Electrogenic Na+/Ca2+-exchange of nerve and muscle cells

The plasma membrane Na+/Ca2+-exchanger is a bi-directional electrogenic (3Na+:1Ca2+) and voltage-sensitive ion transport mechanism, which is mainly responsible for Ca2+-extrusion. The Na+-gradient, required for normal mode operation, is created by the Na+-pump, which is also electrogenic (3Na+:2K+) and voltage-sensitive. The Na+/Ca2+-exchanger operational modes are very similar to those of the Na+-pump, except that the uncoupled flux (Na+-influx or -efflux?) is missing. The reversal potential of the exchanger is around −40 mV; therefore, during the upstroke of the AP it is probably transiently activated, leading to Ca2+-influx. The Na+/Ca2+-exchange is regulated by transported and non-transported external and internal cations, and shows ATPi-, pH- and temperature-dependence. The main problem in determining the role of Na+/Ca2+-exchange in excitation-secretion/contraction coupling is the lack of specific (mode-selective) blockers. During recent years, evidence has been accumulated for co-localisation of the Na+-pump, and the Na+/Ca2+-exchanger and their possible functional interaction in the “restricted” or “fuzzy space.” In cardiac failure, the Na+-pump is down-regulated, while the exchanger is up-regulated. If the exchanger is working in normal mode (Ca2+-extrusion) during most of the cardiac cycle, upregulation of the exchanger may result in SR Ca2+-store depletion and further impairment in contractility. If so, a normal mode selective Na+/Ca2+-exchange inhibitor would be useful therapy for decompensation, and unlike CGs would not increase internal Na+. In peripheral sympathetic nerves, pre-synaptic α2-receptors may regulate not only the VSCCs but possibly the reverse Na+/Ca2+-exchange as well.