Na+ occupancy and Mg2+ block of the N-methyl-D-aspartate receptor channel

Abstract

The effect of extracellular and intracellular Na+ on the single-channel kinetics of Mg2+ block was studied in recombinant NR1-NR2B NMDA receptor channels. Na+ prevents Mg2+ access to its blocking site by occupying two sites in the external portion of the permeation pathway. The occupancy of these sites by intracellular, but not extracellular, Na+ is voltage-dependent. In the absence of competing ions, Mg2+ binds rapidly (>108 M-1s-1, with no membrane potential) to a site that is located 0.60 through the electric field from the extracellular surface. Occupancy of one of the external sites by Na+ may be sufficient to prevent Mg2+ dissociation from the channel back to the extracellular compartment. With no membrane potential; and in the absence of competing ions, the Mg2+ dissociation rate constant is >10 times greater than the Mg2+ permeation rate constant, and the Mg2+ equilibrium dissociation constant is ∼12 μM. Physiological concentrations of extracellular Na+ reduce the Mg2+ association rate constant ∼40-fold but, because of the "lock-in" effect, reduce the Mg2+ equilibrium dissociation constant only ∼18-fold.