |
Metazoa, Platyhelminthes | DAT of Schistosoma mansoni (E9LD23) |
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2.A.22.1.7 | Dopamine transporter. The 3-d structure is known to 3.0 Å resolution (Penmatsa et al. 2013). The crystal structure, bound to the tricyclic antidepressant nortriptyline, shows the transporter locked in an outward-open conformation with nortriptyline wedged between transmembrane helices 1, 3, 6 and 8, blocking the transporter from binding substrate and from isomerizing to an inward-facing conformation. Although the overall structure is similar to that of its prokaryotic relative LeuT, there are multiple distinctions, including a kink in transmembrane helix 12 halfway across the membrane bilayer, a latch-like carboxy-terminal helix that caps the cytoplasmic gate, and a cholesterol molecule wedged within a groove formed by transmembrane helices 1a, 5 and 7. | Eukaryota |
Metazoa, Arthropoda | Dopamine transporter of Drosophila melanogaster |
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2.A.22.1.8 | Snf-10 transporter. Required for protease-mediated activation of sperm motility. Present in the plasma membrane before activation, but assumes a polarized localization to the cell body region that is dependent on membrane fusions mediated by the dysferlin FER-1 (Fenker et al. 2014). | Eukaryota |
Metazoa, Nematoda | Snf-10 of Caenorabditis elegans |
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2.A.22.1.9 | The sodium-dependent serotonin transporter of 622 aas and 12 TMSs, SERT or SerT. It terminates the action of serotonin by its high affinity reuptake into presynaptic terminals (Demchyshyn et al. 1994). Substrates have been predicted based on modeling studies (Kaufmann et al. 2009). | Eukaryota |
Metazoa, Arthropoda | SerT of Drosophila melanogaster (Fruit fly) |
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2.A.22.1.10 | Serotonin transporter, Mod-5, of 671 aas and 12 TMSs. Functions in thermotaxis memory behavior (Li et al. 2013). | Eukaryota |
Metazoa, Nematoda | Mod-5 of Caenorhabditis elegans |
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2.A.22.1.11 | Serotonin transporter, SERT, of 670 aas and 12 TMSs. it is subject to allosteric regulation involving 2 and possibly 3 distinct allosteric binding sites (Neubauer et al. 2006). Allosteric effectors include the transport inhibitors, duloxetine, RTI-55 and (S)-citalopram, which are antidepressants, and sometimes anti-anxiety and anti-pain medications in humans. | Eukaryota |
Metazoa, Chordata | SERT of Gallus gallus |
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2.A.22.1.12 | Sodium-dependent serotonin (5-HT) transporter, SERT, of 666 aas and 12 TMSs. The pharmacology and potential role in the nervous system have been studied (Camicia et al. 2022). | Eukaryota |
Metazoa, Platyhelminthes | SERT of Echinococcus granulosus |
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2.A.22.2.1 | Proline:Na+ symporter | Eukaryota |
Metazoa, Chordata | Proline transporter of Rattus norvegicus |
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2.A.22.2.2 | Glycine:Na+ symporter, GlyT1c (glycine/2Na+/1Cl- symporter) or Slc6A9, of 638 aas and 12 TMSs. The cell volume-regulatory mouse glycine transporter (GLYT1) is activated following metallopeptidase- mediated detachment of the oocyte from the zona pellucida (Ortman and Baltz 2023). | Eukaryota |
Metazoa, Chordata | Glycine transporter (GlyT1c) of Rattus norvegicus |
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2.A.22.2.3 | Neutral and cationic amino acid:Na+:Cl- symporter, B0+ or ATB(0,+). The rat homologue (NP_001032633) transports basic and zwitterionic amino acids, but not proline, aspartic acid and glutamic acid (Uchiyama et al, 2008). The stoichiometry of Na+:Cl-:amino acid = 3:1:1 (Le Guellec et al. 2022). SLC6A14 depends on heat shock protein HSP90 for trafficking to the cell surface (Rogala-Koziarska et al. 2019). It is upregulated in some forms of cancer; residues important for function have been identified (Palazzolo et al. 2019). Flagellin from Pseudomonas aeruginosa stimulates the ATB(0,+) transporter for arginine and neutral amino acids in human airway epithelial cells (Barilli et al. 2021). Reshaping the binding pocket selectively reduces access for cationic aas and derivatives (Anderson et al. 2022). Machine learning identified SLC6A14 as a biomarker promoting the proliferation and metastasis of pancreatic cancer via Wnt/β-catenin signaling (Dang et al. 2024). | Eukaryota |
Metazoa, Chordata | SLC6A14 of Homo sapiens |
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2.A.22.2.4 | Gut epithelium absorptive neutral amino acid Na+- or K+-dependent transporter, CAATCH1 (electrogenic; Cl--independent. Substrates: L-proline-preferring + Na+; L-threonine-preferring + K+; also transports L-methionine) (CAATCH1 can also function as an amino acid-gated cation [Na+ and K+] channel.) | Eukaryota |
Metazoa, Arthropoda | Neutral amino acid transporter CAATCH1 of Manduca sexta |
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2.A.22.2.5 | Gut epithelium absorptive neutral amino acid, K+- and Na+-dependent transporter KAAT1 (electrogenic; Cl--dependent; activated by alkaline pH; all zwiterionic amino acids except methyl AIB are substrates). CAATCH1 is 95% identical to KAAT1. Leu > Thr and Pro. | Eukaryota |
Metazoa, Arthropoda | Neutral amino acid transporter KAAT1 of Manduca sexta |
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2.A.22.2.6 | Glycine:Na+ transporter, GlyT2b (glycine/3Na+/1Cl- symporter, SLC6A5). GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype (Aubrey et al., 2007). Startle disease in Irish wolfhounds is associated with a microdeletion in the glycine transporter GlyT2 gene (Gill et al., 2011). A dominant hyperekplexia (startle disease) mutation Y705C in humans alters trafficking and the biochemical properties of GlyT2 (Gimenez et al. 2012). Structural determinants of the neuronal glycine transporter 2 for the selective inhibitors ALX1393 and ORG25543 have been determined (Benito-Muñoz et al. 2021). The efficacy of the analgesic GlyT2 inhibitor, ORG25543, is determined by two connected allosteric sites (Chater et al. 2023). | Eukaryota |
Metazoa, Chordata | Glycine transporter (GlyT2b) of Mus musculus |
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2.A.22.2.7 | Acetylcholine/choline:Na+ symporter, Snf-6 (interacts with dystrophin which determines its localization to the neuromuscular junction) (Kim et al., 2004) | Eukaryota |
Metazoa, Nematoda | Snf-6 of Caenorhabditis elegans (O76689) |
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2.A.22.2.8 | Cation-dependent nutrient amino acid transporter, AAT1 (L-phe > cys > his > ala > ser > met > ile > tyr > D-phe > thr > gly) (Bondko et al., 2005) | Eukaryota |
Metazoa, Arthropoda | AAT1 of Aedes aegypti (Q6VS78) |
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2.A.22.2.9 | The densovirus type-2 (BmDNV-2) receptor; putative amino acid transporter, the densonucleosis refractoriness, Nsd-2 protein, of 625 aas and 11-12 TMSs (Abe et al. 2000). Deletion of the nsd2 gene, encoding this transporter in the midgut membrane, causes resistance to this parvo-like virus as well as bidensovirus (Ito et al. 2008; Ito et al. 2016; Ito et al. 2018). | Eukaryota |
Metazoa, Arthropoda | Nsd-2 of Bombyx mori (B2ZXL8) |
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2.A.22.2.10 | Sodium- and chloride-dependent glycine transporter 2 (GlyT-2) (GlyT2) (Solute carrier family 6 member 5). The stoichiometry is Na+:Cl-;Gly = 3:1:1 (Le Guellec et al. 2022). The STAS domain has been solved by x-ray crystalography (PDB# 3LLO). Functions to remove and recycle synaptic glycine from inhibitory synapses. Mutations in GlyT are a common cause of hyperakplexia or startle disease in humans. The ER chaparone, calnexin, facilitates GlyT processing (Arribas-González et al. 2013). An allosteric binding site on GlyT2, for bioactive lipid analgesics has been identified (Mostyn et al. 2019), and it is formed by a crevice between TMSs 5, 7, and 8, and extracellular loop 4. Membrane cholesterol binds to and modulates the function of various SLC6 neurotransmitter transporters, including stabilizing the outward-facing conformation of the dopamine and serotonin transporters. Frangos et al. 2023 investigated how cholesterol binds to GlyT2 (SLC6A5), modulates the glycine transport rate, and influences bioactive lipid inhibition of GlyT2. | Eukaryota |
Metazoa, Chordata | SLC6A5 of Homo sapiens |
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2.A.22.2.11 | Sodium-dependent proline transporter (Solute carrier family 6 member 7) | Eukaryota |
Metazoa, Chordata | SLC6A7 of Homo sapiens |
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2.A.22.2.12 | Sodium- and chloride-dependent glycine transporter 1 (GlyT-1; GlyT1) (Solute carrier family 6 member 9). The stoichometry seems to be 2:1:1 for Na+:Cl-;glycine (Le Guellec et al. 2022). Inhibitors have been identified and patented (Cioffi 2018). Mutations in the gene encoding GlyT1 are associated with GlyT1 encephalopathy (OMIM #601019), a disease causing severe postnatal respiratory deficiency, muscular hypotonia and arthrogryposis, and result in severe impairment of transporter function (Hauf et al. 2020). . | Eukaryota |
Metazoa, Chordata | SLC6A9 of Homo sapiens |
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2.A.22.2.13 | Eukaryota |
Metazoa, Arthropoda | NAAT1 of Drosophila melanogaster | |
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2.A.22.3.1 | Betaine/GABA:Na+ symporter, BGT1. (Substrates include: betaine, GABA, diaminobutyrate, β-alanine, proline, quinidine, dimethylglycine, glycine, and sarcosine with decreasing affinity in that order). Selective inhibitors have been identified (Kragholm et al. 2013). | Eukaryota |
Metazoa, Chordata | SLC6A12 of Homo sapiens |
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2.A.22.3.2 | γ-Aminobutyric acid (GABA):Na+:Cl- symporter, GAT-1 (Stoichiometry, GABA:Na+ = 1:2 where both Na+ binding sites, Na1 and Na2, have been identified. Na2 but not Na1 can accommodate Li+ (Zhou et al., 2006)). Cai et al. 2005 have reported that N-glycosylation increases the stability, trafficking and GABA-uptake of GABA transporter 1. Glutamine 291 is essential for Cl- binding (Ben-Yona et al., 2011). Four human isoforms have been identified, GAT-1, GAT-2, GAT-3, and GAT-4, all about 70% identical to each other (Borden et al., 1992). GAT-2 transports γ-aminobutyric acid and β-alanine (Christiansen et al, 2007) It also concentratively takes up β-alanine and α-fluoro-β-alanine (Liu et al., 1999). GAT1 is capable of intracellular Na+-, Cl-- and GABA-induced outward currents (reverse GABA transport; GABA efflux) (Bertram et al., 2011). An acidic amino acid residue in transmembrane helix 10 conserved in the Neurotransmitter:Sodium:Symporters is essential for the formation of the extracellular gate of GAT-1 (Ben-Yona and Kanner, 2012). It is required for stringent gating and tight coupling of ion- and substrate-fluxes in the GABA transporter family (Dayan et al. 2017). GAT-1 is the target of the antiepileptic drug, tiagabine (Kardos et al. 2010). The monomeric protein has been purified fused to GFP (Hu et al. 2017). The methodology involving the reconstitution of GABA, glycine and glutamate transporters has been described (Danbolt et al. 2021). Neurodevelopmental phenotypes have been associated with pathogenic variants of SLC6A1 (Kahen et al. 2021). 4-Phenylbutyrate restores GABA uptake and reduced seizures in SLC6A1 patient variants (Nwosu et al. 2022). The cryo-EM structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor, tiagabine, has appeared (Motiwala et al. 2022). Inhibition of GAT1 prolongs the GABAergic signaling at the synapse and is a strategy to treat certain forms of epilepsy. Nayak et al. 2023 presented the cryoEM structure of Rattus norvegicus GABA transporter 1 (rGAT1) at a resolution of 3.1 Å. The structure revealed rGAT1 in a cytosol-facing conformation, with a linear density in the primary binding site that accommodates a molecule of GABA, a displaced ion density proximal to Na site 1 and a bound chloride ion. A unique insertion in TM10 aids the formation of a compact, closed extracellular gate (Nayak et al. 2023). The molecular basis for substrate recognition and transport by human GABA transporter GAT1 has been determined (Zhu et al. 2023). These investigators reported four cryogenicEM structures of human GAT1 at resolutions of 2.2–3.2 Å. GAT1 in substrate-free form or in complex with the antiepileptic drug tiagabine exhibits an inward-open conformation. In the presence of GABA or nipecotic acid, inward-occluded structures are captured. The GABA-bound structure reveals an interaction network bridged by hydrogen bonds and ion coordination for GABA recognition. The substrate-free structure unwinds the last helical turn of transmembrane helix TM1a to release sodium ions and substrate (Zhu et al. 2023) who have identified associations between the 3D structure and variant pathogenicity, variant functions, and phenotypes in SLC6A1-related disorders. | Eukaryota |
Metazoa, Chordata | SLC6A1 of Homo sapiens |
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2.A.22.3.3 | The taurine:Na+ symporter, TauT or SLC6A6, (also transports β-alanine and γ-aminobutyric acid (GABA) (Tomi et al., 2008; Anderson et al., 2009). Regulation of the cellular content of taurine in mammalian cells has been reviewed (Lambert 2004). Biallelic mutation of the TauT-encoding gene is linked to early retinal degeneration (Preising et al. 2019). Oral taurine administration of retinal degeneration and cardiomyopathy reverses the phenotype (Ansar et al. 2019). Overexpression of SLC6A6 suppresses neointimal formation by inhibiting vascular smooth muscle cell proliferation and migration via Wnt/beta-catenin signaling (Rong et al. 2023). | Eukaryota |
Metazoa, Chordata | SLC6A6 of Homo sapiens |
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2.A.22.3.4 | Creatine:Na+ symporter | Eukaryota |
Metazoa, Chordata | Creatine transporter of Oryctolagus cuniculus |
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2.A.22.3.5 | Renal apical membrane creatine:Na2+:Cl- symporter (CRT) (Garcia-Delgado et al., 2007) | Eukaryota |
Metazoa, Chordata | CRT of Rattus norvegicus (P28570) |
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2.A.22.3.6 | γ-aminobutyric acid (GABA):Na+:Cl- symporter GAT-1 (stoichiometry = 1:2:1) (Jiang et al., 2005) | Eukaryota |
Metazoa, Nematoda | GAT-1 of Caenorhabditis elegans (AAT02634) |
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2.A.22.3.7 | The GABA transporter, GAT4 (single mutations render this transporter C1- independent) (Zomot et al., 2007) | Eukaryota |
Metazoa, Chordata | GABA transporter GAT4 of Mus musculus (Q8BWA7) |
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2.A.22.3.8 | Mouse GABA, β-alanine, fluoro-β-alanine and taurine transporter-3 (GAT3) (Liu et al. 1999). Orthologous to rat and human GAT2; 72% identical to GAT4 (2.A.22.3.7) (takes up GABA with high affinity into presynaptic terminals). Also takes up the carnitine precursor, gamma-butyrobetaine (Nakanishi et al., 2011). | Eukaryota |
Metazoa, Chordata | GAT3 of Mus musculus (P31649) |
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2.A.22.3.9 | Sodium- and chloride-dependent GABA transporter 3 (GAT-3) (Solute carrier family 6 member 11). Expression of GAT-3 was selectively decreased within the amygdala of alcohol-choosing rats, and a knockdown of this transcript reversed choice preference of rats that originally chose a sweet solution over alcohol. GAT-3 expression was selectively decreased in the central amygdala of alcohol-dependent people as well. Thus, impaired GABA clearance within the amygdala contributes to alcohol addiction (Augier et al. 2018). | Eukaryota |
Metazoa, Chordata | SLC6A11 of Homo sapiens |
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2.A.22.3.10 | Sodium- and chloride-dependent GABA transporter 2 (GAT-2) (Solute carrier family 6 member 13). A deficiency of GAT-2 influences the metabolomics profile of Th1 cells, which provides insight into T cell responses to GAT-2 deficiency in mice (Ding et al. 2021). | Eukaryota |
Metazoa, Chordata | SLC6A13 of Homo sapiens |
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2.A.22.3.11 | Sodium- and chloride-dependent creatine transporter 1 (CT1 or CreaT) (Creatine transporter 1) (Solute carrier family 6 member 8, SLC6A8). The bovine ortholog of the same size, a glycoprotein of about 210 - 230 Da, has been purified to near homogeneity (West et al. 2005). Cooperative Binding of Substrate and Ions Drives Forward Cycling of the Human CT-1. Creatine deficiency disorders have been reviewed (PMID 20301745). Transport of creatine metabolic precursors have also been discussed (Jomura et al. 2022), and the use of SLC6A8 for theraputic purposes has been considered (Kurth et al. 2021). The CreaT2 gene is expressed exclusively in the testes, but CreaT1 is expressed in a variety of tissues (Snow and Murphy 2001). CT1 is present in mouse kidney, skeletal muscle and brown adiose tissue, but not in the pancreas, and levels are suject to organ-specific regulation (Lygate et al. 2022). Variants in GAMT, GATM and SLC6A8 for cerebral creatine deficiency syndromeshave been identified (Goldstein et al. 2024). | Eukaryota |
Metazoa, Chordata | SLC6A8 of Homo sapiens |
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2.A.22.3.12 | Eukaryota |
Metazoa, Arthropoda | Ine of Drosophila melanogaster | |
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2.A.22.4.1 | High affinity tryptophan:Na+ symporter, TnaT, of 501 aas and 12 TMSs (Androutsellis-Theotokis et al., 2003). The Km for Tryptophan is 145 nM; tryptamine and serotonin weakly inhibited with Ki values of 200 and 440 μM, respectively. An evolutionarily conserved role of adjacent transmembrane segments 7 and 8 has been proposed (Kniazeff et al. 2005). | Bacteria |
Bacillota | TnaT of Symbiobacterium thermophilum |
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2.A.22.4.2 | The amino acid (leucine):2 Na+ symporter, LeuTAa (Yamashita et al., 2005). LeuT possesses two ion binding sites, NA1 and NA2, both highly specific for Na+ but with differing mechanisms of binding (Noskov and Roux, 2008). X-ray structures have been determined for LeuT in substrate-free outward-open and apo inward-open states (Krishnamurthy and Gouaux, 2012). Extracytoplasmic substrate binding at an allosteric site controls activity (Zhao et al. 2011). It has been proposed that the 5 TMS repeat derived from a DedA domain (9.B.27; Khafizov et al. 2010). Mechanistic aspect of Na+ binding have been studied (Perez and Ziegler 2013). Structural studies of mutant LeuT proteins suggest how antidepressants bind to biogenic amine transporters (Wang et al. 2013). The detailed mechanism was studied by Zhao and Noskov, 2013. Uptake involves movement of the substrate amino acid from the outward facing binding site, S1, to the inward facing binding site, S2, coupled with confrmational changes in the protein (Cheng and Bahar 2013). The complete substrate translocation pathway has been proposed (Cheng and Bahar 2014). The inward facing conformation of LeuT has been solved (Grouleff et al. 2015). Substrate-induced unlocking of the inner gatemay determinethe catalytic efficiency of the transporter (Billesbølle et al. 2015). Of the two Na+ binding sites, occupation of Na2 stabilizes outward-facing conformations
presumably through a direct interaction between Na+ and transmembrane helices 1 and 8 whereas Na+ binding at Na1 influences conformational change through a network of intermediary interactions (Tavoulari et al. 2015). TMS1A movements revealed a substantially different inward-open conformation in lipid bilayer from that inferred
from the crystal structure, especiallly with respect to the inner vestibule (Sohail et al. 2016). Partial unwinding of transmembrane helices 1, 5, 6 and7 drives LeuT from a substrate-bound, outward-facing occluded conformation toward an inward-facing open state (Merkle et al. 2018). A conserved tyrosine residue in the substrate binding site is required for substrate binding to convert LeuT to inward-open states by establishing an interaction between the two transporter domains (Zhang et al. 2018). The X-ray structure of LeuT in an inward-facing occluded conformation has revealed the mechanism of substrate release (Gotfryd et al. 2020). This involves a major tilting of the cytoplasmic end of TMS5, which, together with release of the N-terminus but without coupled movement of TM1) opens a wide cavity towards the second Na+ binding site. The X-ray structure of LeuT in an inward-facing occluded conformation has been solved, revealing the mechanism of substrate release (Gotfryd et al. 2020). In nine transporters having the LeuT fold, the bundle (first two TMSs of each 5 TMS repeat) rotates
relative to the hash (third and fourth TMSs). Motions of the arms (fifth
TMS) to close or open the intracellular and outer vestibules are common,
as is a TMS1a swing, with notable variations in the opening-closing
motions of the outer vestibule. These analyses suggest that LeuT-fold
transporters layer distinct motions on a common bundle-hash rock (Licht et al. 2024). | Bacteria |
Aquificota | LeuTAa of Aquifex aeolicus (2A65_A) |
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2.A.22.4.3 | The methionine/alanine uptake porter, MetPS (Trotschel et al., 2008) (MetP is the transporter; MetS is an essential auxiliary subunit). | Bacteria |
Actinomycetota | MetPS of Corynebacterium glutamicum MetP (563aas; Q8NRL8) MetS (60aas; Q8NRL9) |
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2.A.22.5.1 | Hypothetical Na+-dependent permease | Archaea |
Euryarchaeota | MJ1319 of Methanococcus jannaschii |
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2.A.22.5.2 | The 11 TMS Na+-dependent tyrosine transporter, Tyt1 (Quick et al., 2006) | Bacteria |
Fusobacteriota | Tyt1 of Fusobacterium nucleatum (Q8RHM5) |
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2.A.22.5.3 | Neurotransmitter:sodium symporter of 455 aas, MhsT. The x-ray structures of two occluded inward-facing states with bound Na+ ions and L-tryptophan have been solved (4US4; Malinauskaite et al. 2014). These structures provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na+2 site. Solvation through this TMS 5 pathway may facilitate Na+ release from the Na+2 site to the inward-open state (Malinauskaite et al. 2014). TMS5 plays a role in the binding and release of Na+ from the Na+2 site and in mediating conformational changes (Stolzenberg et al. 2017). MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na+ -dependent symporters for amino acids, neurotransmitters, osmolytes, and creatine. A non-helical region in TMS 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition (Focht et al. 2020). | Bacteria |
Bacillota | MhsT of Bacillus halodurans |
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2.A.22.5.4 | Uncharacterized protein of 427 aas and 12 TMSs. | Archaea |
Euryarchaeota | UP of Thermococcus profundus |
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2.A.22.5.5 | Na+-dependent hypotaurine transporter of 454 aas and 11 TMSs (Deutschbauer et al. 2011). | Bacteria |
Pseudomonadota | Hypotaurine uptake porter of Shewanella oneidensis |
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2.A.22.6.1 | Na+/Amino acid transporter 1, SIT1/IMINO (SLC6A20). Transports imino acids such as proline (Km=0.2 mM), pipecolate, and N-methylated amino acids such as MeAIB and sarcosine (Na+-dependent, Cl--stimulated, pH-independent, voltage-dependent) (Li+, but not H+ can substitute for Na+) (Takanaga et al., 2005). It is a 2Na+/1Cl--proline cotransporter (Bröer et al., 2009). To identify new inhibitors of the proline transporter SIT1, its expression in Xenopus laevis oocytes was optimized. Trafficking of SIT1 was augmented by co-expression of angiotensin-converting enzyme 2 (ACE2) in oocytes, but there was no strict requirement for co-expression of ACE2. A pharmacophore-guided screen identified tiagabine as a potent non-competitive inhibitor of SIT1 (Bröer et al. 2024). The cryo-EM structure of ACE2-SIT1 bound with tiagabine was determined. The inhibitor binds close to the orthosteric proline binding site with its size extends into the cytosolic vestibule. This causes the transporter to adopt an inward-open conformation, in which the intracellular gate is blocked. This study provides the first structural insight into inhibition of SIT1 and generates tools for a better understanding of the ACE2-SIT1 complex (Bröer et al. 2024). | Eukaryota |
Metazoa, Chordata | SIT1 of Rattus norvegicus (Q64093) |
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2.A.22.6.2 | Synaptic vesicle neutral amino acid:Na+ symporter NTT4/XT1/BOAT3 (SLC6A17) (catalyzes uptake of neurotransmitters into presynaptic vesicles (Zaia and Reimer, 2009). | Eukaryota |
Metazoa, Chordata | NTT4 of Rattus norvegicus (P31662) |
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2.A.22.6.3 | B(O)AT1 or BOAT (SLC6A19; Hartnup's disease protein) is a kidney and intestinal apical membrane epithelial transporter for Na+-dependent, Cl--independent reabsorption of neutral amino acids. Many neutral L-amino acids bind with ~0.5 mM affinities; Leu is the preferred substrate, but all large, neutral, non-aromatic, L-amino acids bind to this transporter. Uptake of leucine is sodium-dependent. In contrast to other members of the neurotransmitter transporter family, this one does not appear to be chloride-dependent. Activity is enhanced by collectrin (Tmem27), a collecting duct transmembrane (1 TMS) glycoprotein (Q9HBJ8) (Danilczyk et al., 2006). The mouse orthologue is (Q9D687) (Broer et al., 2004; 2008) which is deficient due to mutation(s) in its structural gene, and it forms a complex with collectrin and the brush border carboxypeptidase angiotensin-converting enzyme 2 (ACE2; Q9BYF1). Mutations in Hartnup disorder protein, such as B0AT1(R240Q), decrease complex formation (Kraut and Sachs 2005) and lead to neutral aminoaciduria and in some cases pellagra-like symptoms (Kowalczuk et al., 2008; Singer et al. 2012). Collectrin is expressed at high levels in the simple embryonic kidney (the pronephros) of amphibians such as Xenopus (McCoy et al. 2008). ACE2 plays an important role in amino acid transport by acting as a binding partner of SLC6A19 in the intestine, regulating its trafficking, expression on the cell surface and catalytic activity (Kowalczuk et al. 2008, Camargo et al. 2009). ACE2 is also the cellular receptor for SARS-CoV and SARS-CoV-2 ( causitive agent of COVID-19). Yan et al. 2020 presented cryoEM structures of full-length human ACE2 in the presence of B0AT1 with or without the receptor binding domain (RBD) of the surface spike glycoprotein (S protein) of SARS-CoV-2, both at an overall resolution of 2.9 angstroms. The ACE2-B0AT1 complex is assembled as a dimer of heterodimers, with the collectrin-like domain of ACE2 mediating homodimerization. The RBD is recognized by the extracellular peptidase domain of ACE2 mainly through polar residues (Yan et al. 2020). | Eukaryota |
Metazoa, Chordata | SLC6A19 of Homo sapiens |
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2.A.22.6.4 | The neutral amino acid transporter, B0AT3 (Slc6a18); XT2 (55% identical to 2.A.22.6.3) | Eukaryota |
Metazoa, Chordata | SLC6A18 of Homo sapiens |
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2.A.22.6.5 | solute carrier family 6, member 16 | Eukaryota |
Metazoa, Chordata | SLC6A16 of Homo sapiens |
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2.A.22.6.6 | Sodium-dependent vesicular neutral amino acid transporter SLC6A17 (Sodium-dependent neurotransmitter transporter NTT4/BOAT3) (Solute carrier family 6 member 17) (Hägglund et al. 2013). | Eukaryota |
Metazoa, Chordata | SLC6A17 of Homo sapiens |
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2.A.22.6.7 | Sodium-dependent neutral amino acid transporter B(0)AT2 (Sodium- and chloride-dependent neurotransmitter transporter NTT73) (Sodium-coupled branched-chain amino-acid transporter 1) (Solute carrier family 6 member 15) (Transporter v7-3). It is mainly expressed in neurons and plays a role in depression and stress vulnerability (Santarelli et al. 2015). | Eukaryota |
Metazoa, Chordata | SLC6A15 of Homo sapiens |
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2.A.22.6.8 | Sodium- and chloride-dependent transporter XTRP3 (Sodium/amino-acid transporter 1) (Solute carrier family 6 member 20) (Transporter rB21A homologue) | Eukaryota |
Metazoa, Chordata | SLC6A20 of Homo sapiens |
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2.A.22.6.9 | Sea bass amino acid uptake porter, SLC6A19 or B0AT1 of 634 aas. Levels depend on diet (Rimoldi et al. 2015). | Eukaryota |
Metazoa, Chordata | SLC6A19 of Dicentrarchus labrax (European seabass) (Morone labrax) |
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2.A.22.6.10 | Uncharacterized protein of 1608 aas and 12 TMSs in a 3 + 4 + 5 TMS arrangement with long hydrophilic extensions at the N- and C-termini. | Eukaryota |
Metazoa, Arthropoda | UP of Aedes albopictus (Asian tiger mosquito) |
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2.A.22.6.11 | Putative amino acid transporter, NSS1, of 1132 aas with 16 TMSs in a 3 (residues 460 - 530) + 13 TMSs (C-terminal) with a hydrophilic N-terminal 430 aas (Wunderlich 2022). | Eukaryota |
Apicomplexa | NSS1 of Plasmodium falciparum |
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2.A.22.7.1 | Amino acid/GABA uptake porter, NSS3, of 1439 aas and 16 TMSs with an N-terminal hydrophilic region (residues 1 - 480), + 3 TMSs (residues 481 - 590), + 10 TMSs (residues 720 - 1170) + 3 TMSs (residues 1290 - 1430) (Wunderlich 2022). | Eukaryota |
Apicomplexa | NSS3 of Plasmodium falciparum |