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 models of synaptic plasticity, the effect of Pb(+2) on this receptor has been one 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 Sprague-Dawley rats, and binding was measured in 50 mM Tris-acetate with (3)H-MK-801 in the presence of saturating concentrations of glutamate and glycine. The potency of Pb(+2) to inhibit access to the receptor channel (IC(50) = 0.55 microM) was greater than that of Zn(+2) (IC(50) = 1.30 microM). Dissociation of MK-801 from its binding site exhibited two-component kinetics, and both rate constants were significantly slowed in the presence of Pb(+2) or Zn(+2). To directly address the question of whether Pb(+2) inhibited the receptor channel by binding to the Zn(+2) modulatory site, changes in inhibitory potency for the receptor channel were measured when both metals were present. The results demonstrate that multiple levels of Pb(+2) produce a concentration-dependent downward shift of the Zn(+2) inhibition curve, indicating a noncompetitive inhibition of MK-801 binding by Pb(+2) with respect to that of Zn(+2). Moreover, Zn(+2) IC(50) values significantly decreased as a function of increasing Pb(+2) concentrations. Analogous results were obtained when Pb(+2) inhibition curves were determined in the presence of multiple levels of Zn(+2). These findings indicate that the inhibitory properties of free Pb(+2) and Zn(+2) on the NMDA receptor channel are similar in nature but are exerted via independent allosteric binding sites.
Lasley
S M
SM
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria, Illinois, 61656-1649, USA.
Gilbert
M E
ME
D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007854:Lead / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D016291:Dizocilpine Maleate; D015032:Zinc