Vol. 282, Issue 3, 1458-1464, 1997

Lead Inhibition of N-Methyl-D-aspartate Receptors Containing NR2A, NR2C and NR2D Subunits¹

Irina A. Omelchenko, Cole S. Nelson and Charles N. Allen

Center for Research on Environmental and Occupational Toxicology (I.A.O., C.S.N., C.N.A.), Departments of Physiology and Pharmacology (C.N.A.) and of Psychiatry (C.S.N.), Oregon Health Sciences University, Portland, Oregon

The potency of Pb²⁺ inhibition of glutamate-activated currents mediated by N-methyl-D-aspartate (NMDA) receptors was dependent on the subunits composing the receptors when functionally expressed in Xenopus laevis oocytes. Pb²⁺ reduced the amplitudes of glutamate-activated currents and shifted the agonist EC₅₀ values of NMDA receptors consisting of different subunit compositions. The IC₅₀ values for Pb²⁺ ranged from 1.52 to 8.19 µM, with a rank order of potency of NR1b-2A > NR1b-2C > NR1b-2D > NR1b-2AC. For NR1b-2AC NMDA receptors, the IC₅₀ value was dependent on the agonist concentration; at saturating agonist concentrations (300 µM), the IC₅₀ value was 8.19 µM, whereas at 3 µM glutamate, the IC₅₀ value was 3.39 µM. Pb²⁺ was a noncompetitive inhibitor of NR1b-2A, NR1b-2C and NR1b-2D NMDA receptors. At low concentrations (<1 µM) Pb²⁺ potentiated NR1b-2AC NMDA receptors. These data provide further evidence to support the hypothesis that the actions of Pb²⁺ on NMDA receptors are determined by the receptor subunit composition.