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

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