Lead inhibition of N-methyl-D-aspartate receptors containing NR2A, NR2C and NR2D subunits

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 lu va e was 3.39 μM. Pb 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.