Skip to main content

Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family

Abstract

The SLC13 family in humans and other mammals consists of sodium-coupled transporters for anionic substrates: three transporters for dicarboxylates/citrate and two transporters for sulfate. This review will focus on the di- and tricarboxylate transporters: NaDC1 (SLC13A2), NaDC3 (SLC13A3), and NaCT (SLC13A5). The substrates of these transporters are metabolic intermediates of the citric acid cycle, including citrate, succinate, and α-ketoglutarate, which can exert signaling effects through specific receptors or can affect metabolic enzymes directly. The SLC13 transporters are important for regulating plasma, urinary and tissue levels of these metabolites. NaDC1, primarily found on the apical membranes of renal proximal tubule and small intestinal cells, is involved in regulating urinary levels of citrate and plays a role in kidney stone development. NaDC3 has a wider tissue distribution and high substrate affinity compared with NaDC1. NaDC3 participates in drug and xenobiotic excretion through interactions with organic anion transporters. NaCT is primarily a citrate transporter located in the liver and brain, and its activity may regulate metabolic processes. The recent crystal structure of the Vibrio cholerae homolog, VcINDY, provides a new framework for understanding the mechanism of transport in this family. This review summarizes current knowledge of the structure, function, and regulation of the di- and tricarboxylate transporters of the SLC13 family.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Amanzadeh J, Gitomer WL, Zerwekh JE, Preisig PA, Moe OW, Pak CY, Levi M (2003) Effect of high protein diet on stone-forming propensity and bone loss in rats. Kidney Int 64:2142–2149

    CAS  PubMed  Google Scholar 

  2. 2.

    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 58:206–215

    CAS  PubMed  Google Scholar 

  3. 3.

    Bai X, Chen X, Feng Z, Hou K, Zhang P, Fu B, Shi S (2006) Identification of basolateral membrane targeting signal of human sodium-dependent dicarboxylate transporter 3. J Cell Physiol 206:821–830

    CAS  PubMed  Google Scholar 

  4. 4.

    Bai XY, Chen X, Sun AQ, Feng Z, Hou K, Fu B (2007) Membrane topology structure of human high-affinity, sodium-dependent dicarboxylate transporter. FASEB J 21:2409–2417

    CAS  PubMed  Google Scholar 

  5. 5.

    Baric I, Wagner L, Feyh P, Liesert M, Buckel W, Hoffmann GF (1999) Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable-isotope dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis 22:867–881

    CAS  PubMed  Google Scholar 

  6. 6.

    Bento JL, Palmer ND, Zhong M, Roh B, Lewis JP, Wing MR, Pandya H, Freedman BI, Langefeld CD, Rich SS, Bowden DW, Mychaleckyj JC (2008) Heterogeneity in gene loci associated with type 2 diabetes on human chromosome 20q13.1. Genomics 92:226–234

    CAS  PubMed Central  PubMed  Google Scholar 

  7. 7.

    Bergeron MJ, Burzle M, Kovacs G, Simonin A, Hediger MA (2011) Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B. J Biol Chem 286:11242–11253

    CAS  PubMed  Google Scholar 

  8. 8.

    Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer AF, Jordan J, Fromm MF, Konig J, Lieske S, Carmean CM, Frederick DW, Weismann D, Knauf F, Irusta PM, De CR, Helfand SL, Samuel VT, Shulman GI (2011) Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab 14:184–195

    CAS  PubMed Central  PubMed  Google Scholar 

  9. 9.

    Boehmer C, Embark HM, Bauer A, Palmada M, Yun CH, Weinman EJ, Endou H, Cohen P, Lahme S, Bichler KH, Lang F (2004) Stimulation of renal Na+ dicarboxylate cotransporter 1 by Na+/H+ exchanger regulating factor 2, serum and glucocorticoid inducible kinase isoforms, and protein kinase B. Biochem Biophys Res Commun 313:998–1003

    CAS  PubMed  Google Scholar 

  10. 10.

    Brauburger K, Burckhardt G, Burckhardt BC (2011) The sodium-dependent di- and tricarboxylate transporter, NaCT, is not responsible for the uptake of D-, L-2-hydroxyglutarate and 3-hydroxyglutarate into neurons. J Inherit Metab Dis 34:477–482

    CAS  PubMed Central  PubMed  Google Scholar 

  11. 11.

    Brennan TS, Klahr S, Hamm LL (1986) Citrate transport in rabbit nephron. Am J Physiol 251:F683–F689

    CAS  PubMed  Google Scholar 

  12. 12.

    Browne JL, Sanford PA, Smyth DH (1978) Transfer and metabolism of citrate, succinate, α-ketoglutarate and pyruvate by hamster small intestine. Proc R Soc Lond 200:117–135

    CAS  PubMed  Google Scholar 

  13. 13.

    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 13:2628–2638

    CAS  PubMed  Google Scholar 

  14. 14.

    Burckhardt BC, Lorenz J, Kobbe C, Burckhardt G (2005) Substrate specificity of the human renal sodium dicarboxylate cotransporter, hNaDC-3, under voltage-clamp conditions. Am J Physiol Renal Physiol 288:F792–F799

    CAS  PubMed  Google Scholar 

  15. 15.

    Cebotaru V, Kaul S, Devuyst O, Cai H, Racusen L, Guggino WB, Guggino SE (2005) High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Kidney Int 68:642–652

    CAS  PubMed  Google Scholar 

  16. 16.

    Cesquini M, Stoppa GR, Prada PO, Torsoni AS, Romanatto T, Souza A, Saad MJ, Velloso LA, Torsoni MA (2008) Citrate diminishes hypothalamic acetyl-CoA carboxylase phosphorylation and modulates satiety signals and hepatic mechanisms involved in glucose homeostasis in rats. Life Sci 82:1262–1271

    CAS  PubMed  Google Scholar 

  17. 17.

    Chen XZ, Shayakul C, Berger UV, Tian W, Hediger MA (1998) Characterization of rat Na+-dicarboxylate cotransporter. J Biol Chem 273:20972–20981

    CAS  PubMed  Google Scholar 

  18. 18.

    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 103:1159–1168

    CAS  PubMed Central  PubMed  Google Scholar 

  19. 19.

    Correa PR, Kruglov EA, Thompson M, Leite MF, Dranoff JA, Nathanson MH (2007) Succinate is a paracrine signal for liver damage. J Hepatol 47:262–269

    CAS  PubMed Central  PubMed  Google Scholar 

  20. 20.

    Deen PM, Robben JH (2011) Succinate receptors in the kidney. J Am Soc Nephrol 22:1416–1422

    CAS  PubMed  Google Scholar 

  21. 21.

    Di GG, Anzai N, Endou H, Torres AM (2009) Oat5 and NaDC1 protein abundance in kidney and urine after renal ischemic reperfusion injury. J Histochem Cytochem 57:17–27

    Google Scholar 

  22. 22.

    Donowitz M, Singh S, Salahuddin FF, Hogema BM, Chen Y, Gucek M, Cole RN, Ham A, Zachos NC, Kovbasnjuk O, Lapierre LA, Broere N, Goldenring J, deJonge H, Li X (2007) Proteome of murine jejunal brush border membrane vesicles. J Proteome Res 6:4068–4079

    CAS  PubMed  Google Scholar 

  23. 23.

    Etcheverry A, Aubry M, de TM, Vauleon E, Boniface R, Guenot F, Saikali S, Hamlat A, Riffaud L, Menei P, Quillien V, Mosser J (2010) DNA methylation in glioblastoma: impact on gene expression and clinical outcome. BMC Genomics 11:701-

  24. 24.

    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 278:6136–6144

    CAS  PubMed  Google Scholar 

  25. 25.

    Fei YJ, Liu JC, Inoue K, Zhuang L, Miyake K, Miyauchi S, Ganapathy V (2004) Relevance of NAC-2, an Na+-coupled citrate transporter, to life span, body size and fat content in Caenorhabditis elegans. Biochem J 379:191–198

    CAS  PubMed  Google Scholar 

  26. 26.

    Forrest LR, Rudnick G (2009) The rocking bundle: a mechanism for ion-coupled solute flux by symmetrical transporters. Physiology (Bethesda) 24:377–386

    CAS  Google Scholar 

  27. 27.

    Fraenkl SA, Muser J, Groell R, Reinhard G, Orgul S, Flammer J, Goldblum D (2011) Plasma citrate levels as a potential biomarker for glaucoma. J Ocul Pharmacol Ther 27:577–580

    CAS  PubMed  Google Scholar 

  28. 28.

    Gabriels G, Werners A, Mauss S, Greven J (1999) Evidence for differential regulation of renal proximal tubular p-aminohippurate and sodium-dependent dicarboxylate transport. J Pharmacology and Experimental Therapeutics 290:710–715

    CAS  Google Scholar 

  29. 29.

    Ganapathy V, Ganapathy ME, Tiruppathi C, Miyamoto Y, Mahesh VB, Leibach FH (1988) Sodium-gradient-driven, high-affinity, uphill transport of succinate in human placental brush border membrane vesicles. Biochem J 249:179–184

    CAS  PubMed  Google Scholar 

  30. 30.

    George RL, Huang W, Naggar HA, Smith SB, Ganapathy V (2004) Transport of N-acetylaspartate via murine sodium/dicarboxylate cotransporter NaDC3 and expression of this transporter and aspartoacylase II in ocular tissues in mouse. Biochim Biophys Acta 1690:63–69

    CAS  PubMed  Google Scholar 

  31. 31.

    Gopal E, Miyauchi S, Martin PM, Ananth S, Srinivas SR, Smith SB, Prasad PD, Ganapathy V (2007) Expression and functional features of NaCT, a sodium-coupled citrate transporter, in human and rat livers and cell lines. Am J Physiol Gastrointest Liver Physiol 292:G402–G408

    CAS  PubMed  Google Scholar 

  32. 32.

    Griffith DA, Pajor AM (1999) Acidic residues involved in cation and substrate interactions in the Na/dicarboxylate cotransporter, NaDC-1. Biochemistry 38:7524–7531

    CAS  PubMed  Google Scholar 

  33. 33.

    Hagos Y, Burckhardt BC, Larsen A, Mathys C, Gronow T, Bahn A, Wolff NA, Burckhardt G, Steffgen J (2004) Regulation of sodium-dicarboxylate cotransporter-3 from winter flounder kidney by protein kinase C. Am J Physiol Renal Physiol 286:F86–F93

    CAS  PubMed  Google Scholar 

  34. 34.

    Hagos Y, Krick W, Braulke T, Muhlhausen C, Burckhardt G, Burckhardt BC (2008) Organic anion transporters OAT1 and OAT4 mediate the high affinity transport of glutarate derivatives accumulating in patients with glutaric acidurias. Pflugers Arch 457:223–231

    CAS  PubMed  Google Scholar 

  35. 35.

    Hagos Y, Steffgen J, Rizwan AN, Langheit D, Knoll A, Burckhardt G, Burckhardt BC (2006) Functional roles of cationic amino acid residues in the sodium-dicarboxylate cotransporter 3 (NaDC-3) from winter flounder. Am J Physiol Renal Physiol 291:F1224–F1231

    CAS  PubMed  Google Scholar 

  36. 36.

    Hall JA, Pajor AM (2005) Functional characterization of a Na+-coupled dicarboxylate carrier protein from Staphylococcus aureus. J Bacteriol 187:5189–5194

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37.

    Hamm LL (1990) Renal handling of citrate. Kidney Int 38:728–735

    CAS  PubMed  Google Scholar 

  38. 38.

    He W, Miao FJP, Lin DCH, Schwander RT, Wang Z, Gao J, Chen JL, Tian H, Ling L (2004) Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429:188–193

    CAS  PubMed  Google Scholar 

  39. 39.

    Ho HT, Ko BC, Cheung AK, Lam AK, Tam S, Chung SK, Chung SS (2007) Generation and characterization of sodium-dicarboxylate cotransporter-deficient mice. Kidney Int 72:63–71

    CAS  PubMed  Google Scholar 

  40. 40.

    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 295:392–403

    CAS  PubMed  Google Scholar 

  41. 41.

    Inoue K, Fei YJ, Zhuang L, Gopal E, Miyauchi S, Ganapathy V (2004) Functional features and genomic organization of mouse NaCT, a sodium-coupled transporter for tricarboxylic acid cycle intermediates. Biochem J 378:949–957

    CAS  PubMed  Google Scholar 

  42. 42.

    Inoue K, Zhuang L, Ganapathy V (2002) Human Na+-coupled citrate transporter: primary structure, genomic organization, and transport function. Biochem Biophys Res Commun 299:465–471

    CAS  PubMed  Google Scholar 

  43. 43.

    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 277:39469–39476

    CAS  PubMed  Google Scholar 

  44. 44.

    Inoue K, Zhuang L, Maddox DM, Smith SB, Ganapathy V (2003) Human sodium-coupled citrate transporter, the orthologue of Drosophila Indy, as a novel target for lithium action. Biochem J 374:21–26

    CAS  PubMed  Google Scholar 

  45. 45.

    Joshi AD, Pajor AM (2009) Identification of conformationally sensitive amino acids in the Na+/dicarboxylate Symporter (SdcS). Biochemistry 48:3017–3024

    CAS  PubMed Central  PubMed  Google Scholar 

  46. 46.

    Karlin A, Akabas MH (1998) Substituted-cysteine accessibility method. Methods Enzymol 293:123–145

    CAS  PubMed  Google Scholar 

  47. 47.

    Kaufhold M, Schulz K, Breljak D, Gupta S, Henjakovic M, Krick W, Hagos Y, Sabolic I, Burckhardt BC, Burckhardt G (2011) Differential interaction of dicarboxylates with human sodium-dicarboxylate cotransporter 3 and organic anion transporters 1 and 3. Am J Physiol Renal Physiol 301:F1026–F1034

    CAS  PubMed  Google Scholar 

  48. 48.

    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 274:3422–3429

    CAS  PubMed  Google Scholar 

  49. 49.

    Knauf F, Mohebbi N, Teichert C, Herold D, Rogina B, Helfand S, Gollasch M, Luft FC, Aronson PS (2006) The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochem J 397:25–29

    CAS  PubMed  Google Scholar 

  50. 50.

    Knauf F, Rogina B, Jiang Z, Aronson PS, Helfand SL (2002) Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy. Proc Natl Acad Sci U S A 99:14315–14319

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51.

    Krishnamurthy H, Piscitelli CL, Gouaux E (2009) Unlocking the molecular secrets of sodium-coupled transporters. Nature 459:347–355

    CAS  PubMed  Google Scholar 

  52. 52.

    Kushnir MM, Komaromy-Hiller G, Shushan B, Urry FM, Roberts WL (2001) Analysis of dicarboxylic acids by tandem mass spectrometry. High-throughput quantitative measurement of methylmalonic acid in serum, plasma, and urine. Clin Chem 47:1993–2002

    CAS  PubMed  Google Scholar 

  53. 53.

    Lamp J, Keyser B, Koeller DM, Ullrich K, Braulke T, Muhlhausen C (2011) Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J Biol Chem 286:17777–17784

    CAS  PubMed  Google Scholar 

  54. 54.

    Landry GM, Martin S, McMartin KE (2011) Diglycolic acid is the nephrotoxic metabolite in diethylene glycol poisoning inducing necrosis in human proximal tubule cells in vitro. Toxicol Sci 124:35–44

    CAS  PubMed  Google Scholar 

  55. 55.

    Lash LH (2005) Role of glutathione transport processes in kidney function. Toxicol Appl Pharmacol 204:329–342

    CAS  PubMed  Google Scholar 

  56. 56.

    Li B, Lee MS, Lee RS, Donaldson PJ, Lim JC (2012) Characterization of glutathione uptake, synthesis, and efflux pathways in the epithelium and endothelium of the rat cornea. Cornea 31:1304–1312

    PubMed  Google Scholar 

  57. 57.

    Liu W, Hong Q, Bai XY, Fu B, Xie Y, Zhang X, Li J, Shi S, Lv Y, Sun X, Chen X (2010) High-affinity Na(+)-dependent dicarboxylate cotransporter promotes cellular senescence by inhibiting SIRT1. Mech Ageing Dev 131:601–613

    CAS  PubMed  Google Scholar 

  58. 58.

    Liu S, Tang W, Fang J, Ren J, Li H, Xiao Z, Quarles LD (2009) Novel regulators of Fgf23 expression and mineralization in Hyp bone. Mol Endocrinol 23:1505–1518

    CAS  PubMed  Google Scholar 

  59. 59.

    Liu L, Zacchia M, Tian X, Wan L, Sakamoto A, Yanagisawa M, Alpern RJ, Preisig PA (2010) Acid regulation of NaDC-1 requires a functional endothelin B receptor. Kidney Int 78:895–904

    CAS  PubMed  Google Scholar 

  60. 60.

    MacLennan NK, Rahib L, Shin C, Fang Z, Horvath S, Dean J, Liao JC, McCabe ER, Dipple KM (2006) Targeted disruption of glycerol kinase gene in mice: expression analysis in liver shows alterations in network partners related to glycerol kinase activity. Hum Mol Genet 15:405–415

    CAS  PubMed  Google Scholar 

  61. 61.

    Mancusso R, Gregorio GG, Liu Q, Wang DN (2012) Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter. Nature 491:622–627

    CAS  PubMed Central  PubMed  Google Scholar 

  62. 62.

    Markovich D (2012) Sodium–sulfate/carboxylate cotransporters (SLC13). Curr Top Membr 70:239–256

    CAS  PubMed  Google Scholar 

  63. 63.

    Mazurek MP, Prasad PD, Gopal E, Fraser SP, Bolt L, Rizaner N, Palmer CP, Foster CS, Palmieri F, Ganapathy V, Stuhmer W, Djamgoz MB, Mycielska ME (2010) Molecular origin of plasma membrane citrate transporter in human prostate epithelial cells. EMBO Rep 11:431–437

    CAS  PubMed Central  PubMed  Google Scholar 

  64. 64.

    Meinild AK, Loo DD, Pajor AM, Zeuthen T, Wright EM (2000) Water transport by the renal Na+-dicarboxylate cotransporter. Am J Physiol Renal Physiol 278:F777–F783

    CAS  PubMed  Google Scholar 

  65. 65.

    Moe OW, Preisig PA (2006) Dual role of citrate in mammalian urine. Curr Opin Nephrol Hypertens 15:419–424

    CAS  PubMed  Google Scholar 

  66. 66.

    Nicar MJ, Skurla C, Sakhaee K, Pak CYC (1983) Low urinary citrate excretion in nephrolithiasis. Urology 21:8–14

    CAS  PubMed  Google Scholar 

  67. 67.

    Nielsen TT, Sorensen NS (1979) Citrate in plasma and urine during total fasting. Acta Med Scand 205:303–307

    CAS  PubMed  Google Scholar 

  68. 68.

    Nowik M, Lecca MR, Velic A, Rehrauer H, Brandli AW, Wagner CA (2008) Genome-wide gene expression profiling reveals renal genes regulated during metabolic acidosis. Physiol Genomics 32:322–334

    CAS  PubMed  Google Scholar 

  69. 69.

    Ohana E, Shcheynikov N, Moe OW, Muallem S (2013) SLC26A6 and NaDC-1 transporters interact to regulate oxalate and citrate homeostasis. J Am Soc Nephrol 10:1617–1626

    Google Scholar 

  70. 70.

    Oshiro N, Pajor AM (2006) Ala-504 is a determinant of substrate binding affinity in the mouse Na(+)/dicarboxylate cotransporter. Biochim Biophys Acta 1758:781–788

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71.

    Pajor AM (1995) Sequence and functional characterization of a renal sodium/dicarboxylate cotransporter. J Biol Chem 270:5779–5785

    CAS  PubMed  Google Scholar 

  72. 72.

    Pajor AM (2001) Conformationally-sensitive residues in transmembrane domain 9 of the Na+/dicarboxylate cotransporter. J Biol Chem 276:29961–29968

    CAS  PubMed  Google Scholar 

  73. 73.

    Pajor AM (2006) Molecular properties of the SLC13 family of dicarboxylate and sulfate transporters. Pflugers Arch 451:597–605

    CAS  PubMed Central  PubMed  Google Scholar 

  74. 74.

    Pajor AM, Gangula R, Yao N (2001) Cloning and functional characterization of a high-affinity Na+/dicarboxylate cotransporter from mouse brain. Am J Phyiol Cell 280:C1215–C1223

    CAS  Google Scholar 

  75. 75.

    Pajor AM, Hirayama BA, Loo DDF (1998) Sodium and lithium interactions with the Na+/dicarboxylate cotransporter. J Biol Chem 273:18923–18929

    CAS  PubMed  Google Scholar 

  76. 76.

    Pajor AM, Krajewski SJ, Sun N, Gangula R (1999) Cysteine residues in the Na+/dicarboxylate cotransporter, NaDC-1. Biochem J 344:205–209

    CAS  PubMed  Google Scholar 

  77. 77.

    Pajor AM, Randolph KM (2005) Conformationally sensitive residues in extracellular loop 5 of the Na+/dicarboxylate co-transporter. J Biol Chem 280:18728–18735

    CAS  PubMed Central  PubMed  Google Scholar 

  78. 78.

    Pajor AM, Randolph KM (2007) Inhibition of the Na+/dicarboxylate cotransporter by anthranilic acid derivatives. Mol Pharmacol 72:1330–1336

    CAS  PubMed Central  PubMed  Google Scholar 

  79. 79.

    Pajor AM, Sun N (1996) Characterization of the rabbit renal Na+/dicarboxylate cotransporter using anti-fusion protein antibodies. Am J Physiol Cell Physiol 271:C1808–C1816

    CAS  Google Scholar 

  80. 80.

    Pajor AM, Sun N (1996) Functional differences between rabbit and human Na+-dicarboxylate cotransporters, NaDC-1 and hNaDC-1. Am J Physiol Renal Physiol 271:F1093–F1099

    CAS  Google Scholar 

  81. 81.

    Pajor AM, Sun N (1999) Protein kinase C-mediated regulation of the renal Na+/dicarboxylate cotransporter, NaDC-1. Biochim Biophys Acta 77654:1–8

    Google Scholar 

  82. 82.

    Pajor AM, Sun NN (2010) Role of isoleucine-554 in lithium binding by the Na+/dicarboxylate cotransporter NaDC1. Biochemistry 49:8937–8943

    CAS  PubMed Central  PubMed  Google Scholar 

  83. 83.

    Pajor AM, Sun NN (2010) Single nucleotide polymorphisms in the human Na+-dicarboxylate cotransporter affect transport activity and protein expression. Am J Physiol Renal Physiol 299:F704–F711

    CAS  PubMed  Google Scholar 

  84. 84.

    Pajor AM, Sun NN (2013) Non-steroidal anti-inflammatory drugs and other anthranilic acids inhibit the Na+/dicarboxylate symporter from Staphylococcus aureus. Biochemistry 52:2924–2932

    CAS  PubMed  Google Scholar 

  85. 85.

    Pajor AM, Sun NN, Joshi AD, Randolph KM (2011) Transmembrane helix 7 in the Na+/dicarboxylate cotransporter 1 is an outer helix that contains residues critical for function. Biochim Biophys Acta 1808:1454–1461

    CAS  PubMed Central  PubMed  Google Scholar 

  86. 86.

    Prakash S, Cooper G, Singhi S, Saier MH Jr (2003) The ion transporter superfamily. Biochim Biophys Acta 1618:79–92

    CAS  PubMed  Google Scholar 

  87. 87.

    Rogina B, Reenan RA, Nilsen SP, Helfand SL (2000) Extended life-span conferred by cotransporter gene mutations in Drosophila. Science 290:2137–2140

    CAS  PubMed  Google Scholar 

  88. 88.

    Ruderman NB, Saha AK, Vavvas D, Witters LA (1999) Malonyl-CoA, fuel sensing, and insulin resistance. Am J Physiol 276:E1–E18

    CAS  PubMed  Google Scholar 

  89. 89.

    Sadagopan N, Li W, Roberds SL, Major T, Preston GM, Yu Y, Tones MA (2007) Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens 20:1209–1215

    CAS  PubMed  Google Scholar 

  90. 90.

    Sapieha P, Sirinyan M, Hamel D, Zaniolo K, Joyal JS, Cho JH, Honore JC, Kermorvant-Duchemin E, Varma DR, Tremblay S, Leduc M, Rihakova L, Hardy P, Klein WH, Mu X, Mamer O, Lachapelle P, Di PA, Beausejour C, Andelfinger G, Mitchell G, Sennlaub F, Chemtob S (2008) The succinate receptor GPR91 in neurons has a major role in retinal angiogenesis. Nat Med 14:1067–1076

    CAS  PubMed  Google Scholar 

  91. 91.

    Sarvari M, Kallo I, Hrabovszky E, Solymosi N, Toth K, Liko I, Molnar B, Tihanyi K, Liposits Z (2010) Estradiol replacement alters expression of genes related to neurotransmission and immune surveillance in the frontal cortex of middle-aged, ovariectomized rats. Endocrinology 151:3847–3862

    CAS  PubMed  Google Scholar 

  92. 92.

    Sekine T, Cha SH, Hosoyamada M, Kanai Y, Watanabe N, Furuta Y, Fukuda K, Igarishi T, Endou H (1998) Cloning, functional characterization and localization of a rat renal Na+-dicarboxylate cotransporter. Am J Physiol (Renal Fluid Electrolyte Physiol ) 275:F298–F305

    CAS  Google Scholar 

  93. 93.

    Shuprisha A, Lynch RM, Wright SH, Dantzler WH (1999) Real-time assessment of alpha-ketoglutarate effect on organic anion secretion in perfused rabbit proximal tubules. Am J Physiol 277:F513–F523

    CAS  PubMed  Google Scholar 

  94. 94.

    Srisawang P, Chatsudthipong A, Chatsudthipong V (2007) Modulation of succinate transport in Hep G2 cell line by PKC. Biochim Biophys Acta 1768:1378–1388

    CAS  PubMed  Google Scholar 

  95. 95.

    Stellmer F, Keyser B, Burckhardt BC, Koepsell H, Streichert T, Glatzel M, Jabs S, Thiem J, Herdering W, Koeller DM, Goodman SI, Lukacs Z, Ullrich K, Burckhardt G, Braulke T, Muhlhausen C (2007) 3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3. J Mol Med (Berl) 85:763–770

    CAS  Google Scholar 

  96. 96.

    Strickler MA, Hall JA, Gaiko O, Pajor AM (2009) Functional characterization of a Na+-coupled dicarboxylate transporter from Bacillus licheniformis. Biochim Biophys Acta 1788:2489–2496

    CAS  PubMed Central  PubMed  Google Scholar 

  97. 97.

    Strungaru MH, Footz T, Liu Y, Berry FB, Belleau P, Semina EV, Raymond V, Walter MA (2011) PITX2 is involved in stress response in cultured human trabecular meshwork cells through regulation of SLC13A3. Invest Ophthalmol Vis Sci 52:7625–7633

    CAS  PubMed  Google Scholar 

  98. 98.

    Sun QF, Sun QH, Du J, Wang S (2008) Differential gene expression profiles of normal human parotid and submandibular glands. Oral Dis 14:500–509

    PubMed  Google Scholar 

  99. 99.

    Tanner GA (1998) Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease. J Am Soc Nephrol 9:1242–1248

    CAS  PubMed  Google Scholar 

  100. 100.

    Tokonami N, Morla L, Centeno G, Mordasini D, Ramakrishnan SK, Nikolaeva S, Wagner CA, Bonny O, Houillier P, Doucet A, Firsov D (2013) α-Ketoglutarate regulates acid–base balance through an intrarenal paracrine mechanism. J Clin Invest 123:3166–3171

    CAS  PubMed Central  PubMed  Google Scholar 

  101. 101.

    van den Bosch HM, Bunger M, de Groot PJ, van der MJ, Hooiveld GJ, Muller M (2007) Gene expression of transporters and phase I/II metabolic enzymes in murine small intestine during fasting. BMC Genomics 8:267-

  102. 102.

    Vargas SL, Toma I, Kang JJ, Meer EJ, Peti-Peterdi J (2009) Activation of the succinate receptor GPR91 in macula densa cells causes renin release. J Am Soc Nephrol 20:1002–1011

    CAS  PubMed  Google Scholar 

  103. 103.

    Wada M, Shimada A, Fujita T (2006) Functional characterization of Na+-coupled citrate transporter NaC2/NaCT expressed in primary cultures of neurons from mouse cerebral cortex. Brain Res 1081:92–100

    CAS  PubMed  Google Scholar 

  104. 104.

    Wang H, Fei YJ, Kekuda R, Yang-Feng TL, Devoe LD, Leibach FH, Prasad PD, Ganapathy ME (2000) Structure, function and genomic organization of human Na+-dependent high-affinity dicarboxylate transporter. Am J Physiol (Cell Physiol ) 278:C1019–C1030

    CAS  Google Scholar 

  105. 105.

    Wang PY, Neretti N, Whitaker R, Hosier S, Chang C, Lu D, Rogina B, Helfand SL (2009) Long-lived Indy and calorie restriction interact to extend life span. Proc Natl Acad Sci U S A 106:9262–9267

    CAS  PubMed Central  PubMed  Google Scholar 

  106. 106.

    Weerachayaphorn J, Pajor AM (2007) Sodium-dependent extracellular accessibility of Lys-84 in the sodium/dicarboxylate cotransporter. J Biol Chem 282:20213–20220

    CAS  PubMed Central  PubMed  Google Scholar 

  107. 107.

    Weerachayaphorn J, Pajor AM (2008) Threonine-509 is a determinant of apparent affinity for both substrate and cations in the human Na+/dicarboxylate cotransporter. Biochemistry 47:1087–1093

    CAS  PubMed Central  PubMed  Google Scholar 

  108. 108.

    Wolffram S, Unternahrer R, Grenacher B, Scharrer E (1994) Transport of citrate across the brush border and basolateral membrane of rat small intestine. Comp Biochem Physiol 109A:39–52

    CAS  Google Scholar 

  109. 109.

    Wright SH, Kippen I, Klinenberg JR, Wright EM (1980) Specificity of the transport system for tricarboxylic acid cycle intermediates in renal brush borders. J Membrane Biol 57:73–82

    CAS  Google Scholar 

  110. 110.

    Wright EM, Wright SH, Hirayama BA, Kippen I (1982) Interactions between lithium and renal transport of Krebs cycle intermediates. Proc Natl Acad Sci U S A 79:7514–7517

    CAS  PubMed Central  PubMed  Google Scholar 

  111. 111.

    Wright SH, Wunz TM (1987) Succinate and citrate transport in renal basolateral and brush-border membranes. Am J Physiol 253:F432–F439

    CAS  PubMed  Google Scholar 

  112. 112.

    Yao X, Pajor AM (2000) The transport properties of the human renal Na+/dicarboxylate cotransporter under voltage clamp conditions. Am J Physiol (Renal Fluid Electrolyte Physiol) 279:F54–F64

    CAS  Google Scholar 

  113. 113.

    Yodoya E, Wada M, Shimada A, Katsukawa H, Okada N, Yamamoto A, Ganapathy V, Fujita T (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons. J Neurochem 97:162–173

    CAS  PubMed  Google Scholar 

  114. 114.

    Youn JW, Jolkver E, Kramer R, Marin K, Wendisch VF (2008) Identification and characterization of the dicarboxylate uptake system DccT in Corynebacterium glutamicum. J Bacteriol 190:6458–6466

    CAS  PubMed Central  PubMed  Google Scholar 

  115. 115.

    Zhang FF, Pajor AM (2001) Topology of the Na+/dicarboxylate cotransporter: the N-terminus and hydrophilic loop 4 are located intracellularly. Biochim Biophys Acta 1511:80–89

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ana M. Pajor.

Additional information

This article has been submitted as part of the Special Issue on “Sodium-dependent transporters in health and disease.”

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Pajor, A.M. Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family. Pflugers Arch - Eur J Physiol 466, 119–130 (2014). https://doi.org/10.1007/s00424-013-1369-y

Download citation

Keywords

  • Sodium
  • Citrate
  • Succinate
  • Dicarboxylate
  • Transporter
  • Indy
  • DASS
  • NaDC1
  • NaDC3
  • NaCT