2.A.22 The Neurotransmitter:Sodium Symporter (NSS) Family
Members of the NSS family (SLC59) 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). Paudel et al. 2021 determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA). They identified (1) critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, (2) critical residues on the compounds that bound to the transporters, and (3) the functional role of a DA reuptake inhibitor in regulating D2R function. 1, 5-disubstituted tetrazoles are also monoamine neurotransmitter reuptake inhibitors (Paudel et al. 2021).
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). Shared dynamics of LeuT superfamily members and allosteric differentiation by structural irregularities and multimerization have been analyzed and reviewed (Ponzoni et al. 2018).
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). Dual inhibition of serotonin and norepinephrine transporters (hSERT and hNET) (serotonin-norepinephrine reuptake inhibitors, SNRIs) gives greatly improved efficacy and tolerability for treating major depressive disorder (MDD) compared with selective reuptake inhibitors (Xue et al. 2018).
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.
Transporters of the NSS family, or SLC6 family mediate the reuptake of neurotransmitters such as dopamine, norepinephrine, serotonin, GABA, and glycine. These transporters assume various quaternary arrangements ranging from monomers to complex stoichiometries with multiple subunits (Jayaraman et al. 2020). Dopamine and serotonin transporter oligomerization has been implicated in trafficking of newly formed proteins from the endoplasmic reticulum to the plasma membrane with a pre-fixed assembly. Once at the plasma membrane, oligomers are kept fixed in their quaternary assembly by interaction with phosphoinositides. It has been shown that oligomerization supports the activity of release-type psychostimulants. Single molecule microscopy revealed that the stoichiometry differs between individual members of the SLC6 family (Jayaraman et al. 2020). Moreover, handling of intracellular K+ determines the voltage dependence of plasmalemmal monoamine transporter function. Thus, DAT and NET differ from SERT in intracellular handling of K+. In DAT and NET, substrate uptake is voltage-dependent due to the transient nature of intracellular K+ binding, which precluded K+ antiport. SERT, however, antiports K+ and achieves voltage-independent transport (Bhat et al. 2021).
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.
|Abe, H., T. Sugasaki, M. Kanehara, T. Shimada, S.J. Gomi, F. Ohbayashi, and T. Oshiki. (2000). Identification and genetic mapping of RAPD markers linked to the densonucleosis refractoriness gene, nsd-2, in the silkworm, Bombyx mori. Genes Genet Syst 75: 93-96.|
|Andersen, J., N. Stuhr-Hansen, L. Zachariassen, S. Toubro, S.M. Hansen, J.N. Eildal, A.D. Bond, K.P. Bøgesø, B. Bang-Andersen, A.S. Kristensen, and K. Strømgaard. (2011). Molecular determinants for selective recognition of antidepressants in the human serotonin and norepinephrine transporters. Proc. Natl. Acad. Sci. USA 108: 12137-12142.|
|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.|
|Anderson, C.M.H., N. Edwards, A.K. Watson, M. Althaus, and D.T. Thwaites. (2022). Reshaping the Binding Pocket of the Neurotransmitter:Solute Symporter (NSS) Family Transporter SLC6A14 (ATB0,+) Selectively Reduces Access for Cationic Amino Acids and Derivatives. Biomolecules 12:.|
|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. |
|Ansar, M., E. Ranza, M. Shetty, S.A. Paracha, M. Azam, I. Kern, J. Iwaszkiewicz, O. Farooq, C.J. Pournaras, A. Malcles, M. Kecik, C. Rivolta, W. Muzaffar, A. Qurban, L. Ali, Y. Aggoun, F.A. Santoni, P. Makrythanasis, J. Ahmed, R. Qamar, M.T. Sarwar, L.K. Henry, and S.E. Antonarakis. (2019). Taurine treatment of retinal degeneration and cardiomyopathy in a consanguineous family with SLC6A6 taurine transporter deficiency. Hum Mol Genet. [Epub: Ahead of Print]|
|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.|
|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.|
|Augier, E., E. Barbier, R.S. Dulman, V. Licheri, G. Augier, E. Domi, R. Barchiesi, S. Farris, D. Nätt, R.D. Mayfield, L. Adermark, and M. Heilig. (2018). A molecular mechanism for choosing alcohol over an alternative reward. Science 360: 1321-1326.|
|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.|
|Barilli, A., R. Visigalli, F. Ferrari, G. Borsani, V. Dall''Asta, and B.M. Rotoli. (2021). Flagellin From Stimulates ATB Transporter for Arginine and Neutral Amino Acids in Human Airway Epithelial Cells. Front Immunol 12: 641563.|
|Bartolomé-Martín, D., I. Ibáñez, D. Piniella, E. Martínez-Blanco, S.G. Pelaz, and F. Zafra. (2019). Identification of potassium channel proteins Kv7.2/7.3 as common partners of the dopamine and glutamate transporters DAT and GLT-1. Neuropharmacology. [Epub: Ahead of Print]|
|Beckman, M.L. and M.W. Quick. (1998). Neurotransmitter transporter: regulators of function and functional regulation. J. Membr. Biol. 164: 1-10.|
|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.|
|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.|
|Benito-Muñoz, C., A. Perona, R. Felipe, G. Pérez-Siles, E. Núñez, C. Aragón, and B. López-Corcuera. (2021). Structural Determinants of the Neuron.al Glycine Transporter 2 for the Selective Inhibitors ALX1393 and ORG25543. ACS Chem Neurosci 12: 1860-1872.|
|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.|
|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.|
|Bhat, S., M. Niello, K. Schicker, C. Pifl, H.H. Sitte, M. Freissmuth, and W. Sandtner. (2021). Handling of intracellular K determines voltage dependence of plasmalemmal monoamine transporter function. Elife 10:.|
|Billesbolle CB., Kruger MB., Shi L., Quick M., Li Z., Stolzenberg S., Kniazeff J., Gotfryd K., Mortensen JS., Javitch JA., Weinstein H., Loland CJ. and Gether U. (2015). Substrate-induced Unlocking of the Inner Gate Determines the Catalytic Efficiency of a Neurotransmitter:Sodium Symporter. J Biol Chem. 290(44):26725-38.|
|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. |
|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. |
|Bröer, S. (2008). Amino acid transport across mammalian intestinal and renal epithelia. Physiol. Rev. 88: 249-286.|
|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.|
|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.|
|Cai, G., P.S. Salonikidis, J. Fei, W. Schwarz, R. Schülein, W. Reutter, and H. Fan. (2005). The role of N-glycosylation in the stability, trafficking and GABA-uptake of GABA-transporter 1. Terminal N-glycans facilitate efficient GABA-uptake activity of the GABA transporter. FEBS J. 272: 1625-1638.|
|Caltagarone J., Ma S. and Sorkin A. (2015). Dopamine transporter is enriched in filopodia and induces filopodia formation. Mol Cell Neurosci. 68:120-130.|
|Camargo, S.M., D. Singer, V. Makrides, K. Huggel, K.M. Pos, C.A. Wagner, K. Kuba, U. Danilczyk, F. Skovby, R. Kleta, J.M. Penninger, and F. Verrey. (2009). Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology 136: 872-882.|
|Camicia, F., H.R. Vaca, I. Guarnaschelli, U. Koziol, O.V. Mortensen, and A.C.K. Fontana. (2022). Molecular characterization of the serotonergic transporter from the cestode Echinococcus granulosus: pharmacology and potential role in the nervous system. Parasitol Res. [Epub: Ahead of Print]|
|Cao, H., X. Liu, Y. An, G. Zhou, Y. Liu, M. Xu, W. Dong, S. Wang, F. Yan, K. Jiang, and B. Wang. (2017). Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine. Sci Rep 7: 10322.|
|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.|
|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.|
|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.|
|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.|
|Castillero, E., E. Fitzpatrick, S.J. Keeney, A.M. D''Angelo, B.B. Pressly, M.T. Simpson, M. Kurade, W.C. Erwin, V. Moreno, C. Camillo, H.J. Shukla, V.V. Inamdar, A. Aghali, J.B. Grau, E. Salvati, I. Nissim, L. Rauova, M.A. Oyama, S.J. Stachelek, C. Brown, A.M. Krieger, R.J. Levy, and G. Ferrari. (2023). Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation. Sci Transl Med 15: eadc9606.|
|Chan, M.C., E. Procko, and D. Shukla. (2022). Structural Rearrangement of the Serotonin Transporter Intracellular Gate Induced by Thr276 Phosphorylation. ACS Chem Neurosci 13: 933-945.|
|Chen, J.-G. and G. Rudnik. (2000). Permeation and gating residues in serotonin transporter. Proc. Natl. Acad. Sci. USA 97: 1044-1049.|
|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. |
|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.|
|Cheng, M.H. and I. Bahar. (2014). Complete Mapping of Substrate Translocation Highlights the Role of LeuT N-terminal Segment in Regulating Transport Cycle. PLoS Comput Biol 10: e1003879.|
|Cheng, M.H., J. Garcia-Olivares, S. Wasserman, J. DiPietro, and I. Bahar. (2017). Allosteric Modulation of Human Dopamine Transporter Activity under Conditions Promoting its Dimerization. J. Biol. Chem. [Epub: Ahead of Print]|
|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.|
|Cioffi, C.L. (2018). Glycine transporter-1 inhibitors: a patent review (2011-2016). Expert Opin Ther Pat 28: 197-210.|
|Clark, J.A. and S.G. Amara. (1993). Amino acid neurotransmitter transporters: structure, function, and molecular diversity. BioEssays 15: 323-332.|
|Coleman, J.A., D. Yang, Z. Zhao, P.C. Wen, C. Yoshioka, E. Tajkhorshid, and E. Gouaux. (2019). Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature 569: 141-145.|
|Coleman, J.A., E.M. Green, and E. Gouaux. (2016). X-ray structures and mechanism of the human serotonin transporter. Nature 532: 334-339.|
|Danbolt, N.C., B. López-Corcuera, and Y. Zhou. (2021). Reconstitution of GABA, Glycine and Glutamate Transporters. Neurochem Res. [Epub: Ahead of Print]|
|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. |
|Dayan, O., A. Nagarajan, R. Shah, A. Ben-Yona, L.R. Forrest, and B.I. Kanner. (2017). An extra amino acid residue in transmembrane domain 10 of the GABA transporter GAT-1 is required for efficient ion-coupled transport. J. Biol. Chem. [Epub: Ahead of Print]|
|Demchyshyn, L.L., Z.B. Pristupa, K.S. Sugamori, E.L. Barker, R.D. Blakely, W.J. Wolfgang, M.A. Forte, and H.B. Niznik. (1994). Cloning, expression, and localization of a chloride-facilitated, cocaine-sensitive serotonin transporter from Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 91: 5158-5162.|
|Deng, J., X. Zheng, L. Shang, C.G. Zhan, and F. Zheng. (2022). Gender differences in cocaine-induced hyperactivity and dopamine transporter trafficking to the plasma membrane. Addict Biol 27: e13236.|
|Deutschbauer, A., M.N. Price, K.M. Wetmore, W. Shao, J.K. Baumohl, Z. Xu, M. Nguyen, R. Tamse, R.W. Davis, and A.P. Arkin. (2011). Evidence-based annotation of gene function in Shewanella oneidensis MR-1 using genome-wide fitness profiling across 121 conditions. PLoS Genet 7: e1002385.|
|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.|
|Ding, X., D. Yan, X. Zhang, B. Liu, and G. Zhu. (2021). Metabolomics Analysis of the Effect of GAT-2 Deficiency on Th1 Cells in Mice. J Proteome Res 20: 5054-5063.|
|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.|
|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.|
|Fenker KE., Hansen AA., Chong CA., Jud MC., Duffy BA., Norton JP., Hansen JM. and Stanfield GM. (2014). SLC6 family transporter SNF-10 is required for protease-mediated activation of sperm motility in C. elegans. Dev Biol. 393(1):171-82.|
|Fenollar-Ferrer, C., T. Stockner, T.C. Schwarz, A. Pal, J. Gotovina, T. Hofmaier, K. Jayaraman, S. Adhikary, O. Kudlacek, A.R. Mehdipour, S. Tavoulari, G. Rudnick, S.K. Singh, R. Konrat, H.H. Sitte, and L.R. Forrest. (2014). Structure and regulatory interactions of the cytoplasmic terminal domains of serotonin transporter. Biochemistry 53: 5444-5460.|
|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.|
|Focht, D., C. Neumann, J. Lyons, A. Eguskiza Bilbao, R. Blunck, L. Malinauskaite, I.O. Schwarz, J.A. Javitch, M. Quick, and P. Nissen. (2020). A non-helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition. EMBO. J. e105164. [Epub: Ahead of Print]|
|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.|
|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.|
|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.|
|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. |
|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.|
|Gimenez C., Perez-Siles G., Martinez-Villarreal J., Arribas-Gonzalez E., Jimenez E., Nunez E., de Juan-Sanz J., Fernandez-Sanchez E., Garcia-Tardon N., Ibanez I., Romanelli V., Nevado J., James VM., Topf M., Chung SK., Thomas RH., Desviat LR., Aragon C., Zafra F., Rees MI., Lapunzina P., Harvey RJ. and Lopez-Corcuera B. (2012). A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2. J Biol Chem. 287(34):28986-9002.|
|Gotfryd, K., T. Boesen, J.S. Mortensen, G. Khelashvili, M. Quick, D.S. Terry, J.W. Missel, M.V. LeVine, P. Gourdon, S.C. Blanchard, J.A. Javitch, H. Weinstein, C.J. Loland, P. Nissen, and U. Gether. (2020). X-ray structure of LeuT in an inward-facing occluded conformation reveals mechanism of substrate release. Nat Commun 11: 1005.|
|Gradisch, R., D. Szöllősi, M. Niello, E. Lazzarin, H.H. Sitte, and T. Stockner. (2022). Occlusion of the human serotonin transporter is mediated by serotonin-induced conformational changes in the bundle domain. J. Biol. Chem. 101613. [Epub: Ahead of Print]|
|Grouleff, J., S. Søndergaard, H. Koldsø, and B. Schiøtt. (2015). Properties of an Inward-Facing State of LeuT: Conformational Stability and Substrate Release. Biophys. J. 108: 1390-1399.|
|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.|
|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.|
|Hauf, K., L. Barsch, D. Bauer, R. Buchert, A. Armbruster, L. Frauenfeld, U. Grasshoff, and V. Eulenburg. (2020). GlyT1 Encephalopathy: Characterization of presumably disease causing GlyT1 mutations. Neurochem Int 104813. [Epub: Ahead of Print]|
|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.|
|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.|
|Hopkins, S.C., S. Sunkaraneni, E. Skende, J. Hing, J.A. Passarell, A. Loebel, and K.S. Koblan. (2015). Pharmacokinetics and Exposure-Response Relationships of Dasotraline in the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults. Clin Drug Investig. [Epub: Ahead of Print]|
|Hu, J., C. Weise, C. Böttcher, H. Fan, and J. Yin. (2017). Expression, purification and structural analysis of functional GABA transporter 1 using the baculovirus expression system. Beilstein J Org Chem 13: 874-882.|
|Ito, K., K. Kidokoro, H. Sezutsu, J. Nohata, K. Yamamoto, I. Kobayashi, K. Uchino, A. Kalyebi, R. Eguchi, W. Hara, T. Tamura, S. Katsuma, T. Shimada, K. Mita, and K. Kadono-Okuda. (2008). Deletion of a gene encoding an amino acid transporter in the midgut membrane causes resistance to a Bombyx parvo-like virus. Proc. Natl. Acad. Sci. USA 105: 7523-7527.|
|Ito, K., S. Shimura, S. Katsuma, Y. Tsuda, J. Kobayashi, H. Tabunoki, T. Yokoyama, T. Shimada, and K. Kadono-Okuda. (2016). Gene expression and localization analysis of Bombyx mori bidensovirus and its putative receptor in B. mori midgut. J Invertebr Pathol 136: 50-56.|
|Ito, K., T. Fujii, T. Yokoyama, and K. Kadono-Okuda. (2018). Decrease in the expression level of the gene encoding the putative Bombyx mori bidensovirus receptor during virus infection. Arch Virol 163: 3327-3338.|
|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.|
|Jayaraman, K., A.K. Das, D. Luethi, D. Szöllősi, G.J. Schütz, M.E.A. Reith, H.H. Sitte, and T. Stockner. (2020). SLC6 transporter oligomerization. J Neurochem. [Epub: Ahead of Print]|
|Jayaraman, K., A.N. Morley, D. Szöllősi, T.A. Wassenaar, H.H. Sitte, and T. Stockner. (2018). Dopamine transporter oligomerization involves the scaffold domain, but spares the bundle domain. PLoS Comput Biol 14: e1006229.|
|Jha, P., L. Ragnarsson, and R.J. Lewis. (2020). Structure-Function of the High Affinity Substrate Binding Site (S1) of Human Norepinephrine Transporter. Front Pharmacol 11: 217.|
|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. |
|Jomura, R., S.I. Akanuma, M. Tachikawa, and K.I. Hosoya. (2022). SLC6A and SLC16A family of transporters: Contribution to transport of creatine and creatine precursors in creatine biosynthesis and distribution. Biochim. Biophys. Acta. Biomembr 1864: 183840.|
|Just, H., H.H. Sitte, J.A. Schmid, M. Freissmuth, and O. Kudlacek. (2004). Identification of an additional interaction domain in transmembrane domains 11 and 12 that supports oligomer formation in the human serotonin transporter. J. Biol. Chem. 279: 6650-6657.|
|Kahen, A., H. Kavus, A. Geltzeiler, C. Kentros, C. Taylor, E. Brooks, L. Green Snyder, and W. Chung. (2021). Neurodevelopmental phenotypes associated with pathogenic variants in. J Med Genet. [Epub: Ahead of Print]|
|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. |
|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.|
|Kaufmann, K.W., E.S. Dawson, L.K. Henry, J.R. Field, R.D. Blakely, and J. Meiler. (2009). Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies. Proteins 74: 630-642.|
|Kavanaugh, M.P. (1998). Neurotransmitter transport: models in flux. Proc. Natl. Acad. Sci. USA 95: 12737-12738.|
|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.|
|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.|
|Kilic, F. and G. Rudnick. (2000). Oligomerization of serotonin transporter and its functional consequences. Proc. Natl. Acad. Sci. USA 97: 3106-3111.|
|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. |
|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.|
|Kniazeff, J., C.J. Loland, N. Goldberg, M. Quick, S. Das, H.H. Sitte, J.A. Javitch, and U. Gether. (2005). Intramolecular cross-linking in a bacterial homolog of mammalian SLC6 neurotransmitter transporters suggests an evolutionary conserved role of transmembrane segments 7 and 8. Neuropharmacology 49: 715-723.|
|Koijam, A.S., A.C. Hijam, A.S. Singh, P. Jaiswal, K. Mukhopadhyay, U. Rajamma, and R. Haobam. (2020). Association of Dopamine Transporter Gene with Heroin Dependence in an Indian Subpopulation from Manipur. J Mol Neurosci. [Epub: Ahead of Print]|
|Kortagere S., Fontana AC., Rose DR. and Mortensen OV. (2013). Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action. Neuropharmacology. 72:282-90.|
|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.|
|Kragholm, B., T. Kvist, K.K. Madsen, L. Jørgensen, 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.|
|Kraut, J.A. and G. Sachs. (2005). Hartnup disorder: unraveling the mystery. Trends Pharmacol Sci 26: 53-55.|
|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.|
|Krout, D., A.B. Pramod, R.A. Dahal, M.J. Tomlinson, B. Sharma, J.D. Foster, M.F. Zou, C. Boatang, A.H. Newman, J.R. Lever, R.A. Vaughan, and L.K. Henry. (2017). Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs. Biochem Pharmacol. [Epub: Ahead of Print]|
|Kurth, I., N. Yamaguchi, C. Andreu-Agullo, H.S. Tian, S. Sridhar, S. Takeda, F.C. Gonsalves, J.M. Loo, A. Barlas, K. Manova-Todorova, R. Busby, J.C. Bendell, J. Strauss, M. Fakih, A.J. McRee, A.E. Hendifar, L.S. Rosen, A. Cercek, R. Wasserman, M. Szarek, S.L. Spector, S. Raza, M.F. Tavazoie, and S.F. Tavazoie. (2021). Therapeutic targeting of SLC6A8 creatine transporter suppresses colon cancer progression and modulates human creatine levels. Sci Adv 7: eabi7511.|
|Lambert, I.H. (2004). Regulation of the cellular content of the organic osmolyte taurine in mammalian cells. Neurochem Res 29: 27-63.|
|Larsen, M.B., A.C. Fontana, L.G. Magalhães, 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.|
|Le Guellec, B., F. Rousseau, M. Bied, and S. Supplisson. (2022). Flux coupling, not specificity, shapes the transport and phylogeny of SLC6 glycine transporters. Proc. Natl. Acad. Sci. USA 119: e2205874119.|
|Li, Y., Y. Zhao, X. Huang, X. Lin, Y. Guo, D. Wang, C. Li, and D. Wang. (2013). Serotonin control of thermotaxis memory behavior in nematode Caenorhabditis elegans. PLoS One 8: e77779.|
|Lin, Z. and G.R. Uhl. (2005). Proline mutations induce negative-dosage effects on uptake velocity of the dopamine transporter. J Neurochem 94: 276-287.|
|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.|
|Luethi, D., J. Maier, D. Rudin, D. Szöllősi, T.J.F. Angenoorth, S. Stankovic, M. Schittmayer, I. Burger, J.W. Yang, K. Jaentsch, M. Holy, A.K. Das, M. Brameshuber, G.A. Camacho-Hernandez, A. Casiraghi, A.H. Newman, O. Kudlacek, R. Birner-Gruenberger, T. Stockner, G.J. Schütz, and H.H. Sitte. (2022). Phosphatidylinositol 4,5-bisphosphate (PIP) facilitates norepinephrine transporter dimerization and modulates substrate efflux. Commun Biol 5: 1259.|
|Lygate, C.A., H.A. Lake, D.J. McAndrew, S. Neubauer, and S. Zervou. (2022). Influence of homoarginine on creatine accumulation and biosynthesis in the mouse. Front Nutr 9: 969702.|
|Lynagh T., Khamu TS. and Bryan-Lluka LJ. (2014). Extracellular loop 3 of the noradrenaline transporter contributes to substrate and inhibitor selectivity. Naunyn Schmiedebergs Arch Pharmacol. 387(1):95-107.|
|Malinauskaite L., Quick M., Reinhard L., Lyons JA., Yano H., Javitch JA. and Nissen P. (2014). A mechanism for intracellular release of Na+ by neurotransmitter/sodium symporters. Nat Struct Mol Biol. 21(11):1006-12.|
|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.|
|McCoy, K.E., X. Zhou, and P.D. Vize. (2008). Collectrin/tmem27 is expressed at high levels in all segments of the developing Xenopus pronephric nephron and in the Wolffian duct. Gene Expr Patterns 8: 271-274.|
|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. |
|Merkle, P.S., K. Gotfryd, M.A. Cuendet, K.Z. Leth-Espensen, U. Gether, C.J. Loland, and K.D. Rand. (2018). Substrate-modulated unwinding of transmembrane helices in the NSS transporter LeuT. Sci Adv 4: eaar6179.|
|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.|
|Mostyn, S.N., K.A. Wilson, A. Schumann-Gillett, Z.J. Frangos, S. Shimmon, T. Rawling, R.M. Ryan, M.L. O''Mara, and R.J. Vandenberg. (2019). Identification of an allosteric binding site on the human glycine transporter, GlyT2, for bioactive lipid analgesics. Elife 8:.|
|Motiwala, Z., N.G. Aduri, H. Shaye, G.W. Han, J.H. Lam, V. Katritch, V. Cherezov, and C. Gati. (2022). Structural basis of GABA reuptake inhibition. Nature 606: 820-826.|
|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.|
|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.|
|Nass, R., M.K. Hahn, T. Jessen, P.W. McDonald, L. Carvelli, and R.D. Blakely. (2005). A genetic screen in Caenorhabditis elegans for dopamine neuron insensitivity to 6-hydroxydopamine identifies dopamine transporter mutants impacting transporter biosynthesis and trafficking. J Neurochem 94: 774-785.|
|Neubauer, H.A., C.G. Hansen, and O. Wiborg. (2006). Dissection of an allosteric mechanism on the serotonin transporter: a cross-species study. Mol Pharmacol 69: 1242-1250.|
|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.|
|Nwosu, G., F. Mermer, C. Flamm, S. Poliquin, W. Shen, K. Rigsby, and J.Q. Kang. (2022). 4-Phenylbutyrate restored γ-aminobutyric acid uptake and reduced seizures in patient variant-bearing cell and mouse models. Brain Commun 4: fcac144.|
|Paczkowski, F.A. and L.J. Bryan-Lluka. (2004). Role of proline residues in the expression and function of the human noradrenaline transporter. J Neurochem 88: 203-211.|
|Pak, K., S. Seo, M.J. Lee, H.J. Im, K. Kim, and I.J. Kim. (2022). Limited power of dopamine transporter mRNA mapping for predicting dopamine transporter availability. Synapse e22226. [Epub: Ahead of Print]|
|Palazzolo, L., C. Paravicini, T. Laurenzi, S. Adobati, S. Saporiti, U. Guerrini, E. Gianazza, C. Indiveri, C.M.H. Anderson, D.T. Thwaites, and I. Eberini. (2019). SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure. SLAS Discov 2472555219867317. [Epub: Ahead of Print]|
|Paudel, S., E. Kim, A. Zhu, S. Acharya, X. Min, S.H. Cheon, and K.M. Kim. (2021). Structural Requirements for Modulating 4-Benzylpiperidine Carboxamides from Serotonin/Norepinephrine Reuptake Inhibitors to Triple Reuptake Inhibitors. Biomol Ther (Seoul). [Epub: Ahead of Print]|
|Paudel, S., S. Wang, E. Kim, D. Kundu, X. Min, C.Y. Shin, and K.M. Kim. (2021). Design, Synthesis, and Functional Evaluation of 1, 5-Disubstituted Tetrazoles as Monoamine Neurotransmitter Reuptake Inhibitors. Biomol Ther (Seoul). [Epub: Ahead of Print]|
|Pedersen AV., Andreassen TF. and Loland CJ. (2014). A conserved salt bridge between transmembrane segments 1 and 10 constitutes an extracellular gate in the dopamine transporter. J Biol Chem. 289(50):35003-14.|
|Perez, C. and C. Ziegler. (2013). Mechanistic aspects of sodium-binding sites in LeuT-like fold symporters. Biol Chem 394: 641-648.|
|Piniella, D., E. Martínez-Blanco, D. Bartolomé-Martín, A.B. Sanz-Martos, and F. Zafra. (2021). Identification by proximity labeling of novel lipidic and proteinaceous potential partners of the dopamine transporter. Cell Mol Life Sci. [Epub: Ahead of Print]|
|Ponzoni, L., S. Zhang, M.H. Cheng, and I. Bahar. (2018). Shared dynamics of LeuT superfamily members and allosteric differentiation by structural irregularities and multimerization. Philos Trans R Soc Lond B Biol Sci 373:.|
|Preising, M.N., B. Görg, C. Friedburg, N. Qvartskhava, B.S. Budde, M. Bonus, M.R. Toliat, C. Pfleger, J. Altmüller, D. Herebian, M. Beyer, H.J. Zöllner, H.J. Wittsack, J. Schaper, D. Klee, U. Zechner, P. Nürnberg, J. Schipper, A. Schnitzler, H. Gohlke, B. Lorenz, D. Häussinger, and H.J. Bolz. (2019). Biallelic mutation of human encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J. fj201900914RR. [Epub: Ahead of Print]|
|Qin, G., Y. Zhang, and S.K. Yao. (2020). Serotonin transporter and cholecystokinin in diarrhea-predominant irritable bowel syndrome: Associations with abdominal pain, visceral hypersensitivity and psychological performance. World J Clin Cases 8: 1632-1641.|
|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.|
|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. |
|Ramamoorthy, S. and R.D. Blakely. (1999). Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285: 763-766.|
|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.|
|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.|
|Reizer, J., A. Reizer, and M.H. Saier, Jr. (1994). A functional superfamily of sodium/solute symporters. Biochim. Biophys. Acta 1197: 133-166.|
|Rimoldi, S., E. Bossi, S. Harpaz, A.G. Cattaneo, G. Bernardini, M. Saroglia, and G. Terova. (2015). Intestinal B(0)AT1 (SLC6A19) and PEPT1 (SLC15A1) mRNA levels in European sea bass (Dicentrarchus labrax) reared in fresh water and fed fish and plant protein sources. J Nutr Sci 4: e21.|
|Rogala-Koziarska, K., &.#.3.2.1.;. Samluk, and K.A. Nałęcz. (2019). Amino acid transporter SLC6A14 depends on heat shock protein HSP90 in trafficking to the cell surface. Biochim. Biophys. Acta. Mol. Cell Res 1866: 1544-1555.|
|Rudnick G., Kramer R., Blakely RD., Murphy DL. and Verrey F. (2014). The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction. Pflugers Arch. 466(1):25-42.|
|Saenz, J., O. Yao, E. Khezerlou, M. Aggarwal, X. Zhou, D.J. Barker, E. DiCicco-Bloom, and P.Y. Pan. (2023). Cocaine-regulated trafficking of dopamine transporters in cultured neurons revealed by a pH sensitive reporter. iScience 26: 105782.|
|Sahai, M.A., C. Davidson, G. Khelashvili, V. Barrese, N. Dutta, H. Weinstein, and J. Opacka-Juffry. (2016). Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances - The case of the benzofuran 5-MAPB. Prog Neuropsychopharmacol Biol Psychiatry. [Epub: Ahead of Print]|
|Santarelli, S., K.V. Wagner, C. Labermaier, A. Uribe, C. Dournes, G. Balsevich, J. Hartmann, M. Masana, F. Holsboer, A. Chen, M.B. Müller, and M.V. Schmidt. (2015). SLC6A15, a novel stress vulnerability candidate, modulates anxiety and depressive-like behavior: involvement of the glutamatergic system. Stress 1-8. [Epub: Ahead of Print]|
|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.|
|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. |
|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.|
|Sealover, N.R., B. Felts, C.P. Kuntz, R.E. Jarrard, G.H. Hockerman, E.L. Barker, and L.K. Henry. (2016). The external gate of the human and Drosophila serotonin transporters requires a basic/acidic amino acid pair for 3,4-methylenedioxymethamphetamine (MDMA) translocation and the induction of substrate efflux. Biochem Pharmacol 120: 46-55.|
|Seyer, P., F. Vandermoere, E. Cassier, J. Bockaert, and P. Marin. (2016). Physical and functional interactions between the serotonin transporter and the neutral amino acid transporter ASCT2. Biochem. J. 473: 1953-1965.|
|Shekar, A., J.I. Aguilar, G. Galli, N.V. Cozzi, S.D. Brandt, A.E. Ruoho, M.H. Baumann, H.J.G. Matthies, and A. Galli. (2017). Atypical dopamine efflux caused by 3,4-methylenedioxypyrovalerone (MDPV) via the human dopamine transporter. J Chem Neuroanat 83-84: 69-74.|
|Singer, D., S.M. Camargo, T. Ramadan, M. Schäfer, L. Mariotta, B. Herzog, K. Huggel, D. Wolfer, S. Werner, J.M. Penninger, and F. Verrey. (2012). Defective intestinal amino acid absorption in Ace2 null mice. Am. J. Physiol. Gastrointest Liver Physiol 303: G686-695.|
|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.|
|Snow, R.J. and R.M. Murphy. (2001). Creatine and the creatine transporter: a review. Mol. Cell Biochem 224: 169-181.|
|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.|
|Sohail, A., K. Jayaraman, S. Venkatesan, K. Gotfryd, M. Daerr, U. Gether, C.J. Loland, K.T. Wanner, M. Freissmuth, H.H. Sitte, W. Sandtner, and T. Stockner. (2016). The Environment Shapes the Inner Vestibule of LeuT. PLoS Comput Biol 12: e1005197.|
|Sorkina, T., M.H. Cheng, T.R. Bagalkot, C. Wallace, S.C. Watkins, I. Bahar, and A. Sorkin. (2021). Direct coupling of oligomerization and oligomerization-driven endocytosis of the dopamine transporter to its conformational mechanics and activity. J. Biol. Chem. 100430. [Epub: Ahead of Print]|
|Sorkina, T., S. Ma, M.B. Larsen, S.C. Watkins, and A. Sorkin. (2018). Small molecule induced oligomerization, clustering and clathrin-independent endocytosis of the dopamine transporter. Elife 7:.|
|Stolzenberg, S., Z. Li, M. Quick, L. Malinauskaite, P. Nissen, H. Weinstein, J.A. Javitch, and L. Shi. (2017). The Role of TM5 in Na2 Release and the Conformational Transition of Neurotransmitter:Sodium Symporters toward the Inward-Open State. J. Biol. Chem. [Epub: Ahead of Print]|
|Sucic, S. and L.J. Bryan-Lluka. (2007). Investigation of the functional roles of the MELAL and GQXXRXG motifs of the human noradrenaline transporter using cysteine mutants. Eur J Pharmacol 556: 27-35.|
|Supplisson, S. and M.J. Roux. (2002). Why glycine transporters have different stoichiometries. FEBS Lett. 529: 93-101. |
|Sweeney, C.G., B.P. Tremblay, T. Stockner, H.H. Sitte, and H.E. Melikian. (2016). Dopamine Transporter Amino- and Carboxy-Termini Synergistically Contribute to Substrate and Inhibitor Affinities. J. Biol. Chem. [Epub: Ahead of Print]|
|Szöllősi, D. and T. Stockner. (2021). Investigating the Mechanism of Sodium Binding to SERT Using Direct Simulations. Front Cell Neurosci 15: 673782.|
|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. |
|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.|
|Tavoulari, S., E. Margheritis, A. Nagarajan, D.C. DeWitt, Y.W. Zhang, E. Rosado, S. Ravera, E. Rhoades, L.R. Forrest, and G. Rudnick. (2015). Two Na+ Sites Control Conformational Change in a Neurotransmitter Transporter Homolog. J. Biol. Chem. [Epub: Ahead of Print]|
|Thal, L.B., I.D. Tomlinson, M.A. Quinlan, O. Kovtun, R.D. Blakely, and S.J. Rosenthal. (2018). Single Quantum Dot Imaging Reveals PKCβ-Dependent Alterations in Membrane Diffusion and Clustering of an Attention-Deficit Hyperactivity Disorder/Autism/Bipolar Disorder-Associated Dopamine Transporter Variant. ACS Chem Neurosci. [Epub: Ahead of Print]|
|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.|
|Trotschel C., Follmann M., Nettekoven JA., Mohrbach T., Forrest LR., Burkovski A., Marin K. and Kramer R. (2008). Methionine uptake in Corynebacterium glutamicum by MetQNI and by MetPS, a novel methionine and alanine importer of the NSS neurotransmitter transporter family. Biochemistry. 47(48):12698-709.|
|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.|
|Vandenberg, R.J., K. Shaddick, and P. Ju. (2007). Molecular Basis for Substrate Discrimination by Glycine Transporters. J. Biol. Chem. 282: 14447-14453.|
|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.|
|Walline, C.C., D.E. Nichols, F.I. Carroll, and E.L. Barker. (2008). Comparative molecular field analysis using selectivity fields reveals residues in the third transmembrane helix of the serotonin transporter associated with substrate and antagonist recognition. J Pharmacol Exp Ther 325: 791-800.|
|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.|
|West, M., D. Park, J.R. Dodd, J. Kistler, and D.L. Christie. (2005). Purification and characterization of the creatine transporter expressed at high levels in HEK293 cells. Protein Expr Purif 41: 393-401.|
|Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.|
|Xu, L. and L.Y. Chen. (2021). Association of sigma-1 receptor with dopamine transporter attenuates the binding of methamphetamine via distinct helix-helix interactions. Chem Biol Drug Des. [Epub: Ahead of Print]|
|Xue, W., F. Yang, P. Wang, G. Zheng, Y. Chen, X. Yao, and F. Zhu. (2018). What Contributes to Serotonin-Norepinephrine Reuptake Inhibitors'' Dual-Targeting Mechanism? The Key Role of Transmembrane Domain 6 in Human Serotonin and Norepinephrine Transporters Revealed by Molecular Dynamics Simulation. ACS Chem Neurosci 9: 1128-1140.|
|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. |
|Yan, R., Y. Zhang, Y. Li, L. Xia, Y. Guo, and Q. Zhou. (2020). Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 367: 1444-1448.|
|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.|
|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.|
|Zeppelin, T., L.K. Ladefoged, S. Sinning, X. Periole, and B. Schiøtt. (2018). A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition. PLoS Comput Biol 14: e1005907.|
|Zhang, Y.W. and G. Rudnick. (2006). The cytoplasmic substrate permeation pathway of serotonin transporter.
J. Biol. Chem. 281: 36213-36220. |
|Zhang, Y.W., B.E. Turk, and G. Rudnick. (2016). Control of serotonin transporter phosphorylation by conformational state. Proc. Natl. Acad. Sci. USA 113: E2776-2783.|
|Zhang, Y.W., J. Gesmonde, S. Ramamoorthy, and G. Rudnick. (2007). Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder. J. Neurosci. 27: 10878-10886.|
|Zhang, Y.W., S. Tavoulari, S. Sinning, A.A. Aleksandrova, L.R. Forrest, and G. Rudnick. (2018). Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT. Proc. Natl. Acad. Sci. USA 115: E8854-E8862.|
|Zhao, C. and S.Y. Noskov. (2013). The molecular mechanism of ion-dependent gating in secondary transporters. PLoS Comput Biol 9: e1003296.|
|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.|
|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. |
|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.|
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).
SERT or SLC6A4 of Homo sapiens
Serotonin transporter, Mod-5, of 671 aas and 12 TMSs. Functions in thermotaxis memory behavior (Li et al. 2013).
Mod-5 of Caenorhabditis elegans
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.
SERT of Gallus gallus
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).
SERT of Echinococcus granulosus
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).
SLC6A2 of Homo sapiens
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).
DAT (SLC6A3) of Homo sapiens
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).
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)). ||animals (insects)||OAT of Trichoplusia ni (Q95VZ4) |
The dopamine/norepinephrine transporter (SmDAT) (Larsen et al. 2011).
DAT of Schistosoma mansoni (E9LD23)
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.
Dopamine transporter of Drosophila melanogaster
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).
Snf-10 of Caenorabditis elegans
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).
SerT of Drosophila melanogaster (Fruit fly)
|2.A.22.2.1||Proline:Na+ symporter ||Animals ||Proline transporter of Rattus norvegicus|
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.
SLC6A5 of Homo sapiens
|2.A.22.2.11||Sodium-dependent proline transporter (Solute carrier family 6 member 7)||Animals||SLC6A7 of Homo sapiens|
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).
SLC6A9 of Homo sapiens
Sodium-dependent nutrient amino acid transporter 1 (DmNAAT1)
|Animals||NAAT1 of Drosophila melanogaster |
|2.A.22.2.2||Glycine:Na+ symporter, GlyT1c (glycine/2Na+/1Cl- symporter)||Animals ||Glycine transporter (GlyT1c) of Rattus norvegicus|
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).
SLC6A14 of Homo sapiens
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.)
Neutral amino acid transporter CAATCH1 of Manduca sexta
|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.||Animals||Neutral amino acid transporter KAAT1 of Manduca sexta |
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).
Glycine transporter (GlyT2b) of Mus musculus
Acetylcholine/choline:Na+ symporter, Snf-6 (interacts with dystrophin which determines its localization to the neuromuscular junction) (Kim et al., 2004)
Snf-6 of Caenorhabditis elegans (O76689)
|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)||Animals|
AAT1 of Aedes aegypti (Q6VS78)
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).
Nsd-2 of Bombyx mori (B2ZXL8)
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).
SLC6A12 of Homo sapiens
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).
SLC6A13 of Homo sapiens
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).
SLC6A8 of Homo sapiens
Sodium- and chloride-dependent GABA transporter, Ine (Protein inebriated) (Protein receptor oscillation A)
|Animals||Ine of Drosophila melanogaster |
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).
SLC6A1 of Homo sapiens
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).
SLC6A6 of Homo sapiens
|2.A.22.3.4||Creatine:Na+ symporter ||Animals ||Creatine transporter of Oryctolagus cuniculus|
|2.A.22.3.5||Renal apical membrane creatine:Na2+:Cl- symporter (CRT) (Garcia-Delgado et al., 2007)||Animals ||CRT of Rattus norvegicus (P28570)|
|2.A.22.3.6||γ-aminobutyric acid (GABA):Na+:Cl- symporter GAT-1 (stoichiometry = 1:2:1) (Jiang et al., 2005)||Animals||GAT-1 of Caenorhabditis elegans (AAT02634)|
|2.A.22.3.7||The GABA transporter, GAT4 (single mutations render this transporter C1- independent) (Zomot et al., 2007)||Animals||GABA transporter GAT4 of Mus musculus (Q8BWA7)|
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).
GAT3 of Mus musculus (P31649)
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).
SLC6A11 of Homo sapiens
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).
TnaT of Symbiobacterium thermophilum
|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).|
LeuTAa of Aquifex aeolicus (2A65_A)
|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).|
MetPS of Corynebacterium glutamicum
MetP (563aas; Q8NRL8)
MetS (60aas; Q8NRL9)
|2.A.22.5.1||Hypothetical Na+-dependent permease ||Archaea ||MJ1319 of Methanococcus jannaschii |
|2.A.22.5.2||The 11 TMS Na+-dependent tyrosine transporter, Tyt1 (Quick et al., 2006)||Bacteria||Tyt1 of Fusobacterium nucleatum (Q8RHM5)|
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).
MhsT of Bacillus halodurans
Uncharacterized protein of 427 aas and 12 TMSs.
UP of Thermococcus profundus
Na+-dependent hypotaurine transporter of 454 aas and 11 TMSs (Deutschbauer et al. 2011).
Hypotaurine uptake porter of Shewanella oneidensis
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).
SIT1 of Rattus norvegicus (Q64093)
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.
UP of Aedes albopictus (Asian tiger mosquito)
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).
NSS1 of Plasmodium falciparum
Synaptic vesicle neutral amino acid:Na+ symporter NTT4/XT1/BOAT3 (SLC6A17) (catalyzes uptake of neurotransmitters into presynaptic vesicles (Zaia and Reimer, 2009).
NTT4 of Rattus norvegicus (P31662)
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).
SLC6A19 of Homo sapiens
The neutral amino acid transporter, B0AT3 (Slc6a18); XT2 (55% identical to 2.A.22.6.3)
|Animals||SLC6A18 of Homo sapiens|
|2.A.22.6.5|| solute carrier family 6, member 16||Animals||SLC6A16 of Homo sapiens|
Sodium-dependent vesicular neutral amino acid transporter SLC6A17 (Sodium-dependent neurotransmitter transporter NTT4/BOAT3) (Solute carrier family 6 member 17) (Hägglund et al. 2013).
SLC6A17 of Homo sapiens
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).
SLC6A15 of Homo sapiens
Sodium- and chloride-dependent transporter XTRP3 (Sodium/amino-acid transporter 1) (Solute carrier family 6 member 20) (Transporter rB21A homologue)
SLC6A20 of Homo sapiens
Sea bass amino acid uptake porter, SLC6A19 or B0AT1 of 634 aas. Levels depend on diet (Rimoldi et al. 2015).
SLC6A19 of Dicentrarchus labrax (European seabass) (Morone labrax)
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).
NSS3 of Plasmodium falciparum