The Squid Preparation as a General Model for Ionic and Metabolic Na+/Ca2+ Exchange Interactions

: We propose an integrated kinetic model for the squid nerve Na+/Ca2+ exchanger based on experimental evidences obtained in dialyzed axons. This model satisfactorily explains the interrelationship between ionic (Na+i–H+i–Ca2+i) and metabolic (ATP, phosphoarginine (PA)) regulation of the exchanger. Data in dialyzed axons show that the Cai‐regulatory site located in the large intracellular loop plays a central role in the modulation by ATP by antagonizing the inhibitory Na+i–H+i synergism. We have used the Nao/Nai exchange mode to unequivocally measure the affinity of the Cai‐regulatory site. This allowed us to separate Cai‐regulatory from Cai‐transport sites and to estimate their respective affinities. In this work we show for the first time that under conditions of saturation of the Cai‐regulatory site (10 μM Ca2+i, pHi 8.0), ATP have no effect on the Cai‐transport site. In addition, we have expanded our equilibrium kinetic model of ionic and metabolic interactions to a complete exchange cycle (circular model). This model, in which the Cai‐regulatory site plays a central role, accounts for the decrease in Nai inactivation, at high pHi, high Ca2+i, and MgATP. Furthermore, the model also predicts the net Ca2+ movements across the exchanger based on the exchanger complexes redistribution both during physiological and pathological conditions (ischemia).