Na-Ca exchange: stoichiometry and electrogenicity

This review discusses the evidence concerning the stoichiometry of Na-Ca exchange. In particular we consider whether the Na-Ca exchange has been shown to transport more than two Na+ ions per Ca2+ ion and therefore whether it generates an electric current. The first part of this review discusses both direct and indirect evidence concerning the stoichiometry of the exchange and its possible voltage dependence. We find that, although there is some evidence suggesting that more than two Na+ ions may exchange for each Ca2+ ion, most of the available evidence is equivocal and cannot fix the stoichiometry precisely. Furthermore, using a simple and explicit circulating carrier model for the Na-Ca exchange, we show that the effect of membrane potential on the Na-Ca exchange may be considerably more complicated than is generally believed. In particular we find that both electrogenic and electroneutral exchanges will be affected by membrane potential. We therefore conclude that the demonstration of the voltage dependence of the Na-Ca exchange does not necessarily imply that it is electrogenic. Additionally, this analysis shows that, apart from a restricted range near thermodynamic equilibrium, it is impossible to predict either the magnitude or the direction of the effects of membrane potential on the exchange. In the second part of the review we consider whether any known membrane currents may be attributed to Na-Ca exchange. We show, in contrast to previous suggestions, that the Na-Ca exchange can theoretically produce a current that appears to be activated by intracellular Ca and that has a reversal potential. However, the experimental demonstration that a given current is produced by Na-Ca exchange is hampered by the existence of other Ca- and Na-dependent currents. In conclusion, we feel that there is no evidence that allows any particular membrane current to be unambiguously identified with the Na-Ca exchange.