Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

SLC34

Reference work entry
First Online:
DOI: https://doi.org/10.1007/978-3-319-67199-4_101997
How to cite

Synonyms

 Inorganic phosphate transporter type II (a, b, or c);  NaPi-IIa;  NaPi-IIb;  NaPi-IIc;  NPT2a;  NPT2b;  NPT2c;  Sodium/phosphate cotransporter type 2;  Solute carrier family 34 (sodium phosphate)

Historical Background

Phosphorus is one of the six essential elements for life. Molecules containing anionic phosphate (PO43−) are constituents of genetic material (DNA, RNA) and are an essential building block of phospholipid membranes, bones, and teeth; high-energy phosphate bonds drive cell energetics via ATP/ADP hydrolysis; phosphorylation/dephosphorylation reactions are key events in intracellular signaling, and phosphate acts as an intra- and extracellular pH buffer. In mammals, phosphate is obtained from the diet in the form of inorganic phosphate (Pi) that exists in solution as negatively charged mono- (H2PO4−) and divalent (HPO42−) ions in the physiological pH range. As such Pimust be actively transported “uphill” across the cell membrane from the external medium against...

This is a preview of subscription content, log in to check access.

References

  1. Andrini O, Ghezzi C, Murer H, Forster IC. The leak mode of type II Na(+)-P(i) cotransporters. Channels (Austin). 2008;2(5):346–57.Google Scholar
  2. Andrini O, Meinild AK, Ghezzi C, Murer H, Forster IC. Lithium interactions with Na+-coupled inorganic phosphate cotransporters: insights into the mechanism of sequential cation binding. Am J Phys Cell Phys. 2012;302(3):C539–54.Google Scholar
  3. Bacconi A, Virkki LV, Biber J, Murer H, Forster IC. Renouncing electrogenicity is not free of charge: switching on electrogenicity in a Na+-coupled phosphate cotransporter. Proc Natl Acad Sci U S A. 2005;102:12606–11.PubMedPubMedCentralGoogle Scholar
  4. Bergwitz C, Juppner H. Regulation of phosphate homeostasis by PTH, vitamin D, and FGF23. Annu Rev Med. 2010;61:91–104.PubMedPubMedCentralGoogle Scholar
  5. Dinour D, Davidovits M, Ganon L, Ruminska J, Forster IC, Hernando N, Eyal E, Holtzman EJ, Wagner CA. Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol. 2016;31(12):2289–97.PubMedPubMedCentralGoogle Scholar
  6. Fenollar-Ferrer C, Patti M, Knopfel T, Werner A, Forster IC, Forrest LR. Structural fold and binding sites of the human Na(+)-phosphate cotransporter NaPi-II. Biophys J. 2014;106(6):1268–79.PubMedPubMedCentralGoogle Scholar
  7. Fenollar-Ferrer C, Forster IC, Patti M, Knoepfel T, Werner A, Forrest LR. Identification of the first sodium binding site of the phosphate cotransporter NaPi-IIa (SLC34A1). Biophys J. 2015;108(10):2465–80.PubMedPubMedCentralGoogle Scholar
  8. Forster IC, Loo DD, Eskandari S. Stoichiometry and Na+ binding cooperativity of rat and flounder renal type II Na+-Pi cotransporters. Am J Physiol. 1999;276(4 Pt 2):F644–9.PubMedPubMedCentralGoogle Scholar
  9. Forster IC, Kohler K, Biber J, Murer H. Forging the link between structure and function of electrogenic cotransporters: the renal type IIa Na+/Pi cotransporter as a case study. Prog Biophys Mol Biol. 2002;80(3):69–108.PubMedPubMedCentralGoogle Scholar
  10. Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate: a molecular perspective. Kidney Int. 2006;70(9):1548–59.PubMedPubMedCentralGoogle Scholar
  11. Forster IC, Hernando N, Biber J, Murer H. Phosphate transport kinetics and structure-function relationships of SLC34 and SLC20 proteins. Curr Top Membr. 2012;70:313–56.PubMedPubMedCentralGoogle Scholar
  12. Forster IC, Hernando N, Biber J, Murer H. Phosphate transporters of the SLC20 and SLC34 families. Mol Asp Med. 2013;34(2–3):386–95.Google Scholar
  13. Ghezzi C, Murer H, Forster IC. Substrate interactions of the electroneutral Na+-coupled inorganic phosphate cotransporter (NaPi-IIc). J Physiol. 2009;587(Pt 17):4293–307.PubMedPubMedCentralGoogle Scholar
  14. Giovannini D, Touhami J, Charnet P, Sitbon M, Battini JL. Inorganic phosphate export by the retrovirus receptor XPR1 in metazoans. Cell Rep. 2013;3(6):1866–73.PubMedPubMedCentralGoogle Scholar
  15. Hu MC, Shi M, Zhang J, Pastor J, Nakatani T, Lanske B, Razzaque MS, Rosenblatt KP, Baum MG, Kuro-o M, Moe OW. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 2010;24(9):3438–50.PubMedPubMedCentralGoogle Scholar
  16. Hu MC, Kuro-o M, Moe OW. Renal and extrarenal actions of Klotho. Semin Nephrol. 2013;33(2):118–29.PubMedPubMedCentralGoogle Scholar
  17. Khadeer MA, Tang Z, Tenenhouse HS, Eiden MV, Murer H, Hernando N, Weinman EJ, Chellaiah MA, Gupta A. Na+-dependent phosphate transporters in the murine osteoclast: cellular distribution and protein interactions. Am J Physiol. 2003;284(6):C1633–44.Google Scholar
  18. Kohl B, Wagner CA, Huelseweh B, Busch AE, Werner A. The Na+-phosphate cotransport system (NaPi-II) with a cleaved protein backbone: implications on function and membrane insertion. J Physiol. 1998;508(Pt 2):341–50.PubMedPubMedCentralGoogle Scholar
  19. Kohler K, Forster IC, Lambert G, Biber J, Murer H. The functional unit of the renal type IIa Na+/Pi cotransporter is a monomer. J Biol Chem. 2000;275(34):26113–20.PubMedPubMedCentralGoogle Scholar
  20. Lederer E, Miyamoto K. Clinical consequences of mutations in sodium phosphate cotransporters. Clin J Am Soc Nephrol. 2012;7(7):1179–87.PubMedPubMedCentralGoogle Scholar
  21. Lin K, Rubinfeld B, Zhang C, Firestein R, Harstad E, Roth L, Tsai SP, Schutten M, Xu K, Hristopoulos M, Polakis P. Preclinical development of an anti-NaPi2b (SLC34A2) antibody-drug conjugate as a therapeutic for non-small cell lung and ovarian cancers. Clin Cancer Res. 2015;21(22):5139–50.PubMedPubMedCentralGoogle Scholar
  22. Loghman-Adham M. Use of phosphonocarboxylic acids as inhibitors of sodium-phosphate cotransport. Gen Pharmacol. 1996;27(2):305–12.PubMedPubMedCentralGoogle Scholar
  23. Magagnin S, Werner A, Markovich D, Sorribas V, Stange G, Biber J, Murer H. Expression cloning of human and rat renal cortex Na/Pi cotransport. Proc Natl Acad Sci U S A. 1993;90(13):5979–83.PubMedPubMedCentralGoogle Scholar
  24. Marks J, Debnam ES, Unwin RJ. The role of the gastrointestinal tract in phosphate homeostasis in health and chronic kidney disease. Curr Opin Nephrol Hypertens. 2013;22(4):481–7.PubMedPubMedCentralGoogle Scholar
  25. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption: molecular mechanisms. Physiol Rev. 2000;80(4):1373–409.PubMedPubMedCentralGoogle Scholar
  26. Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human solute carrier transporter superfamilies. Drug Metab Pharmacokinet. 2008;23(1):22–44.PubMedPubMedCentralGoogle Scholar
  27. Patti M, Forster IC. Correlating charge movements with local conformational changes of a na(+)-coupled cotransporter. Biophys J. 2014;106(8):1618–29.PubMedPubMedCentralGoogle Scholar
  28. Patti M, Fenollar-Ferrer C, Werner A, Forrest LR, Forster IC. Cation interactions and membrane potential induce conformational changes in NaPi-IIb. Biophys J. 2016;111(5):973–88.PubMedPubMedCentralGoogle Scholar
  29. Ravera S, Virkki LV, Murer H, Forster IC. Deciphering PiT transport kinetics and substrate specificity using electrophysiology and flux measurements. Am J Phys Cell Phys. 2007;293(2):C606–20.Google Scholar
  30. Schlingmann KP, Ruminska J, Kaufmann M, Dursun I, Patti M, Kranz B, Pronicka E, Ciara E, Akcay T, Bulus D, Cornelissen EA, Gawlik A, Sikora P, Patzer L, Galiano M, Boyadzhiev V, Dumic M, Vivante A, Kleta R, Dekel B, Levtchenko E, Bindels RJ, Rust S, Forster IC, Hernando N, Jones G, Wagner CA, Konrad M. Autosomal-recessive mutations in SLC34A1 encoding sodium-phosphate cotransporter 2A cause idiopathic infantile hypercalcemia. J Am Soc Nephrol. 2016;27(2):604–14.PubMedPubMedCentralGoogle Scholar
  31. Uwai Y, Arima R, Takatsu C, Furuta R, Kawasaki T, Nabekura T. Sodium-phosphate cotransporter mediates reabsorption of lithium in rat kidney. Pharmacol Res. 2014;87:94–8.PubMedPubMedCentralGoogle Scholar
  32. Vergara-Jaque A, Fenollar-Ferrer C, Kaufmann D, Forrest LR. Repeat-swap homology modeling of secondary active transporters: updated protocol and prediction of elevator-type mechanisms. Front Pharmacol. 2015a;6:1–12.Google Scholar
  33. Vergara-Jaque A, Fenollar-Ferrer C, Mulligan C, Mindell JA, Forrest LR. Family resemblances: a common fold for some dimeric ion-coupled secondary transporters. J Gen Physiol. 2015b;146(5):423–34.PubMedPubMedCentralGoogle Scholar
  34. Villa-Bellosta R, Sorribas V. Role of rat sodium/phosphate cotransporters in the cell membrane transport of arsenate. Toxicol Appl Pharmacol. 2008;232(1):125–34.PubMedPubMedCentralGoogle Scholar
  35. Wagner CA, Rubio-Aliaga I, Biber J, Hernando N. Genetic diseases of renal phosphate handling. Nephrol Dial Transplant. 2014;29(Suppl 4):iv45–54.PubMedPubMedCentralGoogle Scholar
  36. Weinstock J. Inhibitors of sodium-dependent phosphate transport. Expert Opin Ther Pat. 2004;14(1):3.Google Scholar
  37. Ye W, Chen C, Gao Y, Zheng ZS, Xu Y, Yun M, Weng HW, Xie D, Ye S, Zhang JX. Overexpression of SLC34A2 is an independent prognostic indicator in bladder cancer and its depletion suppresses tumor growth via decreasing c-Myc expression and transcriptional activity. Cell Death Dis. 2017;8(2):e2581.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Florey Institute for Neuroscience and Mental HealthParkvilleAustralia
  2. 2.Institute for Cell and Molecular BiosciencesUniversity of Newcastle upon TyneNewcastle upon TyneUK