Stoichiometry of the Na+/Ca2+ exchanger: models and implications

We reevaluated the exchange stoichiometry of the Na(+)/Ca(2+) exchange current by measuring its reversal potential. The exchange current was measured from the inside-out macropatch excised from intact sarcolemma of guinea pig ventricular myocytes. This method provides more accurate control of extracellular and cytoplasmic ion concentrations and of membrane potential than is possible with a whole-cell clamped preparation. The exchange current was isolated as exchanger inhibitory peptide (XIP)-sensitive current or as cytoplasmic Na(+)- and Ca(2+)-induced current. The reversal potential of the Na(+)/Ca(2+) exchange current was, for the most part, close to the equilibrium potential of the 4Na(+):1Ca(2+) exchange, although it tended to get closer to that of 3Na(+): 1Ca(2+) exchange at lower Na(+) concentrations. We concluded that the stoichiometry is 4 or that it may vary depending on the cytoplasmic Na(+). The 4Na(+):1Ca(2+) exchange was further studied with computer modeling. A consecutive 4Na(+):1Ca(2+) exchange model with two active states and two inactive states (E2 model) could not well reconstruct the current-voltage relation of the exchanger. However, a consecutive 4Na(+):1Ca(2+) exchange model with 10 active states and 2 inactive states (E10 model), which included voltage-dependent Na(+) and Ca(2+) occlusions, well simulated the current-voltage relation. Implications of 4Na(+):1Ca(2+) exchange is also discussed.