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Modulation by permeant ions of Mg²⁺ inhibition of NMDA-activated whole-cell currents in rat cortical neurons

Anqi Qian, Sergei M. Antonov * and Jon W. Johnson

Whole-cell N-methyl-D-aspartate (NMDA)-activated currents were recorded from cultured rat cortical neurons. We report here a powerful effect of changing permeant ion concentrations on the voltage-dependent inhibition by external Mg²⁺ (Mg) of these currents. Internal Cs⁺ (Cs) affected Mg inhibition of the NMDA-activated currents in a voltage-dependent manner. A decrease in Cs concentration ([Cs⁺]_i) from 125 to 8 mM reduced Mg IC₅₀ by 1.4-fold at -105 mV and by 11.5-fold at -15 mV. A decrease in external Na⁺ (Na) concentration ([Na⁺]_o) also reduced Mg IC₅₀. This effect was voltage independent. A decrease in [Na⁺]_o from 140 to 70 mM reduced Mg IC₅₀ by 1.4-fold at -105 mV and by 1.6-fold at -15 mV. Varying external Ca²⁺ (Ca) concentrations ([Ca²⁺]_o) from 0.1 to1 mM did not affect Mg inhibition, even though changing [Ca²⁺]_o in the same range strongly influenced the magnitude of NMDA-activated currents in the absence of Mg. However, increasing [Ca²⁺]_o to higher concentrations (2-20 mM) greatly increased Mg IC₅₀ at hyperpolarized voltages. These data are consistent with a model in which Na and Cs modulate Mg inhibition of NMDA-activated currents by occupying external permeant ion binding sites. The Mg IC₅₀ values reported here are similar to Mg K_D values calculated from previous single-channel measurements of Mg blocking kinetics. This similarity implies that Mg does not affect gating while blocking the channel.

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