TCDB is operated by the Saier Lab Bioinformatics Group

2.A.22 The Neurotransmitter:Sodium Symporter (NSS) Family

Members of the NSS family catalyze uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism (Rudnick et al. 2013). Sometimes Cl- is cotransported, and some exhibit a K+ dependency. The human dopamine transporter probably co-transports the positively charged or zwitterionic dopamine species with 2Na+ and 1Cl-. The human betaine/GABA transporter cotransports 3Na+ and 1 or 2Cl- with one molecule of betaine or GABA. Two different glycine transporters, GlyT1 (TC #2.A.22.2.2) and GlyT2 (TC #2.A.22.2.6), cotransport glycine with 2Na+ and 3Na+, respectively as well as 1Cl-. Most characterized members are from animals, but bacterial and archaeal homologues have been sequenced, and one bacterial homologue, TnaT of Symbiobacterium thermophilum, TC #2.A.22.5.2, has been shown to be a Na+-dependent tryptophan uptake permease with high affinity (145 nM) (Androutsellis-Theotokis et al., 2003) while a second is a tyrosine-specific Na+ symporter. Eukaryotic NSS proteins are generally of 600-800 amino acyl residues in length and possess 12 putative transmembrane helical spanners, but about 70% of prokaryotic homologues have 11 TMSs (Quick et al., 2006).  Several NSS family members have been characterized from marine invertebrates (Kinjo et al. 2013).

Neurotransmitter: sodium symporters (NSS) have a critical role in regulating neurotransmission and are targets for psychostimulants, anti-depressants and other drugs. In eukaryotic NSS, chloride is transported together with the neurotransmitter. However, transport by the bacterial homologues LeuT, Tyt1 and TnaT is chloride independent. The crystal structure of LeuT reveals an occluded binding pocket containing leucine and two sodium ions. Zomot et al, (2007) found that introduction of a negatively charged amino acid at or near one of the two putative sodium-binding sites of the GABA (γ-aminobutyric acid) transporter GAT-1 from rat brain (also called SLC6A1) renders both net flux and exchange of GABA largely chloride independent. In contrast to wild-type GAT-1, a marked stimulation of the rate of net flux (but not of exchange) was observed when the internal pH was lowered. Equivalent mutations introduced in the mouse GABA transporter GAT4 (SLC6A11) and the human dopamine transporter DAT (SLC6A3) similarly resulted in chloride-independent transport. The reciprocal mutations in LeuT and Tyt1 rendered substrate binding and/or uptake by these bacterial NSS chloride dependent. Their data indicated that the negative charge, provided either by chloride or by the transporter itself, is required during binding and translocation of the neurotransmitter, probably to counterbalance the charge of the co-transported sodium ions.

Evidence supports the conclusion that some members of the NSS family are dimers while others are monomers, and still others can be oligomeric depending on their localization. Thus, the glycine transporter is monomeric in the plasma membrane but oligomeric when intracellular. Both the serotonin and dopamine transporters may be dimeric. In the latter case, the extracellular end of TMS6 may be at a symmetrical dimer interface (Hastrup et al., 2001).  In mammals, several isoforms of these transporters (e.g., DAT and NET) can be generated by tissue-specific alternative splicing (Sogawa et al. 2010).

Tavoulari et al. (2011) described conversion of the Cl- -independent prokaryotic tryptophan transporter TnaT (2.A.22.4.1) to a fully functional Cl- -dependent form by a single point mutation, D268S. Mutations in TnaT-D268S, in wild type TnaT and in a serotonin transporter (SERT; 2.A.22.1.1) provided direct evidence for the involvement of each of the proposed residues in Cl- coordination. In both SERT and TnaT-D268S, Cl- and Na+ mutually increase each other's potency, consistent with am electrostatic interaction through adjacent binding sites.

Several members of the NSS family have been shown to exhibit channel-like properties under certain experimental conditions. Thus, sizable unitary ionic currents have been reported for membrane patches containing either the γ-aminobutyrate, norepinephrine or serotonin transporter. In the presence of Zn2+ (10 μM), the dopamine transporter (DAT) catalyzes uncoupled Cl- conductance (Meinild et al., 2004). Channel-like currents have also been measured for mammalian Na+/H+/K+-coupled glutamate transporters of the DAACS family (TC #2.A.23). Evidence shows that these channels can accommodate neurotransmitters as well as inorganic ions. One of these, CAATCH1 (TC #2.A.22.2.4) can function as an amino acid-gated cation (K+ and Na+) channel (Quick and Stevens, 2001). Different amino acids (pro, thr, met) differentially affect the state probability of the channel. These observations suggest that, as has been demonstrated for carriers of a few other families, neurotransmitter transporters can be induced to function as voltage-gated channels.

The GABA transporter, GAT-1 (TC #2.A.23.3.2), can catalyze channel-like fluxes of Li+ and K+. Mutations in TMS1 can lock the permease in the 'cation leak' mode (Kanner, 2003). The leak in the G63C (but not the G63S) mutant could be blocked by addition of membrane impermeable sulfhydryl reagents, suggesting that this position is accessible from the external aqueous medium. Thus, TMS1 contains determinants of both Na+-coupled GABA transport and the cation leak.

Cocaine and related drugs act by inhibiting clearance of released monoamine neurotransmitters from the synaptic cleft. Cocaine inhibits uptake of serotonin via SERT, dopamine via DAT, and norepinephrine via NET. Cocaine binds with high affinity to all three transporters, exhibiting competitive inhibition with the monoamine substrates, probably by binding to the active sites (Rasmussen et al., 2001).

The differential expression patterns and physiological roles of the glycine transporter subtypes have been exploited in the development of novel transport inhibitors to treat schizophrenia (GLYT1 inhibitors). GLYT1 transports glycine and also the N-methyl derivative of glycine, sarcosine, whereas GLYT2 only transports glycine. Glycine is an inhibitory neurotransmitter in the spinal cord and brain stem, where it acts on strychnine-sensitive glycine receptors, and is also an excitatory neurotransmitter throughout the brain and spinal cord, where it acts as a coagonist with L-glutamate on the N-methyl-D-aspartate subtypes of glutamate receptors. Glycine transporters regulate glycine concentrations within both inhibitory and excitatory synapses. The GLYT1 subtypes of glycine transporters are expressed in glial cells surrounding both excitatory and inhibitory synapses, whereas the GLYT2 subtypes of glycine transporters are expressed in presynaptic inhibitory glycinergic neurons (Vandenberg et al. 2007).

There are two Na+/Cl- -dependent glycine transporters, GLYT1 and GLYT2, which control extracellular glycine concentrations, and these transporters show differences in substrate selectivity and blocker sensitivity. Differences in substrate selectivity can be attributed to a single difference of a glycine residue in transmembrane domain 6 of GLYT1 for a serine residue at the corresponding position of GLYT2 (Vandenberg et al., 2007).

The crystal structure of a bacterial member of the NSS family has been determined complexed to leucine and 2 Na+ (Yamashita et al., 2005). The protein core consists of the first ten of the 12 TMSs with segments 1-5 and 6-10 exhibiting a pseudo-2-fold axis in the plane of the membrane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The binding pocket of LeuT contains two metal binding sites (Caplan et al., 2008). The first ion in site NA1 is directly coupled to the bound substrte (Leu) with the second ion in the neighboring site (NA2) only approximately 7 A away. Double ion occupancy of the binding pocket is required to ensure substrate coupling to Na+ (but not to Li+ or K+ cations). The presence of the ion in site NA2 is required for structural stability of the binding pocket as well as amplified selectivity for Na+ in the case of double ion occupancy (Caplan et al., 2008).

Substrate binding from the extracellular side of LeuT facilitates intracellular gate opening and substrate release at the intracellular face of the protein (Zhao et al., 2011). In the presence of alanine, a substrate that is transported ∼10-fold faster than leucine, alanine-induced dynamics are induced in the intracellular gate region of LeuT that directly correlate with transport efficiency. Thus, binding of a second substrate (S2) in the extracellular vestibule appears to act cooperatively with the primary substrate (S1) to control intracellular gating more than 30 Å away.

In the presence of Na+, the leucine-bound state of the invertebrate neutral amino acid transporter, KAAT1 of Manduca sexta (TC#2.A.22.2.5) is supposed to be relatively stable, while in the presence of K+, and at negative potentials, the progression of the leucine-bound form along the cycle is favoured. In this context, serine 308 appears to be important in allowing the change to the inward-facing conformation of the transporter following substrate binding, rather than in determining the binding specificity (Miszner et al., 2007). This lepidopteran neutral amino acid transporter has an unusual cation selectivity, being activated by K+ and Li+ in addition to Na+. Asp338 is essential for KAAT1 activation by K+ and for the coupling of amino acid transport to ion fluxes. Lys102 is likely to interact with Asp338 (Castagna et al., 2007). Asp338 corresponds to Asn286, a residue located in the Na+ binding site in the crystal structure of the NSS transporter LeuT. Lys102, interacting with Asp338, could contribute to the spatial organization of the KAAT1 cation binding site and the permeation pathway.

The generalized transport reaction for the members of this family is:

solute (out) + Na+ (out) → solute (in) + Na+ (in).

 

This family belongs to the: APC Superfamily.

References associated with 2.A.22 family:

Andersen, J., N. Stuhr-Hansen, L. Zachariassen, S. Toubro, S.M. Hansen, J.N. Eildal, A.D. Bond, K.P. Břgesř, B. Bang-Andersen, A.S. Kristensen, and K. Strřmgaard. (2011). Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proc. Natl. Acad. Sci. USA 108: 12137-12142. 21730142
Anderson, C.M., A. Howard, J.R. Walters, V. Ganapathy, and D.T. Thwaites. (2009). Taurine uptake across the human intestinal brush-border membrane is via two transporters: H+-coupled PAT1 (SLC36A1) and Na+- and Cl--dependent TauT (SLC6A6). J. Physiol. 587: 731-744. 19074966
Androutsellis-Theotokis, A., N.R. Goldberg, K. Ueda, T. Beppu, M.L. Beckman, S. Das, J.A. Javitch, and G. Rudnick. (2003). Characterization of a functional bacterial homologue of sodium-dependent neurotransmitter transporters. J. Biol. Chem. 278: 12703-12709. 12569103
Arribas-González, E., P. Alonso-Torres, C. Aragón, and B. López-Corcuera. (2013). Calnexin-Assisted Biogenesis of the Neuron.al Glycine Transporter 2 (GlyT2). PLoS One 8: e63230. 23650557
Aubrey, K.R., F.M. Rossi, R. Ruivo, S. Alboni, G.C. Bellenchi, A. Le Goff, B. Gasnier, and S. Supplisson. (2007). The transporters GlyT2 and VIAAT cooperate to determine the vesicular glycinergic phenotype. J. Neurosci. 27: 6273-6281. 17554001
Banović, M., T. Bordukalo-Niksić, M. Balija, L. Cicin-Sain, and B. Jernej. (2010). Platelet serotonin transporter (5HTt): physiological influences on kinetic characteristics in a large human population. Platelets 21: 429-438. 20528260
Beckman, M.L. and M.W. Quick. (1998). Neurotransmitter transporter: regulators of function and functional regulation. J. Membr. Biol. 164: 1-10. 9636239
Ben-Yona A. and Kanner BI. (2012). An Acidic Amino Acid Transmembrane Helix 10 Residue Conserved in the Neurotransmitter:Sodium:Symporters Is Essential for the Formation of the Extracellular Gate of the gamma-Aminobutyric Acid (GABA) Transporter GAT-1. J Biol Chem. 287(10):7159-68. 22235131
Ben-Yona, A., A. Bendahan, and B.I. Kanner. (2011). A glutamine residue conserved in the neurotransmitter:sodium:symporters is essential for the interaction of chloride with the GABA transporter GAT-1. J. Biol. Chem. 286: 2826-2833. 21098479
Berfield, J.L., L.C. Wang, and M.E.A. Reith. (1999). Which form of dopamine is the substrate for the human dopamine transporter: the cationic or the uncharged species? J. Biol. Chem. 274: 4876-4882. 9988729
Bertram S., Cherubino F., Bossi E., Castagna M. and Peres A. (2011). GABA reverse transport by the neuronal cotransporter GAT1: influence of internal chloride depletion. Am J Physiol Cell Physiol. 301(5):C1064-73. 21775701
Borden, L.A., K.E. Smith, P.R. Hartig, T.A. Branchek, and R.L. Weinshank. (1992). Molecular heterogeneity of the γ-aminobutyric acid (GABA) transport system. J. Biol. Chem. 267: 21098-21104. 1400419
Boudko, D.Y., A.B. Kohn, E.A. Meleshkevitch, M.K. Dasher, T.J. Seron, B.R. Stevens, and W.R. Harvey. (2005). Ancestry and progeny of nutrient amino acid transporters. Proc. Natl. Acad. Sci. USA 102: 1360-1365. 15665107
Bröer, S. (2008). Amino acid transport across mammalian intestinal and renal epithelia. Physiol. Rev. 88: 249-286. 18195088
Broer A., K. Klingel, S. Kowalczuk, J.E. Rasko, J. Cavanaugh, S. Broer. (2004). Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J. Biol. Chem. 279: 24467-24476. 15044460
Bröer, A., S. Balkrishna, G. Kottra, S. Davis, A. Oakley, and S. Bröer. (2009). Sodium translocation by the iminoglycinuria associated imino transporter (SLC6A20). Mol. Membr. Biol. 26: 333-346. 19657969
Caplan, D.A., J.O. Subbotina, and S.Y. Noskov. (2008). Molecular mechanism of ion-ion and ion-substrate coupling in the Na+-dependent leucine transporter LeuT. Biophys. J. 95: 4613-4621. 18708457
Carvelli, L., R.D. Blakely, and L.J. DeFelice. (2008). Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission. Proc. Natl. Acad. Sci. USA 105: 14192-14197. 18768815
Castagna, M., A. Soragna, S.A. Mari, M. Santacroce, S. Betté, P.G. Mandela, G. Rudnick, A. Peres, and V.F. Sacchi. (2007). Interaction between lysine 102 and aspartate 338 in the insect amino acid cotransporter KAAT1. Am. J. Physiol. Cell Physiol. 293: C1286-1295. 17626242
Castagna, M., C. Shayakul, D. Trotti, V.F. Sacchi, W.R. Harvey, and M.A. Hediger. (1998). Cloning and characterization of a potassium-coupled amino acid transporter. Proc. Natl. Acad. Sci. USA 95: 5395-5400. 9560287
Chen, J.-G. and G. Rudnik. (2000). Permeation and gating residues in serotonin transporter. Proc. Natl. Acad. Sci. USA 97: 1044-1049. 10655481
Chen, N., J. Rickey, J.L. Berfield, and M.E.A. Reith. (2004). Aspartate 345 of the dopamine transporter is critical for conformational changes in substrate translocation and cocaine binding. J. Biol. Chem. 279: 5508-5519. 14660644
Cheng, M.H. and I. Bahar. (2013). Coupled global and local changes direct substrate translocation by neurotransmitter-sodium symporter ortholog LeuT. Biophys. J. 105: 630-639. 23931311
Christiansen, B., A.K. Meinild, A.A. Jensen, and H. Braüner-Osborne. (2007). Cloning and characterization of a functional human γ-aminobutyric acid (GABA) transporter, human GAT-2. J. Biol. Chem. 282: 19331-19341. 17502375
Clark, J.A. and S.G. Amara. (1993). Amino acid neurotransmitter transporters: structure, function, and molecular diversity. BioEssays 15: 323-332. 8102052
Danilczyk, U., R. Sarao, C. Remy, C. Benabbas, G. Stange, A. Richter, S. Arya, J.A. Pospisilik, D. Singer, S.M. Camargo, V. Makrides, T. Ramadan, F. Verrey, C.A. Wagner, and J.M. Penninger. (2006). Essential role for collectrin in renal amino acid transport. Nature 444: 1088-1091. 17167413
Devlin, A.M., U. Brain, J. Austin, and T.F. Oberlander. (2010). Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS One 5: e12201. 20808944
Donly, C., L. Verellen, W. Cladman, and S. Caveney. (2007). Functional comparison of full-length and N-terminal-truncated octopamine transporters from Lepidoptera. Insect Biochem Mol Biol 37: 933-940. 17681232
Feldman, D.H., W.R. Harvey, and B.R. Stevens. (2000). A novel electrogenic amino acid transporter is activated by K+ or Na+, is alkaline pH-dependent, and is Cl--independent. J. Biol. Chem. 275: 24518-24526. 10829035
Fenker, K.E., A.A. Hansen, C.A. Chong, M.C. Jud, B.A. Duffy, J.P. Norton, J.M. Hansen, and G.M. Stanfield. (2014). SLC6 family transporter SNF-10 is required for protease-mediated activation of sperm motility in C. elegans. Dev Biol. [Epub: Ahead of Print] 24929237
Fjorback, A.W., S. Sundbye, J.C. Dächsel, S. Sinning, O. Wiborg, and P.H. Jensen. (2011). P25α / TPPP expression increases plasma membrane presentation of the dopamine transporter and enhances cellular sensitivity to dopamine toxicity. FEBS J. 278: 493-505. 21182589
Foster, J.D., J.W. Yang, A.E. Moritz, S. Challasivakanaka, M.A. Smith, M. Holy, K. Wilebski, H.H. Sitte, and R.A. Vaughan. (2012). Dopamine transporter phosphorylation site threonine 53 regulates substrate reuptake and amphetamine-stimulated efflux. J. Biol. Chem. 287: 29702-29712. 22722938
Gabrielsen, M., A.W. Ravna, K. Kristiansen, and I. Sylte. (2012). Substrate binding and translocation of the serotonin transporter studied by docking and molecular dynamics simulations. J Mol Model 18: 1073-1085. 21670993
Galli, A., R.D. Blakely, and L.J. DeFelice. (1998) Patch-clamp and amperometric recordings from norepinephrine transporters: channels activity and voltage-dependent uptake. Proc. Natl. Acad. Sci. USA 95: 13260-13265. 9789076
García-Delgado, M., P. García-Miranda, M.J. Peral, M.L. Calonge, and A.A. Ilundáin. (2007). Ontogeny up-regulates renal Na+/Cl-/creatine transporter in rat. Biochim. Biophys. Acta. 1768: 2841-2848. 17916324
Gill, J.L., D. Capper, J.F. Vanbellinghen, S.K. Chung, R.J. Higgins, M.I. Rees, G.D. Shelton, and R.J. Harvey. (2011). Startle disease in Irish wolfhounds associated with a microdeletion in the glycine transporter GlyT2 gene. Neurobiol Dis 43: 184-189. 21420493
Gimenez, C., G. Perez-Siles, J. Martinez-Villarreal, E. Arribas-Gonzalez, E. Jimenez, E. Nunez, J. de Juan-Sanz, E. Fernandez-Sanchez, N. Garcia-Tardon, I. Ibanez, V. Romanelli, J. Nevado, V.M. James, M. Topf, S.K. Chung, R.H. Thomas, L.R. Desviat, C. Aragon, F. Zafra, M.I. Rees, P. Lapunzina, R.J. Harvey, and B. Lopez-Corcuera. (2012). A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. J. Biol. Chem. [Epub: Ahead of Print] 22753417
Hastrup, H., A. Karlin, and J.A. Javitch. (2001). Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment. Proc. Natl. Acad. Sci. USA 98: 10055-10060. 11526230
Henry, L.K., H. Iwamoto, J.R. Field, K. Kaufmann, E.S. Dawson, M.T. Jacobs, C. Adams, B. Felts, I. Zdravkovic, V. Armstrong, S. Combs, E. Solis, G. Rudnick, S.Y. Noskov, L.J. DeFelice, J. Meiler, and R.D. Blakely. (2011). A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport. J. Biol. Chem. 286: 30823-30836. 21730057
Hong, W.C. and S.G. Amara. (2010). Membrane cholesterol modulates the outward facing conformation of the dopamine transporter and alters cocaine binding. J. Biol. Chem. 285: 32616-32626. 20688912
Hägglund, M.G., S.V. Hellsten, S. Bagchi, A. Ljungdahl, V.C. Nilsson, S. Winnergren, O. Stephansson, J. Rumaks, S. Svirskis, V. Klusa, H.B. Schiöth, and R. Fredriksson. (2013). Characterization of the transporterB0AT3 (Slc6a17) in the rodent central nervous system. BMC Neurosci 14: 54. 23672601
Jayanthi, L.D., S. Apparsundaram, M.D. Malone, E. Ward, D.M. Miller, M. Eppler, and R.D. Blakely. (1998). Mol. Pharmacol. 54: 601-609.
Jiang, G., L. Zhuang, S. Miyauchi, K. Miyake, Y.-J. Fei, and V. Ganapathy. (2005). A Na+/Cl--coupled GABA transporter, GAT-1, from Caenorhabditis elegans. Structural and functional features, specific expression in GABA-ergic neurons, and involvement in muscle function. J. Biol. Chem. 280: 2065-2077. 15542610
Kanner, B.I. (2003). Transmembrane domain I of the γ-aminobutyric acid transporter GAT-1 plays a crucial role in the transition between cation leak and transport modes. J. Biol. Chem. 278: 3705-3712. 12446715
Kardos, J., A. Palló, A. Bencsura, and A. Simon. (2010). Assessing structure, function and druggability of major inhibitory neurotransmitter γ-aminobutyrate symporter subtypes. Curr. Med. Chem. 17: 2203-2213. 20423300
Kavanaugh, M.P. (1998). Neurotransmitter transport: models in flux. Proc. Natl. Acad. Sci. USA 95: 12737-12738. 9788979
Khafizov, K., R. Staritzbichler, M. Stamm, and L.R. Forrest. (2010). A study of the evolution of inverted-topology repeats from LeuT-fold transporters using AlignMe. Biochemistry 49: 10702-10713. 21073167
Khoshbouei, H., H. Wang, J.D. Lechleiter, J.A. Javitch, and A. Galli. (2003). Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism. J. Biol. Chem. 278: 12070-12077. 12556446
Kilic, F. and G. Rudnick. (2000). Oligomerization of serotonin transporter and its functional consequences. Proc. Natl. Acad. Sci. USA 97: 3106-3111. 10716733
Kim, H., M.J. Rogers, J.E. Richmond, and S.L. McIntire. (2004). SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans. Nature 430: 891-896. 15318222
Kinjo, A., T. Koito, S. Kawaguchi, and K. Inoue. (2013). Evolutionary History of the GABA Transporter (GAT) Group Revealed by Marine Invertebrate GAT-1. PLoS One 8: e82410. 24312660
Kortagere, S., A.C. Fontana, D.R. Rose, and O.V. Mortensen. (2013). Identification of an allosteric modulator of serotonin transporter with novel mechanism of action. Neuropharmacology. [Epub: Ahead of Print] 23632081
Kowalczuk, S., A. Bröer, N. Tietze, J.M. Vanslambrouck, J.E. Rasko, and S. Bröer. (2008). A protein complex in the brush-border membrane explains a Hartnup disorder allele. FASEB J. 22: 2880-2887. 18424768
Kragholm, B., T. Kvist, K.K. Madsen, L. Jřrgensen, S.B. Vogensen, A. Schousboe, R.P. Clausen, A.A. Jensen, and H. Bräuner-Osborne. (2013). Discovery of a subtype selective inhibitor of the human betaine/GABA transporter 1 (BGT-1) with a non-competitive pharmacological profile. Biochem Pharmacol 86: 521-528. 23792119
Krishnamurthy, H. and E. Gouaux. (2012). X-ray structures of LeuT in substrate-free outward-open and apo inward-open states. Nature 481: 469-474. 22230955
Larsen, M.B., A.C. Fontana, L.G. Magalhăes, V. Rodrigues, and O.V. Mortensen. (2011). A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants. Mol Biochem Parasitol 177: 35-41. 21251927
Liu, M., R.L. Russell, L. Beigelman, R.E. Handschumacher, and G. Pizzorno. (1999). β-alanine and α-fluoro-β-alanine concentrative transport in rat hepatocytes is mediated by GABA transporter GAT-2. Am. J. Physiol. 276: G206-210. 9886997
Lynagh, T., T.S. Khamu, and L.J. Bryan-Lluka. (2013). Extracellular loop 3 of the noradrenaline transporter contributes to substrate and inhibitor selectivity. Naunyn Schmiedebergs Arch Pharmacol. [Epub: Ahead of Print] 24081522
Matskevitch, I., C.A. Wagner, C. Stegan, S. Bröer, B. Noll, T. Risler, H.M. Kwon, J.S. Handler, S. Waldegger, A.E. Busch, and F. Lang. (1999). Functional characterization of the betaine/γ-aminobutyric acid transporter BGT-1 expressed in Xenopus oocytes. J. Biol. Chem. 274: 16709-16716. 10358010
Meinild, A.-K., H.H. Sitte, and U. Gether. (2004). Zinc potentiates an uncoupled anion conductance associated with the dopamine transporter. J. Biol. Chem. 279: 49671-49679. 15358780
Miszner, A., A. Peres, M. Castagna, S. Bettè, S. Giovannardi, F. Cherubino, and E. Bossi. (2007). Structural and functional basis of amino acid specificity in the invertebrate cotransporter KAAT1. J. Physiol. 581: 899-913. 17412764
Müller, H.K., O. Wiborg, and J. Haase. (2006). Subcellular redistribution of the serotonin transporter by secretory carrier membrane protein 2. J. Biol. Chem. 281: 28901-28909. 16870614
Nakanishi, T., Y. Fukuyama, M. Fujita, Y. Shirasaka, and I. Tamai. (2011). Carnitine Precursor γ-Butyrobetaine is a Novel Substrate of the Na+- and Cl--dependent GABA Transporter Gat2. Drug Metab Pharmacokinet 26: 632-636. 21997971
Noskov, S.Y., and B. Roux (2008). Control of ion selectivity in LeuT: two Na+ binding sites with two different mechanisms. J. Mol. Biol. 377: 804-818. 18280500
Perez, C. and C. Ziegler. (2013). Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. Biol Chem 394: 641-648. 23362203
Quick, M. and B.R. Stevens. (2001). Amino acid transporter CAATCH1 is also an amino acid-gated cation channel. J. Biol. Chem. 276: 33413-33418. 11445577
Quick, M., H. Yano, N.R. Goldberg, L. Duan, T. Beuming, L. Shi, H. Weinstein, and J.A. Javitch. (2006). State-dependent conformations of the translocation pathway in the tyrosine transporter Tyt1, a novel neurotransmitter:sodium symporter from Fusobacterium nucleatum. J. Biol. Chem. 281: 26444-26454. 16798738
Ramamoorthy, S. and R.D. Blakely. (1999). Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285: 763-766. 10427004
Rappold, P.M., M. Cui, A.S. Chesser, J. Tibbett, J.C. Grima, L. Duan, N. Sen, J.A. Javitch, and K. Tieu. (2011). Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc. Natl. Acad. Sci. USA 108: 20766-20771. 22143804
Rasmussen, S.G.F., F.I. Carroll, M.J. Maresch, A.D. Jensen, C.G. Tate, and U. Gether. (2001). Biophysical characterization of the cocaine binding pocket in the serotonin transporter using a fluorescent cocaine analogue as a molecular reporter. J. Biol. Chem. 276: 4717-4723. 11062247
Reizer, J., A. Reizer, and M.H. Saier, Jr. (1994). A functional superfamily of sodium/solute symporters. Biochim. Biophys. Acta 1197: 133-166. 8031825
Rudnick, G., R. Krämer, R.D. Blakely, D.L. Murphy, and F. Verrey. (2013). The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch. [Epub: Ahead of Print] 24337881
Schlessinger, A., E. Geier, H. Fan, J.J. Irwin, B.K. Shoichet, K.M. Giacomini, and A. Sali. (2011). Structure-based discovery of prescription drugs that interact with the norepinephrine transporter, NET. Proc. Natl. Acad. Sci. USA 108: 15810-15815. 21885739
Schwartz, J.W., G. Novarino, D.W. Piston, and L.J. DeFelice. (2005). Substrate binding stoichiometry and kinetics of the norepinephrine transporter. J. Biol. Chem. 280: 19177-19184. 15757904
Scruggs, S.M., S. Disatian, and E.C. Orton. (2010). Serotonin transmembrane transporter is down-regulated in late-stage canine degenerative mitral valve disease. J Vet Cardiol 12: 163-169. 21036114
Sloan, J. and S. Mager. (1999). Cloning and functional expression of a human Na+ and Cl--dependent neutral and cationic amino acid transporter B0+. J. Biol. Chem. 274: 23740-23745. 10446133
Sogawa, C., C. Mitsuhata, K. Kumagai-Morioka, N. Sogawa, K. Ohyama, K. Morita, K. Kozai, T. Dohi, and S. Kitayama. (2010). Expression and function of variants of human catecholamine transporters lacking the fifth transmembrane region encoded by exon 6. PLoS One 5: e11945. 20700532
Supplisson, S. and M.J. Roux. (2002). Why glycine transporters have different stoichiometries. FEBS Lett. 529: 93-101. 12354619
Takanaga, H., B. Mackenzie, Y. Suzuki, and M.A. Hediger. (2005). Identification of mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. J. Biol. Chem. 280: 8974-8984. 15632147
Tavoulari, S., A.N. Rizwan, L.R. Forrest, and G. Rudnick. (2011). Reconstructing a chloride-binding site in a bacterial neurotransmitter transporter homologue. J. Biol. Chem. 286: 2834-2842. 21115480
Tomi, M., A. Tajima, M. Tachikawa, and K. Hosoya. (2008). Function of taurine transporter (Slc6a6/TauT) as a GABA transporting protein and its relevance to GABA transport in rat retinal capillary endothelial cells. Biochim. Biophys. Acta. 1778: 2138-2142. 18501699
Trötschel, C., M. Follmann, J.A. Nettekoven, T. Mohrbach, L.R. Forrest, A. Burkovski, K. Marin, and R. Krämer. (2008). Methionine Uptake in Corynebacterium glutamicum by MetQNI and by MetPS, a Novel Methionine and Alanine Importer of the NSS Neurotransmitter Transporter Family. Biochemistry. [Epub: Ahead of Print] 18991398
Uchiyama, T., T. Fujita, H.J. Gukasyan, K.J. Kim, Z. Borok, E.D. Crandall, and V.H. Lee. (2008). Functional characterization and cloning of amino acid transporter B(0,+) (ATB0,+) in primary cultured rat pneumocytes. J. Cell. Physiol. 214: 645-654. 17960566
Vandenberg, R.J., K. Shaddick, and P. Ju. (2007). Molecular Basis for Substrate Discrimination by Glycine Transporters. J. Biol. Chem. 282: 14447-14453. 17383967
Vincenti, S., M. Castagna, A. Peres, and V.F. Sacchi. (2000). Substrate selectivity and pH dependence of KAAT1 expressed in Xenopus laevis oocytes. J. Membr. Biol. 174: 213-224. 10758175
Wang, H., A. Goehring, K.H. Wang, A. Penmatsa, R. Ressler, and E. Gouaux. (2013). Structural basis for action by diverse antidepressants on biogenic amine transporters. Nature 503: 141-145. 24121440
Yamashita, A., Singh, S.K., Kawate, T., Jin, Y., and Gouaux, E. (2005). Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. Nature 437: 215-223. 16041361
Zaia, K.A. and R.J. Reimer. (2009). Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport. J. Biol. Chem. 284: 8439-8448. 19147495
Zapata A., B. Kivell, Y. Han, J.A. Javitch, E.A. Bolan, D. Kuraguntla, V. Jaligam, M. Oz, L.D. Jayanthi, D.J. Samuvel, S. Ramamoorthy, T.S. Shippenberg. (2007). Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors. J. Biol. Chem. 282: 35842-35854. 17923483
Zhang, Y.W. and G. Rudnick. (2006). The cytoplasmic substrate permeation pathway of serotonin transporter. J. Biol. Chem. 281: 36213-36220. 17008313
Zhao, C. and S.Y. Noskov. (2013). The molecular mechanism of ion-dependent gating in secondary transporters. PLoS Comput Biol 9: e1003296. 24204233
Zhao, Y., D.S. Terry, L. Shi, M. Quick, H. Weinstein, S.C. Blanchard, and J.A. Javitch. (2011). Substrate-modulated gating dynamics in a Na+-coupled neurotransmitter transporter homologue. Nature 474: 109-113. 21516104
Zhou, Y., E. Zomot, and B.I. Kanner. (2006). Identification of a lithium interaction site in the γ-aminobutyric acid (GABA) transporter GAT-1. J. Biol. Chem. 281: 22092-22099. 16757479
Zomot, E., A. Bendahan, M. Quick, Y. Zhao, J.A. Javitch, and B.I. Kanner (2007). Mechanism of chloride interaction with neurotransmitter:sodium symporters. Nature 449: 726-730. 17704762