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

The cardiac Na+/Ca2+ exchanger(1) (NCX1; ref. 2) is a bi-directional Ca2+ transporter that contributes to the electrical activity of the heart(3,4). When, and if, Ca2+ is exported or imported depends on the Na+/Ca2+ exchange ratio(5). Whereas a ratio of 3:1 (Na+:Ca2+) has been indicated by Ca2+ flux equilibrium studies(6), a ratio closer to 4:1 has been indicated by exchange current reversal potentials(7,8). Here we show, using an ion-selective electrode technique(9) to quantify ion fluxes in giant patches(10), 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.