1. Newcastle University, UK

Abstract

Members of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives [29, 30]. The four transporters show variable tissue expression patterns and are expressed in various cell types at the plasma-membrane and in intracellular organelles. PAT1 is expressed at the luminal surface of the small intestine and absorbs amino acids and derivatives [4]. In lysosomes, PAT1 functions as an efflux mechanism for amino acids produced during intralysosomal proteolysis [2, 26]. PAT2 is expressed at the apical membrane of the renal proximal tubule [7] and at the plasma-membrane in brown/beige adipocytes [31]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [12, 28]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references [3].

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [8].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

1. Abbot EL, Grenade DS, Kennedy DJ, Gatfield KM and Thwaites DT. (2006) Vigabatrin transport across the human intestinal epithelial (Caco-2) brush-border membrane is via the H+ -coupled amino-acid transporter hPAT1. Br J Pharmacol 147: 298-306 [PMID:16331283]
2. Agulhon C, Rostaing P, Ravassard P, Sagné C, Triller A and Giros B. (2003) Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study. J Comp Neurol 462: 71-89 [PMID:12761825]
3. Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ and Sharman JL et al.. (2019) THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol 176 Suppl 1: S397-S493 [PMID:31710713]
4. Anderson CM, Grenade DS, Boll M, Foltz M, Wake KA, Kennedy DJ, Munck LK, Miyauchi S, Taylor PM and Campbell FC et al.. (2004) H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat. Gastroenterology 127: 1410-22 [PMID:15521011]
5. Anderson CM and Thwaites DT. (2005) Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). J Cell Physiol 204: 604-13 [PMID:15754324]
6. Bermingham Jr JR, Shumas S, Whisenhunt T, Sirkowski EE, O'Connell S, Scherer SS and Rosenfeld MG. (2002) Identification of genes that are downregulated in the absence of the POU domain transcription factor pou3f1 (Oct-6, Tst-1, SCIP) in sciatic nerve. J Neurosci 22: 10217-31 [PMID:12451123]
7. Bröer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, Auray-Blais C, Cavanaugh JA, Bröer A and Rasko JE. (2008) Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J Clin Invest 118: 3881-92 [PMID:19033659]
8. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
9. Chen Z, Kennedy DJ, Wake KA, Zhuang L, Ganapathy V and Thwaites DT. (2003) Structure, tissue expression pattern, and function of the amino acid transporter rat PAT2. Biochem Biophys Res Commun 304: 747-54 [PMID:12727219]
10. Edwards N, Anderson CM, Gatfield KM, Jevons MP, Ganapathy V and Thwaites DT. (2011) Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2). Biochim Biophys Acta 1808: 260-70 [PMID:20691150]
11. Edwards N, Anderson CMH, Conlon NJ, Watson AK, Hall RJ, Cheek TR, Embley TM and Thwaites DT. (2018) Resculpting the binding pocket of APC superfamily LeuT-fold amino acid transporters. Cell Mol Life Sci 75: 921-938 [PMID:29058016]
12. Fan SJ and Goberdhan DCI. (2018) PATs and SNATs: Amino Acid Sensors in Disguise. Front Pharmacol 9: 640 [PMID:29971004]
13. Fan SJ, Snell C, Turley H, Li JL, McCormick R, Perera SM, Heublein S, Kazi S, Azad A and Wilson C et al.. (2016) PAT4 levels control amino-acid sensitivity of rapamycin-resistant mTORC1 from the Golgi and affect clinical outcome in colorectal cancer. Oncogene 35: 3004-15 [PMID:26434594]
14. Fazeli G, Levin-Konigsberg R, Bassik MC, Stigloher C and Wehman AM. (2023) A BORC-dependent molecular pathway for vesiculation of cell corpse phagolysosomes. Curr Biol 33: 607-621.e7 [PMID:36652947]
15. Foltz M, Boll M, Raschka L, Kottra G and Daniel H. (2004) A novel bifunctionality: PAT1 and PAT2 mediate electrogenic proton/amino acid and electroneutral proton/fatty acid symport. FASEB J 18: 1758-60 [PMID:15345686]
16. Gan Q, Wang X, Zhang Q, Yin Q, Jian Y, Liu Y, Xuan N, Li J, Zhou J and Liu K et al.. (2019) The amino acid transporter SLC-36.1 cooperates with PtdIns3P 5-kinase to control phagocytic lysosome reformation. J Cell Biol 218: 2619-2637 [PMID:31235480]
17. Kennedy DJ, Gatfield KM, Winpenny JP, Ganapathy V and Thwaites DT. (2005) Substrate specificity and functional characterisation of the H+/amino acid transporter rat PAT2 (Slc36a2). Br J Pharmacol 144: 28-41 [PMID:15644866]
18. Larsen M, Holm R, Jensen KG, Brodin B and Nielsen CU. (2009) Intestinal gaboxadol absorption via PAT1 (SLC36A1): modified absorption in vivo following co-administration of L-tryptophan. Br J Pharmacol 157: 1380-9 [PMID:19594759]
19. Metzner L, Kottra G, Neubert K, Daniel H and Brandsch M. (2005) Serotonin, L-tryptophan, and tryptamine are effective inhibitors of the amino acid transport system PAT1. FASEB J 19: 1468-73 [PMID:16126914]
20. Murata Y, Yoshida M, Sakamoto N, Morimoto S, Watanabe T and Namba K. (2021) Iron uptake mediated by the plant-derived chelator nicotianamine in the small intestine. J Biol Chem 296: 100195 [PMID:33334885]
21. Newton H, Wang YF, Camplese L, Mokochinski JB, Kramer HB, Brown AEX, Fets L and Hirabayashi S. (2020) Systemic muscle wasting and coordinated tumour response drive tumourigenesis. Nat Commun 11: 4653 [PMID:32938923]
22. Nielsen CU, Pedersen M, Müller S, Kæstel T, Bjerg M, Ulaganathan N, Nielsen S, Carlsen KL, Nøhr MK and Holm R. (2021) Inhibitory Effects of 17-α-Ethinyl-Estradiol and 17-β-Estradiol on Transport Via the Intestinal Proton-Coupled Amino Acid Transporter (PAT1) Investigated In Vitro and In Vivo. J Pharm Sci 110: 354-364 [PMID:32835702]
23. Pillai SM and Meredith D. (2011) SLC36A4 (hPAT4) is a high affinity amino acid transporter when expressed in Xenopus laevis oocytes. J Biol Chem 286: 2455-60 [PMID:21097500]
24. Roshanbin S, Hellsten SV, Tafreshiha A, Zhu Y, Raine A and Fredriksson R. (2014) PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells. Brain Res 1557: 12-25 [PMID:24530433]
25. Rubio-Aliaga I, Boll M, Vogt Weisenhorn DM, Foltz M, Kottra G and Daniel H. (2004) The proton/amino acid cotransporter PAT2 is expressed in neurons with a different subcellular localization than its paralog PAT1. J Biol Chem 279: 2754-60 [PMID:14600155]
26. Sagné C, Agulhon C, Ravassard P, Darmon M, Hamon M, El Mestikawy S, Gasnier B and Giros B. (2001) Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc Natl Acad Sci USA 98: 7206-11 [PMID:11390972]
27. Schiöth HB, Roshanbin S, Hägglund MG and Fredriksson R. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol Aspects Med 34: 571-85 [PMID:23506890]
28. Shang P, Valapala M, Grebe R, Hose S, Ghosh S, Bhutto IA, Handa JT, Lutty GA, Lu L and Wan J et al.. (2017) The amino acid transporter SLC36A4 regulates the amino acid pool in retinal pigmented epithelial cells and mediates the mechanistic target of rapamycin, complex 1 signaling. Aging Cell 16: 349-359 [PMID:28083894]
29. Thwaites DT and Anderson CM. (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim Biophys Acta 1768: 179-97 [PMID:17123464]
30. Thwaites DT and Anderson CM. (2011) The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol 164: 1802-16 [PMID:21501141]
31. Ussar S, Lee KY, Dankel SN, Boucher J, Haering MF, Kleinridders A, Thomou T, Xue R, Macotela Y and Cypess AM et al.. (2014) ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med 6: 247ra103 [PMID:25080478]
32. Vastermark A, Wollwage S, Houle ME, Rio R and Saier Jr MH. (2014) Expansion of the APC superfamily of secondary carriers. Proteins 82: 2797-811 [PMID:25043943]
33. Wang J, Onogi Y, Krueger M, Oeckl J, Karlina R, Singh I, Hauck SM, Feederle R, Li Y and Ussar S. (2022) PAT2 regulates vATPase assembly and lysosomal acidification in brown adipocytes. Mol Metab 61: 101508 [PMID:35513259]
34. Wreden CC, Johnson J, Tran C, Seal RP, Copenhagen DR, Reimer RJ and Edwards RH. (2003) The H+-coupled electrogenic lysosomal amino acid transporter LYAAT1 localizes to the axon and plasma membrane of hippocampal neurons. J Neurosci 23: 1265-75 [PMID:12598615]
35. Yoshida A, Bu Y, Qie S, Wrangle J, Camp ER, Hazard ES, Hardiman G, de Leeuw R, Knudsen KE and Diehl JA. (2019) SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Sci Adv 5: eaax6352 [PMID:31555743]