In the squid axon Na+/Ca2+ exchanger the state of the Ca i-regulatory site influences the affinities of the intra- and extracellular transport sites for Na+ and Ca2+.

In squid axons, intracellular Mg2+ reduces the activity of the Na+/Ca2+ exchanger by competing with Ca2+ i for its regulatory site. The state of the Ca i-regulatory site (active-inactive) also alters the apparent affinity of intra- and extracellular transport sites. Conditions that hinder the binding of Ca2+ i (low pH i, low [Ca2+]i, high [Mg2+]i) diminish the apparent affinity of intracellular transport sites, in particular for Na i due to its synergism with H+ inhibition, but less noticeably for Ca2+ i because of its antagonism towards (Ha i + Na+ i) and Mg2+ i inhibitions. These are kinetic effects unrelated to the true affinity of the sites. With the Ca i-regulatory site saturated, the intracellular transporting sites are insensitive to [H+]i and to ATP. Likewise, the state of the Ca i-regulatory site (activated or inactivated) influences the affinity of the extracellular Ca o and Na o-transport sites (trans effects). In this case, the effects are opposite to those predicted by any of the transport schemes proposed for the Na+/Ca2+exchanger; i.e. its mechanism remains unexplained. In addition to their intrinsic importance for a full understanding of the properties of the Na+/Ca2+ exchanger, these findings show a new way by which the state of the Ca i-regulatory site may determine net movements of Ca2+ through this system.