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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Dual effect of Na_i⁺ on Ca²⁺ influx through the Na⁺/Ca²⁺ exchanger in dialyzed squid axons. Experimental data confirming the validity of the squid axon kinetic model

¹Laboratorio de Biofísica, Instituto de Investigación Médica Mercedes y Martín Ferreyra, Consejo Nacional de Investigaciones Científicas y Técnicas, Córdoba, Argentina; ²Laboratorio de Fisiología Celular, Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela; and ³Marine Biological Laboratory, Woods Hole, Massachusetts

Submitted 1 August 2007 ; accepted in final form 24 October 2007

We propose a steady-state kinetic model for the squid Na⁺/Ca²⁺ exchanger that differs from other current models of regulation in that it takes into account, within a single kinetic scheme, all ionic [intracellular Ca²⁺ (Ca_i²⁺)-intracellular Na⁺ (Na_i⁺)-intracellular H_i⁺] and metabolic (ATP) regulations of the exchanger in which the Ca_i²⁺-regulatory pathway plays the central role in regulation. Although the integrated ionic-metabolic model predicts all squid steady-state experimental data on exchange regulation, a critical test for the validity of it is the predicted dual effect of Na_i⁺ on steady-state Ca²⁺ influx through the exchanger. To test this prediction, an improved technique for the estimation of isotope fluxes in squid axons was developed, which allows sequential measurements of ion influx and effluxes. With this method, we report here two novel observations of the squid axon Na⁺/Ca²⁺ exchanger. First, at intracellular pH (7.0) and in the absence of MgATP, Na_i⁺ has a dual effect on Ca²⁺ influx: inhibition at low concentrations followed by stimulation at high Na_i⁺ concentrations, reaching levels higher than those seen without Na_i⁺. Second, in the presence of MgATP, the biphasic response to Na_i⁺ disappears and is replaced by a sigmoid activation. Furthermore, the model predicts that Ca²⁺ efflux is monotonically inhibited by Na_i⁺, more pronouncedly without than with MgATP. These results are predicted by the proposed kinetic model. Although not fully applicable to all exchangers, this scheme might provide some insights on expected net Ca²⁺ movements in other tissues under a variety of intracellular ionic and metabolic conditions.

sodium/calcium exchanger