The sensitivity of N-methyl-D-aspartate receptors to lead inhibition is dependent on the receptor subunit composition

Pb++ is a potent inhibitor of N-methyl-D-aspartate (NMDA) receptors and its action is dependent on neuronal maturation. Developmentally regulated expression of NMDA receptor subunits may underlie the changing sensitivity to Pb++. In oocytes expressing in vitro transcribed cRNAs for zeta 1 epsilon 1 or zeta 1 epsilon 2 NMDA receptor subunits, Pb++ inhibited glutamate-activated currents with IC50 values of 0.87 +/- 0.25 and 1.21 +/- 0.22 mu M, respectively, and NMDA-activated currents with IC50 values of 1.37 +/- 0.47 and 1.11 +/- 0.33 mu M, respectively. In oocytes expressing zeta 1 epsilon 1 epsilon 2 subunits, the IC50 values for Pb++ blockade of NMDA- or glutamate-activated currents were significantly larger when compared to zeta 1 epsilon 1 or zeta 1 epsilon 2 combinations. Pb++ concentrations greater than 1 mu M inhibited glutamate-activated currents with an IC50 of 6.1 +/- 1.22 mu M and NMDA-activated currents with an IC50 of 6.64 +/- 3.34 mu M. Pb++ reduced the maximal current amplitude consistent with a noncompetitive block. zeta 1 epsilon 1 epsilon 2 NMDA receptors were potentiated by low concentrations of Pb++ (<1.0 mu M). These data suggest that brain regions with zeta 1 epsilon 1 or zeta 1 epsilon 2 NMDA receptors subunits would be more vulnerable to Pb++ toxicity than those with zeta 1 epsilon 1 epsilon 2 NMDA-receptors, which are expressed later in development. These data provide a mechanism for the reported changes in the efficacy of block of NMDA receptors by Pb++ during development.