Pflügers Archiv

, Volume 447, Issue 5, pp 594–602

The SLC13 gene family of sodium sulphate/carboxylate cotransporters

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

Abstract

The SLC13 gene family consist of five sequence-related members that have been identified in a variety of animals, plants, yeast and bacteria. Proteins encoded by these genes are divided into two functionally unrelated groups: the Na+-sulphate (NaS) cotransporters and the Na+-carboxylate (NaC) cotransporters. Members of this family include the renal Na+-dependent inorganic sulphate transporter-1 (NaSi-1, SLC13A1), the Na+-dependent dicarboxylate transporters NaDC-1/SDCT1 (SLC13A2), NaDC-3/SDCT2 (SLC13A3), the sulphate transporter-1 (SUT-1, SLC13A4) and the Na+-coupled citrate transporter (NaCT, SLC13A5). The general characteristics of the SLC13 proteins are that they encode multi-spanning proteins with 8–13 transmembrane domains, have a wide tissue distribution with most being expressed in the epithelial cells of the kidney and the gastrointestinal tract. They are Na+-coupled symporters, DIDS-insensitive, with strong cation preference for Na+, with a Na+:anion coupling ratio of around 3:1 and have a substrate preference for divalent anions, which include tetraoxyanions (for the NaS cotransporters) or Krebs cycle intermediates, including mono-, di-, and tri-carboxylates (for the NaC cotransporters). The purpose of this review is to provide an update on the most recent advances and to summarize the biochemical, physiological and structural aspects of the vertebrate SLC13 gene family.

Keywords

Sulphate Thiosulphate Selenate Proximal tubule Dicarboxylates Succinate Citrate α-Ketoglutarate Hypocitraturia Hyposulphataemia 

References

  1. 1.
    Aruga S, Wehrli S, Kaissling B, Moe OW, Preisig PA, Pajor AM, Alpern RJ (2000) Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney Int 58:206–215CrossRefPubMedGoogle Scholar
  2. 2.
    Bai L, Pajor AM (1997) Expression cloning of NaDC-2, an intestinal Na+- or Li+-dependent dicarboxylate transporter. Am J Physiol 273:G267–G274PubMedGoogle Scholar
  3. 3.
    Beck L, Markovich D (2000) The mouse Na+-sulfate cotransporter gene Nas1. Cloning, tissue distribution, gene structure, chromosomal assignment, and transcriptional regulation by vitamin D. J Biol Chem 275:11880–11890PubMedGoogle Scholar
  4. 4.
    Besseghir K, Roch-Ramel F (1987) Renal excretion of drugs and other xenobiotics. Renal Physiol 10:221–241PubMedGoogle Scholar
  5. 5.
    Burckhardt BC, Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146:95–158PubMedGoogle Scholar
  6. 6.
    Burckhardt BC, Drinkuth B, Menzel C, Konig A, Steffgen J, Wright SH, Burckhardt G (2002) The renal Na+-dependent dicarboxylate transporter, NaDC-3, translocates dimethyl- and disulfhydryl-compounds and contributes to renal heavy metal detoxification. J Am Soc Nephrol 13:2628–2638PubMedGoogle Scholar
  7. 7.
    Busch AE, Waldegger S, Herzer T, Biber J, Markovich D, Murer H, Lang F (1994) Electrogenic cotransport of Na+ and sulfate in Xenopus oocytes expressing the cloned Na+SO4 2− transport protein NaSi-1. J Biol Chem 269:12407–12409PubMedGoogle Scholar
  8. 8.
    Chen X, Tsukaguchi H, Chen XZ, Berger UV, Hediger MA (1999) Molecular and functional analysis of SDCT2, a novel rat sodium-dependent dicarboxylate transporter. J Clin Invest 103:1159–1168PubMedGoogle Scholar
  9. 9.
    Chen XZ, Shayakul C, Berger UV, Tian W, Hediger MA (1998) Characterization of a rat Na+-dicarboxylate cotransporter. J Biol Chem 273:20972–20981CrossRefPubMedGoogle Scholar
  10. 10.
    Dawson P, Markovich D (2002) Regulation of the mouse Nas1 gene by Vitamin D and thyroid hormone. Pflugers Arch 444:353–359CrossRefPubMedGoogle Scholar
  11. 11.
    Dawson PA, Beck L, Markovich D (2003) Hyposulfatemia, growth retardation, reduced fertility and seizures in mice lacking the sodium-sulfate cotransporter, Nas1. Proc Natl Acad Sci USA (In press)Google Scholar
  12. 12.
    Fei YJ, Inoue K, Ganapathy V (2003) Structural and Functional Characteristics of two sodium-coupled dicarboxylate transporters (ceNaDC1 and ceNaDC2) from Caenorhabditis elegans and their relevance to life span. J Biol Chem 278:6136–6144CrossRefPubMedGoogle Scholar
  13. 13.
    Fernandes I, Hampson G, Cahours X, Morin P, Coureau C, Couette S, Prie D, Biber J, Murer H, Friedlander G, Silve C (1997) Abnormal sulfate metabolism in vitamin D-deficient rats. J Clin Invest 100:2196–2203PubMedGoogle Scholar
  14. 14.
    Fernandes I, Laouari D, Tutt P, Hampson G, Friedlander G, Silve C (2001) Sulfate homeostasis, NaSi-1 cotransporter, and SAT-1 exchanger expression in chronic renal failure in rats. Kidney Int 59:210–221PubMedGoogle Scholar
  15. 15.
    Girard JP, Baekkevold ES, Feliu J, Brandtzaeg P, Amalric F (1999) Molecular cloning and functional analysis of SUT-1, a sulfate transporter from human high endothelial venules. Proc Natl Acad Sci USA 96:12772–12777CrossRefPubMedGoogle Scholar
  16. 16.
    Griffith DA, Pajor AM (1999) Acidic residues involved in cation and substrate interactions in the Na+/dicarboxylate cotransporter, NaDC-1. Biochemistry 38:7524–7531CrossRefPubMedGoogle Scholar
  17. 17.
    Huang W, Wang H, Kekuda R, Fei YJ, Friedrich A, Wang J, Conway SJ, Cameron RS, Leibach FH, Ganapathy V (2000) Transport of N-acetylaspartate by the Na+-dependent high-affinity dicarboxylate transporter NaDC3 and its relevance to the expression of the transporter in the brain. J Pharmacol Exp Ther 295:392–403Google Scholar
  18. 18.
    Inoue K, Fei YJ, Huang W, Zhuang L, Chen Z, Ganapathy V (2002) Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates. Biochem J 367:313–319CrossRefPubMedGoogle Scholar
  19. 19.
    Inoue K, Zhuang L, Ganapathy V (2002) Human Na+-coupled citrate transporter: primary structure, genomic organization, and transport function. Biochem Biophys Res Commun 299:465–471CrossRefPubMedGoogle Scholar
  20. 20.
    Inoue K, Zhuang L, Maddox DM, Smith SB, Ganapathy V (2002) Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. J Biol Chem 277:39469–39476CrossRefPubMedGoogle Scholar
  21. 21.
    Kekuda R, Wang H, Huang W, Pajor AM, Leibach FH, Devoe LD, Prasad PD, Ganapathy V (1999) Primary structure and functional characteristics of a mammalian sodium-coupled high affinity dicarboxylate transporter. J Biol Chem 274:3422–3429CrossRefPubMedGoogle Scholar
  22. 22.
    Khatri IA, Kovacs SV, Forstner JF (1996) Cloning of the cDNA for a rat intestinal Na+/dicarboxylate cotransporter reveals partial sequence homology with a rat intestinal mucin. Biochim Biophys Acta 1309:58–62CrossRefPubMedGoogle Scholar
  23. 23.
    Lee A, Markovich D (2003) Cloning and characterization of the human renal Na+-sulfate cotransporter gene (NAS1) promoter. Kidney Int (In press)Google Scholar
  24. 24.
    Lee A, Beck L, Markovich D (2000) The human renal Na+-sulfate cotransporter (SLC13A1; hNaSi-1) cDNA and gene: organization, chromosomal localization and functional characterization. Genomics 70:354–363Google Scholar
  25. 25.
    Leustek T, Saito K (1999) Sulfate transport and assimilation in plants. Plant Physiol 120:637–644PubMedGoogle Scholar
  26. 26.
    Levi M, McDonald LA, Preisig PA, Alpern RJ (1991) Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter. Am J Physiol 261:F767–F773PubMedGoogle Scholar
  27. 27.
    Markovich D (2000) Molecular regulation and membrane trafficking of mammalian renal phosphate and sulphate transporters. Eur J Cell Biol 79:531–538PubMedGoogle Scholar
  28. 28.
    Markovich D (2001) The Physiological roles and regulation of mammalian sulfate transporters. Physiol Rev 81:1499–1534PubMedGoogle Scholar
  29. 29.
    Markovich D, Fogelis T (1999) Ontogeny of renal sulfate transporters: postnatal mRNA and protein expression. Pediatr Nephrol 13:806–811CrossRefPubMedGoogle Scholar
  30. 30.
    Markovich D, Knight D (1998) Renal Na-Si cotransporter NaSi-1 is inhibited by heavy metals. Am J Physiol 274:F283–F289PubMedGoogle Scholar
  31. 31.
    Markovich D, Forgo J, Stange G, Biber J, Murer H (1993) Expression cloning of rat renal Na+/SO4 2− cotransport. Proc Natl Acad Sci USA 90:8073–8077PubMedGoogle Scholar
  32. 32.
    Markovich D, Murer H, Biber J, Sakhaee K, Pak C, Levi M (1998) Dietary sulfate regulates the expression of the renal brush border Na/Si cotransporter NaSi-1. J Am Soc Nephrol 9:1568–1573PubMedGoogle Scholar
  33. 33.
    Markovich D, Wang H, Puttaparthi K, Zajicek H, Rogers T, Murer H, Biber J, Levi M (1999) Chronic K depletion inhibits renal brush border membrane Na/sulfate cotransport. Kidney Int 55:244–251PubMedGoogle Scholar
  34. 34.
    Markovich D, Werner A, Murer H (1999) Expression cloning with Xenopus oocytes. In: Hildebrandt F, Igarashi, P (eds) Techniques in molecular medicine. Springer, Berlin Heidelberg New York, pp 310–318Google Scholar
  35. 35.
    Pajor AM (1995) Sequence and functional characterization of a renal sodium/dicarboxylate cotransporter. J Biol Chem 270:5779–5785PubMedGoogle Scholar
  36. 36.
    Pajor AM (1996) Molecular cloning and functional expression of a sodium-dicarboxylate cotransporter from human kidney. Am J Physiol 270:F642–F648Google Scholar
  37. 37.
    Pajor AM (1999) Sodium-coupled transporters for Krebs cycle intermediates. Annu Rev Physiol 61:663–682CrossRefPubMedGoogle Scholar
  38. 38.
    Pajor AM (2000) Molecular properties of sodium/dicarboxylate cotransporters. J. Membr Biol 175:1–8CrossRefPubMedGoogle Scholar
  39. 39.
    Pajor AM, Sun N (1999) Protein kinase C-mediated regulation of the renal Na+/dicarboxylate cotransporter, NaDC-1. Biochim Biophys Acta 1420:223–230PubMedGoogle Scholar
  40. 40.
    Pajor AM, Sun NN (2000) Molecular cloning, chromosomal organization, and functional characterization of a sodium-dicarboxylate cotransporter from mouse kidney. Am J Physiol 279:F482–F490PubMedGoogle Scholar
  41. 41.
    Pajor AM, Sun N, Bai L, Markovich D, Sule P (1998) The substrate recognition domain in the Na+/dicarboxylate and Na+/sulfate cotransporters is located in the carboxy-terminal portion of the protein. Biochim Biophys Acta 1370:98–106CrossRefPubMedGoogle Scholar
  42. 42.
    Pajor AM, Gangula R, Yao X (2001) Cloning and functional characterization of a high-affinity Na+/dicarboxylate cotransporter from mouse brain. Am J Physiol 280:C1215–C1223PubMedGoogle Scholar
  43. 43.
    Puttaparthi K, Markovich D, Halaihel N, Wilson P, Zajicek HK, Wang H, Biber J, Murer H, Rogers T, Levi M (1999) Metabolic acidosis regulates rat renal Na-Si cotransport activity. Am J Physiol 276:C1398–C1404PubMedGoogle Scholar
  44. 44.
    Sagawa K, DuBois DC, Almon RR, Murer H, Morris ME (1998) Cellular mechanisms of renal adaptation of sodium-dependent sulfate cotransport to altered dietary sulfate in rats. J Pharmacol Exp Ther 287:1056–1062PubMedGoogle Scholar
  45. 45.
    Sagawa K, Murer H, Morris ME (1999) Effect of experimentally induced hypothyroidism on sulfate renal transport in rats. Am J Physiol 276:F164–F171PubMedGoogle Scholar
  46. 46.
    Sagawa K, Darling IM, Murer H, Morris ME (2000) Glucocorticoid-Induced Alterations of Renal Sulfate Transport. J Pharmacol Exp Ther 294:658–663PubMedGoogle Scholar
  47. 47.
    Saier MHJ, Eng BH, Fard S, Garg J, Haggerty DA, Hutchinson WJ, Jack DL, Lai EC, Liu HJ, Nusinew DP, Omar AM, Pao SS, Paulsen IT, Quan JA, Sliwinski M, Tseng TT, Wachi S, Young GB (1999) Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim Biophys Acta 1422:1–56PubMedGoogle Scholar
  48. 48.
    Sekine T, Cha SH, Hosoyamada M, Kanai Y, Watanabe N, Furuta Y, Fukuda K, Igarashi T, Endou H (1998) Cloning, functional characterization, and localization of a rat renal Na+-dicarboxylate transporter. Am J Physiol 275:F298–F305PubMedGoogle Scholar
  49. 49.
    Steffgen J, Burckhardt BC, Langenberg C, Kuhne L, Muller GA, Burckhardt G, Wolff NA (1999) Expression cloning and characterization of a novel sodium-dicarboxylate cotransporter from winter flounder kidney. J Biol Chem 274:20191–20196CrossRefPubMedGoogle Scholar
  50. 50.
    Von Heijne G (1992) Membrane protein structure prediction. Hydrophobicity analysis and the positive-inside rule. J Mol Biol 225:487–494PubMedGoogle Scholar
  51. 51.
    Wang H, Fei YJ, Kekuda R, Yang-Feng TL, Devoe LD, Leibach FH, Prasad PD, Ganapathy V (2000) Structure, function, and genomic organization of human Na+-dependent high-affinity dicarboxylate transporter. Am J Physiol 278:C1019–C1030PubMedGoogle Scholar

Copyright information

© Springer-Verlag  2004

Authors and Affiliations

  1. 1.Department of Physiology and Pharmacology, School of Biomedical SciencesUniversity of QueenslandSt. LuciaAustralia
  2. 2.Institute of PhysiologyUniversity of ZürichZürichSwitzerland

Personalised recommendations