Lead inhibits the rat N-methyl-D-aspartate receptor channel by binding to a site distinct from the zinc allosteric site

Due to the importance of the NMDA receptor in cognitive function and in mod els of synaptic plasticity, the effect of Pb+2 on this receptor has been on e focus of attempts to define the bases of Pb-induced cognitive impairments seen in young children, The following study was performed to identify the effects on access to the NMDA receptor channel of acute exposure to free Pb +2 in vitro. Cerebrocortical membranes were prepared from adult male Spragu e-Dawley rats, and binding was measured in 50 mM Tris-acetate with H-3-MK-8 01 in the presence of saturating concentrations of glutamate and glycine, T he potency of Pb+2 to inhibit access to the receptor channel (IC50 0.55 mu M) was greater than that of Zn+2 (IC50 = 1.30 mu M). Dissociation of MK-801 from its binding site exhibited two-component kinetics, and both rate cons tants were significantly slowed in the presence of Pb+2 or Zn+2, To directl y address the question of whether Pb+2 inhibited the receptor channel by bi nding to the Zn+2 modulatory site, changes in inhibitory potency for the re ceptor channel were measured when both metals were present. The results dem onstrate that multiple levels of Pb+2 produce a concentration-dependent dow nward shift of the Zn+2 inhibition curve, indicating a noncompetitive inhib ition of MK-801 binding by Pb+2 With respect to that of Zn+2. Moreover, Zn2 IC50 values significantly decreased as a function of increasing Pb+2 conc entrations. Analogous results were obtained when Pb+2 inhibition curves wer e determined in the presence of multiple levels of Zn+2. These findings ind icate that the inhibitory properties of free Pb+2 and Zn+2 on the NMDA rece ptor channel are similar in nature but are exerted via independent alloster ic binding sites. (C) 1999 Academic Press.