The sodium-bicarbonate cotransporter NBCe1 supports glutamine efflux via SNAT3 (SLC38A3) co-expressed in Xenopus oocytes

  • Christina Wendel
  • Holger M. Becker
  • Joachim W. DeitmerEmail author
Cell and Molecular Physiology


The glutamine transporter SNAT3 contributes to the glutamine fluxes in liver, kidney, and brain. We heterologously co-expressed SNAT3 with the electrogenic sodium-bicarbonate cotransporter NBCe1 in Xenopus laevis oocytes and measured cytosolic pH and membrane current in voltage clamp. Because of the increased buffer capacity contributed by the NBCe1 (Becker and Deitmer in J Biol Chem 279:28057–28062, 2004), we hypothesized that this may enhance the proton-coupled glutamine transport via SNAT3 in the presence of CO2/\( \operatorname{HCO} _{3} ^{ - } \). Addition and removal of glutamine activated not only SNAT3 but also NBCe1, as indicated by the increased membrane current. The NBCe1 current during glutamine removal was more than 50% larger than during glutamine addition, suggesting that NBCe1 enhances glutamine efflux rather than glutamine uptake. This was confirmed by radio-labeled glutamine flux measurements; influx of glutamine was significantly decreased, whereas efflux of glutamine was increased when SNAT3 was co-expressed with NBCe1. A model is presented that attempts to explain the role of intracellular pH, bicarbonate transport, and buffering capacity mediated by NBCe1 for uptake and efflux of glutamine via SNAT3.


Membrane transport Acid/base balance Intracellular pH Bicarbonate transport Protons 



We thank Dr. L. Felipe Barros Olmedo for his valuable comments on an earlier version of this manuscript, and we are grateful for the financial support by grants from the Deutsche Forschungsgemeinschaft (DE 231/16-4; GRK 845).


  1. 1.
    Becker HM, Deitmer JW (2004) Voltage dependence of H+ buffering mediated by sodium-bicarbonate cotransport expressed in Xenopus oocytes. J Biol Chem 279:28057–28062PubMedCrossRefGoogle Scholar
  2. 2.
    Becker HM, Bröer S, Deitmer JW (2004) Facilitated lactate transport by MCT1 when coexpressed with the sodium-bicarbonate cotransporter (NBC) in Xenopus oocytes. Biophys J 86:235–247PubMedCrossRefGoogle Scholar
  3. 3.
    Mackenzie B, Erickson JD (2004) Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Eur J Physiol–Pflügers Arch 447:784–795CrossRefGoogle Scholar
  4. 4.
    Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, Edwards R (1999) Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 99:769–780PubMedCrossRefGoogle Scholar
  5. 5.
    Chaudhry FA, Krizaj D, Larsson P, Reimer RJ, Wreden C, Storm-Mathisen J, Copenhagen D, Kavanaugh M, Edwards RH (2001) Coupled and uncoupled proton movement by amino acid transport system N. EMBO J 20:7041–7051PubMedCrossRefGoogle Scholar
  6. 6.
    Fei Y-J, Sugawara M, Nakanishi T, Huang W, Wang H, Prasad PD, Leibach FH, Ganapathy V (2000) Primary structure, genomic organization, and functional and electrogenic characteristics of human system N 1, a Na+- and H+-coupled glutamine transporter. J Biol Chem 275:23707–23717PubMedCrossRefGoogle Scholar
  7. 7.
    Bröer A, Albers A, Setiawan I, Edwards RH, Chaudhry FA, Lang F, Wagner CA, Bröer S (2002) Regulation of the glutamine transporter SN1 by extracellular pH and intracellular sodium ions. J Physiol 539:3–14PubMedCrossRefGoogle Scholar
  8. 8.
    Moret C, Dave MH, Schulz N, Jiang JX, Verrey F, Wagner CA (2007) Regulation of renal amino acid transporters during metabolic acidosis. Am J Physiol Renal Physiol 292:F555–F566PubMedCrossRefGoogle Scholar
  9. 9.
    Deitmer JW, Bröer A, Bröer S (2003) Glutamine efflux from astrocytes is mediated by multiple pathways. J Neurochem 87:127–135PubMedCrossRefGoogle Scholar
  10. 10.
    Mujais SK, Zahid M (1992) Tubular CO2 production from glutamine in the rat: segmental profile and modulation. Ren Physiol Biochem 15:119–128PubMedGoogle Scholar
  11. 11.
    Karinch AM, Lin CM, Wolfgang CL, Pan M, Souba WW (2002) Regulation of expression of the SN1 transporter during renal adaptation to chronic metabolic acidosis in rats. Am J Physiol Renal Physiol 283:F1011–F1019PubMedGoogle Scholar
  12. 12.
    Romero MF (2005) Molecular pathophysiology of SLC4 bicarbonate transporters. Curr Opin Nephrol Hypertens 14:495–501PubMedCrossRefGoogle Scholar
  13. 13.
    Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA–glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653PubMedCrossRefGoogle Scholar
  14. 14.
    Deitmer JW, Rose C (1996) pH regulation and proton signalling by glial cells. Prog Neurobiol 48:73–103PubMedCrossRefGoogle Scholar
  15. 15.
    Deitmer JW, Chesler M (2007) Neuron-glia pH regulation. In: Squire LR (ed) New Encyclopedia of Neuroscience, Elsevier Publishers, Oxford (in press)Google Scholar
  16. 16.
    Choi I, Romero MF, Khandoudi N, Bril A, Boron WE (1999) Cloning and characterization of a human electrogenic Na+-\( \operatorname{HCO} _{3} ^{ - } \) contranporter isoform (hhNBC). Am J Physiol 276:C576–C584PubMedGoogle Scholar
  17. 17.
    Deitmer JW (1991) Electrogenic sodium-dependent bicarbonate secretion by glial cells of the leech central nervous system. J Gen Physiol 98:637–655PubMedCrossRefGoogle Scholar
  18. 18.
    Bröer S, Schneider H-P, Bröer A, Rahman B, Hamprecht B, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333:167–174PubMedGoogle Scholar
  19. 19.
    Becker HM, Deitmer JW (2007) Carbonic anhydrase II increases the activity of the human electrogenic Na+/\( \operatorname{HCO} _{3} ^{ - } \) cotransporter. J Biol Chem 282:13508–13521PubMedCrossRefGoogle Scholar
  20. 20.
    Schneider HP, Bröer S, Bröer A, Deitmer JW (2007) Heterologous expression of the glutamine transporter SNAT3 in Xenopus oocytes is associated with four modes of uncoupled transport. J Biol Chem 282:3788–3798PubMedCrossRefGoogle Scholar
  21. 21.
    Romero MF, Boron WF (1999) Electrogenic Na+/\( \operatorname{HCO} _{3} ^{ - } \) cotransporters: cloning and physiology. Annu Rev Physiol 61:699–723PubMedCrossRefGoogle Scholar
  22. 22.
    Häussinger D (1997) Liver regulation of acid-base balance. Miner Electrolyte Metab 23:249–252PubMedGoogle Scholar
  23. 23.
    Tapiero H, Mathe G, Couvreur P, Tew KD (2002) Glutamine and glutamate. Biomed Pharmacother 56:446–457PubMedCrossRefGoogle Scholar
  24. 24.
    Karinch AM, Lin CM, Meng Q, Pan M, Souba WW (2007) Glucocorticoids have a role in renal cortical expression of the SNAT3 glutamine transporter during chronic metabolic acidosis. Am J Physiol Renal Physiol 292:F448–F455PubMedCrossRefGoogle Scholar
  25. 25.
    Rae C, Hare N, Bubb WA, McEwan SR, Bröer A, McQuillan JA, Balcar VJ, Conigrave AD, Bröer S (2003) Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation. J Neurochem 85:503–514PubMedGoogle Scholar
  26. 26.
    Liang SL, Carlson GC, Coulter DA (2006) Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J Neurosci 26:8537–8548PubMedCrossRefGoogle Scholar
  27. 27.
    Brune T, Fetzer S, Backus KH, Deitmer JW (1994) Evidence for electrogenic sodium-bicarbonate cotransport in cultured rat cerebellar astrocytes. Eur J Physiol–Pflügers Arch 429:64–71CrossRefGoogle Scholar
  28. 28.
    Bevensee MO, Apkon M, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. II. Electrogenic Na/HCO3 cotransport. J Gen Physiol 110:467–483PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Christina Wendel
    • 1
  • Holger M. Becker
    • 1
  • Joachim W. Deitmer
    • 1
    Email author
  1. 1.Abteilung für Allgemeine ZoologieFB BiologieKaiserslauternGermany

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