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The concentrative nucleoside transporter family, SLC28

  • The ABC of Solute Carriers
  • Guest Editor: Matthias A. Hediger
  • Published:
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Abstract

The SLC28 family consists of three subtypes of sodium-dependent, concentrative nucleoside transporters, CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3, respectively), that transport both naturally occurring nucleosides and synthetic nucleoside analogs used in the treatment of various diseases. These subtypes differ in their substrate specificities: CNT1 is pyrimidine-nucleoside preferring, CNT2 is purine-nucleoside preferring, and CNT3 transports both pyrimidine and purine nucleosides. Recent studies have identified key amino acid residues that are determinants of pyrimidine and purine specificity of CNT1 and CNT2. The tissue distributions of the CNTs vary: CNT1 is localized primarily in epithelia, whereas CNT2 and CNT3 have more generalized distributions. Nucleoside transporters in the SLC28 and SLC29 families play critical roles in nucleoside salvage pathways where they mediate the first step of nucleotide biosynthesis. In addition, these transporters work in concert to terminate adenosine signaling. SLC28 family members are crucial determinants of response to a variety of anticancer and antiviral nucleoside analogs, as they modulate the entry of these analogs into target tissues. Further, this family is involved in the absorption and disposition of many nucleoside analogs. Several CNT single nucleoside polymorphisms (SNPs) have been identified, but have yet to be characterized.

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References

  1. Anderson CM, Xiong W, Young JD, Cass CE, Parkinson FE (1996) Demonstration of the existence of mRNAs encoding N1/cif and N2/cit sodium/nucleoside cotransporters in rat brain. Brain Res Mol Brain Res 42:358–361

    Article  CAS  PubMed  Google Scholar 

  2. Belt JA, Marina NM, Phelps DA, Crawford CR (1993) Nucleoside transport in normal and neoplastic cells. Adv Enzyme Regul 33:235–252

    Article  CAS  PubMed  Google Scholar 

  3. Che M, Ortiz DF, Arias IM (1995) Primary structure and functional expression of a cDNA encoding the bile canalicular, purine-specific Na+-nucleoside cotransporter. J Biol Chem 270:13596–13599

    Article  CAS  PubMed  Google Scholar 

  4. Craig JE, Zhang Y, Gallagher MP (1994) Cloning of the nupC gene of Escherichia coli encoding a nucleoside transport system, and identification of an adjacent insertion element, IS 186. Mol Microbiol 11:1159–1168

    CAS  PubMed  Google Scholar 

  5. Del Santo B, Valdes R, Mata J, Felipe A, Casado FJ, Pastor-Anglada M (1998) Differential expression and regulation of nucleoside transport systems in rat liver parenchymal and hepatoma cells. Hepatology 28:1504–1511

    PubMed  Google Scholar 

  6. Dresser MJ, Gerstin KM, Gray AT, Loo DD, Giacomini KM (2000) Electrophysiological analysis of the substrate selectivity of a sodium-coupled nucleoside transporter (rCNT1) expressed in Xenopus laevis oocytes. Drug Metab Dispos 28:1135–1140

    CAS  PubMed  Google Scholar 

  7. Felipe A, Valdes R, Santo B, Lloberas J, Casado J, Pastor-Anglada M (1998) Na+-dependent nucleoside transport in liver: two different isoforms from the same gene family are expressed in liver cells. Biochem J 330:997–1001

    CAS  PubMed  Google Scholar 

  8. Galmarini CM, Mackey JR, Dumontet C (2001) Nucleoside analogues: mechanisms of drug resistance and reversal strategies. Leukemia 15:875–890

    Article  CAS  PubMed  Google Scholar 

  9. Gerstin KM, Dresser MJ, Wang J, Giacomini KM (2000) Molecular cloning of a Na+-dependent nucleoside transporter from rabbit intestine. Pharm Res 17:906–910

    Article  CAS  PubMed  Google Scholar 

  10. Gerstin KM, Dresser MJ, Giacomini KM (2002) Specificity of human and rat orthologs of the concentrative nucleoside transporter, SPNT. Am J Physiol 283:F344–F349

    CAS  Google Scholar 

  11. Gomez-Angelats M, del Santo B, Mercader J, Ferrer-Martinez A, Felipe A, Casado J, Pastor-Anglada M (1996) Hormonal regulation of concentrative nucleoside transport in liver parenchymal cells. Biochem J 313:915–920

    CAS  PubMed  Google Scholar 

  12. Graham KA, Leithoff J, Coe IR, Mowles D, Mackey JR, Young JD, Cass CE (2000) Differential transport of cytosine-containing nucleosides by recombinant human concentrative nucleoside transporter protein hCNT1. Nucleosides Nucleotides Nucleic Acids 19:415–434

    CAS  PubMed  Google Scholar 

  13. Hamilton SR, Yao SY, Ingram JC, Hadden DA, Ritzel MW, Gallagher MP, Henderson PJ, Cass CE, Young JD, Baldwin SA (2001) Subcellular distribution and membrane topology of the mammalian concentrative Na+-nucleoside cotransporter rCNT1. J Biol Chem 276:27981–27988

    Article  CAS  PubMed  Google Scholar 

  14. Huang QQ, Yao SY, Ritzel MW, Paterson AR, Cass CE, Young JD (1994) Cloning and functional expression of a complementary DNA encoding a mammalian nucleoside transport protein. J Biol Chem 269:17757–17760

    CAS  PubMed  Google Scholar 

  15. Jackson EK, Dubey RK (2001) Role of the extracellular cAMP-adenosine pathway in renal physiology. Am J Physiol 281:F597–F612

    CAS  Google Scholar 

  16. Jakobs ES, Paterson AR (1986) Sodium-dependent, concentrative nucleoside transport in cultured intestinal epithelial cells. Biochem Biophys Res Commun 140:1028–1035

    CAS  PubMed  Google Scholar 

  17. Karle JM, Anderson LW, Dietrick DD, Cysyk RL (1980) Determination of serum and plasma uridine levels in mice, rats, and humans by high-pressure liquid chromatography. Anal Biochem 109:41–46

    CAS  PubMed  Google Scholar 

  18. Lai Y, Bakken AH, Unadkat JD (2002) Simultaneous expression of hCNT1-CFP and hENT1-YFP in Madin-Darby canine kidney cells. Localization and vectorial transport studies. J Biol Chem 277:37711–37717

    Article  CAS  PubMed  Google Scholar 

  19. Le Hir M, Dubach UC (1984) Sodium gradient-energized concentrative transport of adenosine in renal brush border vesicles. Pflugers Arch 401:58–63

    PubMed  Google Scholar 

  20. Le Hir M, Dubach UC (1985) Uphill transport of pyrimidine nucleosides in renal brush border vesicles. Pflugers Arch 404:238–243

    PubMed  Google Scholar 

  21. Loewen SK, Ng AM, Yao SY, Cass CE, Baldwin SA, Young JD (1999) Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na+ nucleoside cotransporters hCNT1 and hCNT2. J Biol Chem 274:24475–24484

    Article  CAS  PubMed  Google Scholar 

  22. Lostao MP, Mata JF, Larrayoz IM, Inzillo SM, Casado FJ, Pastor-Anglada M (2000) Electrogenic uptake of nucleosides and nucleoside-derived drugs by the human nucleoside transporter 1 (hCNT1) expressed in Xenopus laevis oocytes. FEBS Lett 481:137–140

    Article  CAS  PubMed  Google Scholar 

  23. Mackey JR, Yao SY, Smith KM, Karpinski E, Baldwin SA, Cass CE, Young JD (1999) Gemcitabine transport in Xenopus oocytes expressing recombinant plasma membrane mammalian nucleoside transporters. J Natl Cancer Inst 91:1876–1881

    Article  CAS  PubMed  Google Scholar 

  24. Mangravite LM, Lipschutz JH, Mostov KE, Giacomini KM (2001) Localization of GFP-tagged concentrative nucleoside transporters in a renal polarized epithelial cell line. Am J Physiol 280:F879–F885

    CAS  Google Scholar 

  25. Mangravite LM, Xiao G, Giacomini KM (2003) Localization of human equilibrative nucleoside transporters, hENT1 and hENT2, in renal epithelial cells. Am J Physiol 284:F902–F910.

    CAS  Google Scholar 

  26. Mata JF, Garcia-Manteiga JM, Lostao MP, Fernandez-Veledo S, Guillen-Gomez E, Larrayoz IM, Lloberas J, Casado FJ, Pastor-Anglada M (2001) Role of the human concentrative nucleoside transporter (hCNT1) in the cytotoxic action of 5′-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol Pharmacol 59:1542–1548

    CAS  PubMed  Google Scholar 

  27. Ngo LY, Patil SD, Unadkat JD (2001) Ontogenic and longitudinal activity of Na+-nucleoside transporters in the human intestine. Am J Physiol 280:G475–G481

    CAS  Google Scholar 

  28. Norholm MH, Dandanell G (2001) Specificity and topology of the Escherichia coli xanthosine permease, a representative of the NHS subfamily of the major facilitator superfamily. J Bacteriol 183:4900–4904

    Article  CAS  PubMed  Google Scholar 

  29. Pastor-Anglada M, Felipe A, Casado FJ, del Santo B, Mata JF, Valdes R (1998) Nucleoside transporters and liver cell growth. Biochem Cell Biol 76:771–777

    Article  CAS  PubMed  Google Scholar 

  30. Pastor-Anglada M, Casado FJ, Valdes R, Mata J, Garcia-Manteiga J, Molina M (2001) Complex regulation of nucleoside transporter expression in epithelial and immune system cells. Mol Membr Biol 18:81–85

    Article  CAS  PubMed  Google Scholar 

  31. Patel DH, Crawford CR, Naeve CW, Belt JA (2000) Cloning, genomic organization and chromosomal localization of the gene encoding the murine sodium-dependent, purine-selective, concentrative nucleoside transporter (CNT2). Gene 242:51–58

    Article  CAS  PubMed  Google Scholar 

  32. Patil SD, Ngo LY, Glue P, Unadkat JD (1998) Intestinal absorption of ribavirin is preferentially mediated by the Na+-nucleoside purine (N1) transporter. Pharm Res 15:950–952

    Article  CAS  PubMed  Google Scholar 

  33. Pennycooke M, Chaudary N, Shuralyova I, Zhang Y, Coe IR (2001) Differential expression of human nucleoside transporters in normal and tumor tissue. Biochem Biophys Res Commun 280:951–995

    Article  CAS  Google Scholar 

  34. Plagemann PG, Aran JM (1990) Characterization of Na+-dependent, active nucleoside transport in rat and mouse peritoneal macrophages, a mouse macrophage cell line and normal rat kidney cells. Biochim Biophys Acta 1028:289–298

    Article  CAS  PubMed  Google Scholar 

  35. Ritzel MW, Yao SY, Huang MY, Elliott JF, Cass CE, Young JD (1997) Molecular cloning and functional expression of cDNAs encoding a human Na+-nucleoside cotransporter (hCNT1). Am J Physiol 272:C707–C714

    CAS  PubMed  Google Scholar 

  36. Ritzel MW, Yao SY, Ng AM, Mackey JR, Cass CE, Young JD (1998) Molecular cloning, functional expression and chromosomal localization of a cDNA encoding a human Na+/nucleoside cotransporter (hCNT2) selective for purine nucleosides and uridine. Mol Membr Biol 15:203–211

    CAS  PubMed  Google Scholar 

  37. Ritzel MW, Ng AM, Yao SY, Graham K, Loewen SK, Smith KM, Ritzel RG, Mowles DA, Carpenter P, Chen XZ, Karpinski E, Hyde RJ, Baldwin SA, Cass CE, Young JD (2001) Molecular identification and characterization of novel human and mouse concentrative Na+-nucleoside cotransporter proteins (hCNT3 and mCNT3) broadly selective for purine and pyrimidine nucleosides (system cib). J Biol Chem 276:2914–2927

    Article  CAS  Google Scholar 

  38. Ruiz-Montasell B, Martinez-Mas JV, Enrich C, Casado FJ, Felipe A, Pastor-Anglada M (1993) Early induction of Na+-dependent uridine uptake in the regenerating rat liver. FEBS Lett 316:85–88

    Article  CAS  PubMed  Google Scholar 

  39. Schaner ME, Wang J, Zhang L, Su SF, Gerstin KM, Giacomini KM (1999) Functional characterization of a human purine-selective, Na+-dependent nucleoside transporter (hSPNT1) in a mammalian expression system. J Pharmacol Exp Ther 289:1487–1491

    CAS  PubMed  Google Scholar 

  40. Schwenk M, Hegazy E, Lopez del Pino V (1984) Uridine uptake by isolated intestinal epithelial cells of guinea pig. Biochim Biophys Acta 805:370–374

    Article  CAS  PubMed  Google Scholar 

  41. Soler AP, Gilliard G, Xiong Y, Knudsen KA, Martin JL, De Suarez CB, Mota Gamboa JD, Mosca W, Zoppi LB (2001) Overexpression of neural cell adhesion molecule in Chagas' myocarditis. Hum Pathol 32:149–155

    Article  CAS  PubMed  Google Scholar 

  42. Soler C, Felipe A, Mata JF, Casado FJ, Celada A, Pastor-Anglada M (1998) Regulation of nucleoside transport by lipopolysaccharide, phorbol esters, and tumor necrosis factor-alpha in human B-lymphocytes. J Biol Chem 273:26939–26945

    Article  CAS  PubMed  Google Scholar 

  43. Spector R (1980) Thymidine accumulation by choroid plexus in vitro. Arch Biochem Biophys 205:85–93

    CAS  PubMed  Google Scholar 

  44. Spector R (1982) Nucleoside transport in choroid plexus: mechanism and specificity. Arch Biochem Biophys 216:693–703

    CAS  PubMed  Google Scholar 

  45. Spector R, Huntoon S (1984) Specificity and sodium dependence of the active nucleoside transport system in choroid plexus. J Neurochem 42:1048–1052

    CAS  PubMed  Google Scholar 

  46. Strauss PR, Sheehan JM, Kashket ER (1976) Membrane transport by murine lymphocytes. I. A rapid sampling technique as applied to the adenosine and thymidine systems. J Exp Med 144:1009–1021

    CAS  PubMed  Google Scholar 

  47. Ungemach FR, Hegner D (1978) Uptake of thymidine into isolated rat hepatocytes. Evidence for two transport systems. Hoppe Seylers Z Physiol Chem 359:845–856

    CAS  PubMed  Google Scholar 

  48. Valdes R, Casado FJ, Pastor-Anglada M (2002) Cell-cycle-dependent regulation of CNT1, a concentrative nucleoside transporter involved in the uptake of cell-cycle-dependent nucleoside-derived anticancer drugs. Biochem Biophys Res Commun 296:575–579

    Article  CAS  PubMed  Google Scholar 

  49. Vijayalakshmi D, Belt JA (1988) Sodium-dependent nucleoside transport in mouse intestinal epithelial cells. Two transport systems with differing substrate specificities. J Biol Chem 263:19419–19423

    CAS  PubMed  Google Scholar 

  50. Wang J, Giacomini KM (1997) Molecular determinants of substrate selectivity in Na+-dependent nucleoside transporters. J Biol Chem 272:28845–28848

    Article  CAS  PubMed  Google Scholar 

  51. Wang J, Giacomini KM (1999) Serine 318 is essential for the pyrimidine selectivity of the N2 Na+-nucleoside transporter. J Biol Chem 274:2298–2302

    Article  CAS  PubMed  Google Scholar 

  52. Wang J, Su SF, Dresser MJ, Schaner ME, Washington CB, Giacomini KM (1997) Na+-dependent purine nucleoside transporter from human kidney: cloning and functional characterization. Am J Physiol 273:F1058–F1065

    CAS  PubMed  Google Scholar 

  53. Wu X, Yuan G, Brett CM, Hui AC, Giacomini KM (1992) Sodium-dependent nucleoside transport in choroid plexus from rabbit. Evidence for a single transporter for purine and pyrimidine nucleosides. J Biol Chem 267:8813–8818

    CAS  PubMed  Google Scholar 

  54. Xiao G, Wang J, Tangen T, Giacomini KM (2001) A novel proton-dependent nucleoside transporter, CeCNT3, from Caenorhabditis elegans. Mol Pharmacol 59:339–348

    CAS  PubMed  Google Scholar 

  55. Yao SY, Ng AM, Sundaram M, Cass CE, Baldwin SA, Young JD (2001) Transport of antiviral 3′-deoxy-nucleoside drugs by recombinant human and rat equilibrative, nitrobenzylthioinosine (NBMPR)-insensitive (ENT2) nucleoside transporter proteins produced in Xenopus oocytes. Mol Membr Biol 18:161–167

    Article  CAS  PubMed  Google Scholar 

  56. Yao SY, Ng AM, Loewen SK, Cass CE, Baldwin SA, Young JD (2002) An ancient prevertebrate Na+-nucleoside cotransporter (hfCNT) from the Pacific hagfish (Eptatretus stouti). Am J Physiol 283:C155–C168

    CAS  Google Scholar 

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Acknowledgements

This work was supported by GM 61390 and GM 42230.

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Authors and Affiliations

  1. Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Ave., S-926, San Francisco, CA 94143-0446, USA

    Jennifer H. Gray, Ryan P. Owen & Kathleen M. Giacomini

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  1. Jennifer H. Gray
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  2. Ryan P. Owen
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  3. Kathleen M. Giacomini
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Correspondence to Kathleen M. Giacomini.

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Gray, J.H., Owen, R.P. & Giacomini, K.M. The concentrative nucleoside transporter family, SLC28. Pflugers Arch - Eur J Physiol 447, 728–734 (2004). https://doi.org/10.1007/s00424-003-1107-y

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  • DOI: https://doi.org/10.1007/s00424-003-1107-y

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