Lead Inhibits the Rat N-Methyl-d-Aspartate Receptor Channel by Binding to a Site Distinct from the Zinc Allosteric Site

Authors: Lasley S.M.^{1, 3}; Gilbert M.E.^{2, 3}

Source: Toxicology and Applied Pharmacology, Volume 159, Number 3, September 1999 , pp. 224-233(10)

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Abstract:

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 ³H-MK-801 in the presence of saturating concentrations of glutamate and glycine. The potency of Pb⁺² to inhibit access to the receptor channel (IC₅₀ = 0.55 M) was greater than that of Zn⁺² (IC₅₀ = 1.30 M). 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 IC₅₀ 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. Copyright 1999 Academic Press.

Language: English

Document Type: Research article

Affiliations: 1: Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria, Illinois, 61656-1649 2: Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711 3: Department of Psychology, University of North Carolina, Chapel Hill, North Carolina, 27514

Publication date: 1999-09-01

Lead Inhibits the Rat N-Methyl-d-Aspartate Receptor Channel by Binding to a Site Distinct from the Zinc Allosteric Site

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