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

Abstract

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.

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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.

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Acknowledgements

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.

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Correspondence to Donald W. Hilgemann.

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Kang, T., Hilgemann, D. Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature 427, 544–548 (2004). https://doi.org/10.1038/nature02271

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