Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel

Abstract

Two electroneutral, Na+-driven HCO-3 transporters, the Na+-driven Cl-/HCO-3 exchanger and the electroneutral Na+/ HCO-3 cotransporter, have crucial roles in regulating intracellular pH in a variety of cells, including cardiac myocytes1,2, vascular smooth-muscle3,4, neurons5 and fibroblasts6; however, it is difficult to distinguish their Cl- dependence in mammalian cells. Here we report the cloning of three variants of an electroneutral Na+/HCO-3 cotransporter, NBCn1, from rat smooth muscle. They are 89–92% identical to a human skeletal muscle clone7, 55–57% identical to the electrogenic NBCs and 33–43% identical to the anion exchangers8. When expressed in Xenopus oocytes, NBCn1-B (which encodes 1,218 amino acids) is electroneutral, Na+-dependent and HCO-3-dependent, but not Cl--dependent. Oocytes injected with low levels of NBCn1-B complementary RNA exhibit a Na+ conductance that 4,4-diisothiocyanatostilbene-2,2′-disulphonate stimulates slowly and irreversibly.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sequence analysis of NBCn1.
Figure 2: Tissue distribution of NBCn1.
Figure 3: Expression of NBCn1-B in Xenopus oocytes.
Figure 4: Oocyte currents in the nominal absence of HCO-3.

Similar content being viewed by others

References

  1. Dart, C. & Vaughan-Jones, R. D. Na+-HCO-3 symport in the sheep cardiac Purkinje fibre. J. Physiol. 451, 365–385 (1992).

    Article  CAS  Google Scholar 

  2. Lagadic-Gossmann, D., Buckler, K. J. & Vaughan-Jones, R. D. Role of bicarbonate in pH recovery from intracellular acidosis in the guinea-pig ventricular myocyte. J. Physiol. 458, 361–384 (1992).

    Article  CAS  Google Scholar 

  3. Aalkjaer, C. & Hughes, A. Chloride and bicarbonate transport in rat resistance arteries. J. Physiol. 436, 57–73 (1991).

    Article  CAS  Google Scholar 

  4. Aickin, C. C. Regulation of intracellular pH in the smooth muscle of guinea-pig ureter: Na+ dependence. J. Physiol. 479, 301–316 (1994).

    Article  CAS  Google Scholar 

  5. Schwiening, C. J. & Boron, W. F. Regulation of intracellular pH in pyramidal neurons from the rat hippocampus by Na+-dependent Cl--HCO-3 exchange. J. Physiol. 475, 59–67 (1994).

    Article  CAS  Google Scholar 

  6. L’Allemain, G., Paris, S. & Pouyssegur, J. Role of a Na+-dependent Cl-/HCO-3 exchange in regulation of intracellular pH in fibroblasts. J. Biol. Chem. 260, 4877–4883 (1985).

    PubMed  Google Scholar 

  7. Pushkin, A. et al. Cloning, tissue distribution, genomic organization, and functional characterization of NBC3, a new member of the sodium bicarbonate cotransporter family. J. Biol. Chem. 274, 16569–16575 (1999).

    Article  CAS  Google Scholar 

  8. Kopito, R. R. & Lodish, H. F. Primary structure and transmembrane orientation of the murine anion exchange protein. Nature 316, 234–238 (1985).

    Article  ADS  CAS  Google Scholar 

  9. Romero, M. F., Hediger, M. A., Boulpaep, E. L. & Boron, W. F. Expression cloning and characterization of a renal electrogenic Na+/HCO-3 cotransporter. Nature 387, 409–413 (1997).

    Article  ADS  CAS  Google Scholar 

  10. Romero, M. F., Fong, P., Berger, U. V., Hediger, M. A. & Boron, W. F. Cloning and functional expression of rNBC, an electrogenic Na+-HCO-3 cotransporter from rat kidney. Am. J. Physiol. 274, F425–F432 (1998).

    Article  CAS  Google Scholar 

  11. Abuladze, N. et al. Molecular cloning, chromosomal localization, tissue distribution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J. Biol. Chem. 273, 17689–17695 (1998).

    Article  CAS  Google Scholar 

  12. Choi, I., Romero, M. F., Khandoudi, N., Bril, A. & Boron, W. F. Cloning and characterization of a human electrogenic Na+-HCO-3 cotransporter isoform (hhNBC). Am. J. Physiol. 276, C576–C584 (1999).

    Article  CAS  Google Scholar 

  13. Kudrycki, K. E., Newman, P. R. & Shull, G. E. cDNA cloning and tissue distribution of mRNAs for two proteins that are related to the Band 3 Cl-HCO3 exchanger. J. Biol. Chem. 265, 462–471 (1990).

    CAS  PubMed  Google Scholar 

  14. Zhao, J., Hogan, E. M., Bevensee, M. O. & Boron, W. F. Out-of-equilibrium CO2/HCO-3 solutions and their use in characterizing a new K/HCO3 cotransporter. Nature 374, 636–639 (1995).

    Article  ADS  CAS  Google Scholar 

  15. Cabantchik, Z. I., Knauf, P. A. & Rothstein, A. The anion transport system of the red blood cell. The role of membrane protein evaluated by the use of ‘probes’. Biochim. Biophys. Acta 515, 239–302 (1978).

    Article  CAS  Google Scholar 

  16. Wadiche, J. I., Amara, S. G. & Kavanaugh, M. P. Ion fluxes associated with excitatory amino acid transport. Neuron 15, 721–728 (1995).

    Article  CAS  Google Scholar 

  17. Tzounopoulos, T., Maylie, J. & Adelman, J. P. Induction of endogenous channels by high levels of heterologous membrane proteins in Xenopus oocytes. Biophys. J. 69, 904–908 (1995).

    Article  ADS  CAS  Google Scholar 

  18. Bielfeld-Ackermann, A., Range, C. & Korbmacher, C. Maitotoxin (MTX) activates a nonselective cation channel in Xenopus laevis oocytes. Pflügers Arch. 436, 329–337 (1998).

    CAS  PubMed  Google Scholar 

  19. Orchard, C. H. & Kentish, J. C. Effects of changes of pH on the contractile function of cardiac muscle. Am. J. Physiol. 258, C967–C981 (1990).

    Article  CAS  Google Scholar 

  20. Aalkjaer, C. & Poston, L. Effects of pH on vascular tension: which are the important mechanisms? J. Vasc. Res. 33, 347–359 (1996).

    Article  CAS  Google Scholar 

  21. Smith, G. L., Austin, C., Crichton, C. & Wray, S. A review of the actions and control of intracellular pH in vascular smooth muscle. Cardiovasc. Res. 38, 316–331 (1998).

    Article  CAS  Google Scholar 

  22. Yu, M., Sandmann, S. & Unger, T. Angiotensin AT2 receptor mediates expression of Na+-HCO-3 symporter in rat myocardium after experimental myocardial infarction. Hypertension 32, 807 (1998).

    Article  Google Scholar 

  23. Sambrook, J., Fritsch, E. F., Maniatis, T. Molecular Cloning: a Laboratory Manual 2nd edn (Cold Spring Harbor Press, Cold Spring Harbor, 1989).

    Google Scholar 

  24. Trudeau, M. C., Warmke, J. W., Ganetzky, B. & Robertson, G. A. HERG, a human inward rectifier on the voltage-gated potassium channel family. Science 269, 92–95 (1995).

    Article  ADS  CAS  Google Scholar 

  25. Siebens, A. W. & Boron, W. F. Effect of electroneutral luminal and basolateral lactate transport on intracellular pH in salamander proximal tubules. J. Gen. Physiol. 90, 799–831 (1987).

    Article  CAS  Google Scholar 

  26. Kopito, R. R. et al. Regulation of intracellular pH by a neuronal homolog of the erythrocyte anion exchanger. Cell 59, 927–937 (1989).

    Article  CAS  Google Scholar 

  27. Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N. & Sheng, M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378, 85–88 (1995).

    Article  ADS  CAS  Google Scholar 

  28. Short, D. B. et al. An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton. J. Biol. Chem. 273, 19797–19801 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank B. Schmitt, M. Bevensee and M. Romero for valuable discussions. We also thank D. Wong for computer support. This work was supported by NIH grants (W.F.B.) and by the Danish Council (C.A.). I.C. was supported by a postdoctoral fellowship form the American Heart Association.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Walter F. Boron.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choi, I., Aalkjaer, C., Boulpaep, E. et al. An electroneutral sodium/bicarbonate cotransporter NBCn1 and associated sodium channel. Nature 405, 571–575 (2000). https://doi.org/10.1038/35014615

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35014615

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing