Multiple transport modes of the cardiac Na+/Ca2+ exchanger


The cardiac Na+/Ca2+ exchanger1 (NCX1; ref. 2) is a bi-directional Ca2+ transporter that contributes to the electrical activity of the heart3,4. When, and if, Ca2+ is exported or imported depends on the Na+/Ca2+ exchange ratio5. Whereas a ratio of 3:1 (Na+:Ca2+) has been indicated by Ca2+ flux equilibrium studies6, a ratio closer to 4:1 has been indicated by exchange current reversal potentials7,8. Here we show, using an ion-selective electrode technique9 to quantify ion fluxes in giant patches10, that ion flux ratios are approximately 3.2 for maximal transport in either direction. With Na+ and Ca2+ on both sides of the membrane, net current and Ca2+ flux can reverse at different membrane potentials, and inward current can be generated in the absence of cytoplasmic Ca2+, but not Na+. We propose that NCX1 can transport not only 1 Ca2+ or 3 Na+ ions, but also 1 Ca2+ with 1 Na+ ion at a low rate. Therefore, in addition to the major 3:1 transport mode, import of 1 Na+ with 1 Ca2+ defines a Na+-conducting mode that exports 1 Ca2+, and an electroneutral Ca2+ influx mode that exports 3 Na+. The two minor transport modes can potentially determine resting free Ca2+ and background inward current in heart.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: NCX1 ion-flux coupling probed with ISEs within the giant patch pipette.
Figure 2: Reversal potentials of Ca2+ flux and current in a giant cardiac membrane patch.
Figure 3: Refined Na+/Ca2+ exchange model.
Figure 4: Voltage dependence of NCX1 flux coupling.


  1. 1

    Reuter, H. & Seitz, N. The dependence of calcium efflux from cardiac muscle on temperature and external ion composition. J. Physiol. (Lond.) 195, 451–470 (1968)

    CAS  Article  Google Scholar 

  2. 2

    Philipson, K. D. & Nicoll, D. A. Sodium-calcium exchange: a molecular perspective. Annu. Rev. Physiol. 62, 111–133 (2000)

    CAS  Article  Google Scholar 

  3. 3

    Kimura, J., Miyamae, S. & Noma, A. Identification of sodium-calcium exchange current in single ventricular cells of guinea-pig. J. Physiol. (Lond.) 384, 199–222 (1987)

    CAS  Article  Google Scholar 

  4. 4

    Noble, D. The surprising heart: a review of recent progress in cardiac electrophysiology. J. Physiol. (Lond.) 353, 1–50 (1984)

    CAS  Article  Google Scholar 

  5. 5

    Lytton, J., Schnetkamp, P. P. M., Hryshko, L. V. & Blaustein, M. P. Proc. 4th Int. Conf (New York Academy of Science, New York, 2002)

    Google Scholar 

  6. 6

    Reeves, J. P. & Hale, C. C. The stoichiometry of the cardiac sodium-calcium exchange system. J. Biol. Chem. 259, 7733–7739 (1984)

    CAS  PubMed  Google Scholar 

  7. 7

    Fujioka, Y., Komeda, M. & Matsuoka, S. Stoichiometry of Na+-Ca2+ exchange in inside-out patches excised from guinea-pig ventricular myocytes. J. Physiol. (Lond.) 523, 339–351 (2000)

    CAS  Article  Google Scholar 

  8. 8

    Dong, H., Dunn, J. & Lytton, J. Stoichiometry of the cardiac Na+/Ca2+ exchanger NCX1.1 measured in transfected HEK cells. Biophys. J. 82, 1943–1952 (2002)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Smith, P. J. Non-invasive ion probes–tools for measuring transmembrane ion flux. Nature 378, 645–646 (1995)

    ADS  CAS  Article  Google Scholar 

  10. 10

    Kang, T. M., Markin, V. S. & Hilgemann, D. W. Ion fluxes in giant excised cardiac membrane patches detected and quantified with ion-selective microelectrodes. J. Gen. Physiol. 121, 325–348 (2003)

    CAS  Article  Google Scholar 

  11. 11

    DeFelice, L. J. & Galli, A. Fluctuation analysis of norepinephrine and serotonin transporter currents. Methods Enzymol. 296, 578–593 (1998)

    CAS  Article  Google Scholar 

  12. 12

    Mackenzie, B., Loo, D. D. & Wright, E. M. Relationships between Na+/glucose cotransporter (SGLT1) currents and fluxes. J. Membr. Biol. 162, 101–106 (1998)

    CAS  Article  Google Scholar 

  13. 13

    Linck, B. et al. Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am. J. Physiol. 274, C415–C423 (1998)

    CAS  Article  Google Scholar 

  14. 14

    Hilgemann, D. W., Nicoll, D. A. & Philipson, K. D. Charge movement during Na+ translocation by native and cloned cardiac Na+/Ca2+ exchanger. Nature 352, 715–718 (1991)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Hilgemann, D. W. Unitary cardiac Na+, Ca2+ exchange current magnitudes determined from channel-like noise and charge movements of ion transport. Biophys. J. 71, 759–768 (1996)

    ADS  CAS  Article  Google Scholar 

  16. 16

    Robinson, R. A. & Stokes, R. H. Electrolyte solutions (Butterworths, London, 2002)

    Google Scholar 

  17. 17

    Hilgemann, D. W. Regulation and deregulation of cardiac Na+-Ca2+ exchange in giant excised sarcolemmal membrane patches. Nature 344, 242–245 (1990)

    ADS  CAS  Article  Google Scholar 

  18. 18

    Wang, E. et al. Transport properties of the calcium ionophore ETH-129. Biophys. J. 81, 3275–3284 (2001)

    ADS  CAS  Article  Google Scholar 

  19. 19

    Rakowski, R. F., Gadsby, D. C. & De Weer, P. Stoichiometry and voltage dependence of the sodium pump in voltage-clamped, internally dialyzed squid giant axon. J. Gen. Physiol. 93, 903–941 (1989)

    CAS  Article  Google Scholar 

  20. 20

    Reeves, J. P. & Sutko, J. L. Competitive interactions of sodium and calcium with the sodium-calcium exchange system of cardiac sarcolemmal vesicles. J. Biol. Chem. 258, 3178–3182 (1983)

    CAS  PubMed  Google Scholar 

  21. 21

    Matsuoka, S. & Hilgemann, D. W. Steady-state and dynamic properties of cardiac sodium-calcium exchange. Ion and voltage dependencies of the transport cycle. J. Gen. Physiol. 100, 963–1001 (1992)

    CAS  Article  Google Scholar 

  22. 22

    Kang, T. M., Steciuk, M. & Hilgemann, D. W. Sodium-calcium exchange stoichiometry: is the noose tightening? Ann. NY Acad. Sci. 976, 142–151 (2002)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Niggli, E. & Lederer, W. J. Molecular operations of the sodium-calcium exchanger revealed by conformation currents. Nature 349, 621–624 (1991)

    ADS  CAS  Article  Google Scholar 

  24. 24

    Kappl, M. & Hartung, K. Rapid charge translocation by the cardiac Na+-Ca2+ exchanger after a Ca2+ concentration jump. Biophys. J. 71, 2473–2485 (1996)

    ADS  CAS  Article  Google Scholar 

  25. 25

    Cervetto, L., Lagnado, L., Perry, R. J., Robinson, D. W. & McNaughton, P. A. Extrusion of calcium from rod outer segments is driven by both sodium and potassium gradients. Nature 337, 740–743 (1989)

    ADS  CAS  Article  Google Scholar 

  26. 26

    Hinata, M. et al. Stoichiometry of Na+-Ca2+ exchange is 3:1 in guinea-pig ventricular myocytes. J. Physiol. (Lond.) 545, 453–461 (2002)

    CAS  Article  Google Scholar 

  27. 27

    Hilgemann, D. W., Matsuoka, S., Nagel, G. A. & Collins, A. Steady-state and dynamic properties of cardiac sodium-calcium exchange. Sodium-dependent inactivation. J. Gen. Physiol. 100, 905–932 (1992)

    CAS  Article  Google Scholar 

  28. 28

    Hilgemann, D. W. & Lu, C. C. Giant membrane patches: improvements and applications. Methods Enzymol. 293, 267–280 (1998)

    CAS  Article  Google Scholar 

  29. 29

    Hilgemann, D. W. Numerical approximations of sodium-calcium exchange. Prog. Biophys. Mol. Biol. 51, 1–45 (1988)

    CAS  Article  Google Scholar 

Download references


We thank S. Feng and P. Foley for technical assistance; K. Philipson for providing the BHK cell line; L. Hrysko for defining NCX1 IVs with organic NCX1 inhibitors; and A. Ferguson and L. DeFelice for critical comments on the manuscript. This work was supported by an NIH grant to D.W.H. and a Samsung Biomedical Research Institute grant to T.M.K.

Author information



Corresponding author

Correspondence to Donald W. Hilgemann.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kang, T., Hilgemann, D. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature 427, 544–548 (2004).

Download citation

Further reading


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.