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SLC36 family of proton-coupled amino acid transporters C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Members of the SLC36 family of proton-coupled amino acid transporters are involved in membrane transport of amino acids and derivatives [28-29]. 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 [2,25]. PAT2 is expressed at the apical membrane of the renal proximal tubule [7] and at the plasma-membrane in brown/beige adipocytes [30]. PAT1 and PAT4 are involved in regulation of the mTORC1 pathway [11,27]. More comprehensive lists of substrates can be found within the reviews under Further Reading and in the references [3].
Transporters
Targets of relevance to immunopharmacology are highlighted in blue
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PAT1 (Proton-coupled Amino acid Transporter 1 / SLC36A1) C Show summary »« Hide summary
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PAT2 (Proton-coupled Amino acid Transporter 2 / SLC36A2) C Show summary »« Hide summary
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PAT3 (Proton-coupled Amino acid Transporter 3 / SLC36A3) C Show summary »« Hide summary
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PAT4 (Proton-coupled Amino acid Transporter 4 / SLC36A4) C Show summary »« Hide summary
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Further reading
* Key recommended reading is highlighted with an asterisk
Anderson CM, Thwaites DT. (2010) Hijacking solute carriers for proton-coupled drug transport. Physiology (Bethesda), 25 (6): 364-77. [PMID:21186281]
Bermingham JR, Pennington J. (2004) Organization and expression of the SLC36 cluster of amino acid transporter genes. Mamm Genome, 15 (2): 114-25. [PMID:15058382]
Boll M, Daniel H, Gasnier B. (2004) The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis. Pflugers Arch, 447 (5): 776-9. [PMID:12748860]
Bröer S. (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev, 88 (1): 249-86. [PMID:18195088]
Bröer S. (2008) Apical transporters for neutral amino acids: physiology and pathophysiology. Physiology (Bethesda), 23: 95-103. [PMID:18400692]
* Schiöth HB, Roshanbin S, Hägglund MG, Fredriksson R. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol Aspects Med, 34 (2-3): 571-85. [PMID:23506890]
* Thwaites DT, Anderson CM. (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim Biophys Acta, 1768 (2): 179-97. [PMID:17123464]
Thwaites DT, Anderson CM. (2007) H+-coupled nutrient, micronutrient and drug transporters in the mammalian small intestine. Exp Physiol, 92 (4): 603-19. [PMID:17468205]
* Thwaites DT, Anderson CM. (2011) The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol, 164 (7): 1802-16. [PMID:21501141]
References
1. Abbot EL, Grenade DS, Kennedy DJ, Gatfield KM, 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 (3): 298-306. [PMID:16331283]
2. Agulhon C, Rostaing P, Ravassard P, Sagné C, Triller A, 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 (1): 71-89. [PMID:12761825]
3. Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, 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, 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 (5): 1410-22. [PMID:15521011]
5. Anderson CM, Thwaites DT. (2005) Indirect regulation of the intestinal H+-coupled amino acid transporter hPAT1 (SLC36A1). J Cell Physiol, 204 (2): 604-13. [PMID:15754324]
6. Bermingham Jr JR, Shumas S, Whisenhunt T, Sirkowski EE, O'Connell S, Scherer SS, 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 (23): 10217-31. [PMID:12451123]
7. Bröer S, Bailey CG, Kowalczuk S, Ng C, Vanslambrouck JM, Rodgers H, Auray-Blais C, Cavanaugh JA, Bröer A, Rasko JE. (2008) Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters. J Clin Invest, 118 (12): 3881-92. [PMID:19033659]
8. Chen Z, Kennedy DJ, Wake KA, Zhuang L, Ganapathy V, Thwaites DT. (2003) Structure, tissue expression pattern, and function of the amino acid transporter rat PAT2. Biochem Biophys Res Commun, 304 (4): 747-54. [PMID:12727219]
9. Edwards N, Anderson CM, Gatfield KM, Jevons MP, Ganapathy V, Thwaites DT. (2011) Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2). Biochim Biophys Acta, 1808 (1): 260-70. [PMID:20691150]
10. Edwards N, Anderson CMH, Conlon NJ, Watson AK, Hall RJ, Cheek TR, Embley TM, Thwaites DT. (2018) Resculpting the binding pocket of APC superfamily LeuT-fold amino acid transporters. Cell Mol Life Sci, 75 (5): 921-938. [PMID:29058016]
11. Fan SJ, Goberdhan DCI. (2018) PATs and SNATs: Amino Acid Sensors in Disguise. Front Pharmacol, 9: 640. [PMID:29971004]
12. Fan SJ, Snell C, Turley H, Li JL, McCormick R, Perera SM, Heublein S, Kazi S, Azad A, 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 (23): 3004-15. [PMID:26434594]
13. Fazeli G, Levin-Konigsberg R, Bassik MC, Stigloher C, Wehman AM. (2023) A BORC-dependent molecular pathway for vesiculation of cell corpse phagolysosomes. Curr Biol, 33 (4): 607-621.e7. [PMID:36652947]
14. Foltz M, Boll M, Raschka L, Kottra G, Daniel H. (2004) A novel bifunctionality: PAT1 and PAT2 mediate electrogenic proton/amino acid and electroneutral proton/fatty acid symport. FASEB J, 18 (14): 1758-60. [PMID:15345686]
15. Gan Q, Wang X, Zhang Q, Yin Q, Jian Y, Liu Y, Xuan N, Li J, Zhou J, 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 (8): 2619-2637. [PMID:31235480]
16. Kennedy DJ, Gatfield KM, Winpenny JP, Ganapathy V, Thwaites DT. (2005) Substrate specificity and functional characterisation of the H+/amino acid transporter rat PAT2 (Slc36a2). Br J Pharmacol, 144 (1): 28-41. [PMID:15644866]
17. Larsen M, Holm R, Jensen KG, Brodin B, Nielsen CU. (2009) Intestinal gaboxadol absorption via PAT1 (SLC36A1): modified absorption in vivo following co-administration of L-tryptophan. Br J Pharmacol, 157 (8): 1380-9. [PMID:19594759]
18. Metzner L, Kottra G, Neubert K, Daniel H, Brandsch M. (2005) Serotonin, L-tryptophan, and tryptamine are effective inhibitors of the amino acid transport system PAT1. FASEB J, 19 (11): 1468-73. [PMID:16126914]
19. Murata Y, Yoshida M, Sakamoto N, Morimoto S, Watanabe T, Namba K. (2021) Iron uptake mediated by the plant-derived chelator nicotianamine in the small intestine. J Biol Chem, 296: 100195. [PMID:33334885]
20. Newton H, Wang YF, Camplese L, Mokochinski JB, Kramer HB, Brown AEX, Fets L, Hirabayashi S. (2020) Systemic muscle wasting and coordinated tumour response drive tumourigenesis. Nat Commun, 11 (1): 4653. [PMID:32938923]
21. Nielsen CU, Pedersen M, Müller S, Kæstel T, Bjerg M, Ulaganathan N, Nielsen S, Carlsen KL, Nøhr MK, 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 (1): 354-364. [PMID:32835702]
22. Pillai SM, Meredith D. (2011) SLC36A4 (hPAT4) is a high affinity amino acid transporter when expressed in Xenopus laevis oocytes. J Biol Chem, 286 (4): 2455-60. [PMID:21097500]
23. Roshanbin S, Hellsten SV, Tafreshiha A, Zhu Y, Raine A, Fredriksson R. (2014) PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells. Brain Res, 1557: 12-25. [PMID:24530433]
24. Rubio-Aliaga I, Boll M, Vogt Weisenhorn DM, Foltz M, Kottra G, 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 (4): 2754-60. [PMID:14600155]
25. Sagné C, Agulhon C, Ravassard P, Darmon M, Hamon M, El Mestikawy S, Gasnier B, Giros B. (2001) Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc Natl Acad Sci USA, 98 (13): 7206-11. [PMID:11390972]
26. Schiöth HB, Roshanbin S, Hägglund MG, Fredriksson R. (2013) Evolutionary origin of amino acid transporter families SLC32, SLC36 and SLC38 and physiological, pathological and therapeutic aspects. Mol Aspects Med, 34 (2-3): 571-85. [PMID:23506890]
27. Shang P, Valapala M, Grebe R, Hose S, Ghosh S, Bhutto IA, Handa JT, Lutty GA, Lu L, 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 (2): 349-359. [PMID:28083894]
28. Thwaites DT, Anderson CM. (2007) Deciphering the mechanisms of intestinal imino (and amino) acid transport: the redemption of SLC36A1. Biochim Biophys Acta, 1768 (2): 179-97. [PMID:17123464]
29. Thwaites DT, Anderson CM. (2011) The SLC36 family of proton-coupled amino acid transporters and their potential role in drug transport. Br J Pharmacol, 164 (7): 1802-16. [PMID:21501141]
30. Ussar S, Lee KY, Dankel SN, Boucher J, Haering MF, Kleinridders A, Thomou T, Xue R, Macotela Y, Cypess AM et al.. (2014) ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes. Sci Transl Med, 6 (247): 247ra103. [PMID:25080478]
31. Vastermark A, Wollwage S, Houle ME, Rio R, Saier Jr MH. (2014) Expansion of the APC superfamily of secondary carriers. Proteins, 82 (10): 2797-811. [PMID:25043943]
32. Wang J, Onogi Y, Krueger M, Oeckl J, Karlina R, Singh I, Hauck SM, Feederle R, Li Y, Ussar S. (2022) PAT2 regulates vATPase assembly and lysosomal acidification in brown adipocytes. Mol Metab, 61: 101508. [PMID:35513259]
33. Wreden CC, Johnson J, Tran C, Seal RP, Copenhagen DR, Reimer RJ, 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 (4): 1265-75. [PMID:12598615]
34. Yoshida A, Bu Y, Qie S, Wrangle J, Camp ER, Hazard ES, Hardiman G, de Leeuw R, Knudsen KE, Diehl JA. (2019) SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors. Sci Adv, 5 (9): eaax6352. [PMID:31555743]
NC-IUPHAR subcommittee and family contributors
Subcommittee members:
David T. Thwaites (Chairperson)
Catriona M.H. Anderson |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: Transporters. Br J Pharmacol. 180 Suppl 2:S374-469.
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The SLC36 transporters are part of the Amino Acid Auxin Permease (AAAP) family within the Amino Acid-Polyamine-Organocation (APC) superfamily [26,31]. In neuronal tissues, PAT1 is found predominantly in lysosomal membranes and to a lesser extent on neuronal plasma membranes [2,25,33]. PAT1 acts as a driver of mTORC1 signalling, contributing CDK4/6 inhibitor resistance in melanoma [34]. PAT2 is found in myelinated fibres and in the endoplasmic reticulum in spinal cord and brain [6,24]. In brown adipocytes, PAT2 acts as an extracellular amino acid sensor and regulates lysosomal acidification [32]. PAT4 is found in lysosomes in neurones and the plasma membrane of epithelial cells lining the lateral ventricles [23]. High PAT4 expression is associated with reduced relapse-free survival after colorectal cancer surgery [12]. Inhibition of SLC36 transporters by indole-3-propionic acid suppresses proline-dependent tumour growth in Drosophila melanogaster [20]. In C. elegans, a SLC36 transporter is involved in lysosome reformation pathways [13,15].