Stoichiometry of the Na+/Ca2+ Exchanger: Models and Implications

We reevaluated the exchange stoichiometry of the Na⁺/Ca²⁺ exchangecurrent by measuring its reversal potential. The exchange currentwas measured from the inside-out macropatch excised from intactsarcolemma of guinea pig ventricular myocytes. This method providesmore accurate control of extracellular and cytoplasmic ion concentrationsand of membrane potential than is possible with a whole-cellclamped preparation. The exchange current was isolated as exchangerinhibitory peptide (XIP)-sensitive current or as cytoplasmicNa⁺- and Ca²⁺-induced current. The reversal potential of theNa⁺/Ca²⁺ exchange current was, for the most part, close to theequilibrium potential of the 4Na⁺:1Ca²⁺ exchange, although ittended to get closer to that of 3Na⁺: 1Ca²⁺ exchange at lowerNa⁺ concentrations. We concluded that the stoichiometry is 4or that it may vary depending on the cytoplasmic Na⁺. The 4Na⁺:1Ca²⁺exchange was further studied with computer modeling. A consecutive4Na⁺:1Ca²⁺ exchange model with two active states and two inactivestates (E2 model) could not well reconstruct the current-voltagerelation of the exchanger. However, a consecutive 4Na⁺:1Ca²⁺exchange model with 10 active states and 2 inactive states (E10model), which included voltage-dependent Na⁺ and Ca²⁺ occlusions,well simulated the current-voltage relation. Implications of4Na⁺:1Ca²⁺ exchange is also discussed.