The sensitivity of N-methyl-D-aspartate receptors to lead inhibition is dependent on the receptor subunit composition.
Pb+2 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+2. In oocytes expressing in vitro transcribed cRNAs for zeta 1 epsilon 1 or zeta 1 epsilon 2 NMDA receptor subunits, Pb+2 inhibited glutamate-activated currents with IC50 values of 0.87 +/- 0.25 and 1.21 +/- 0.22 microM, respectively, and NMDA-activated currents with IC50 values of 1.37 +/- 0.47 and 1.11 +/- 0.33 microM, respectively. In oocytes expressing zeta 1 epsilon 1 epsilon 2 subunits, the IC50 values for Pb+2 blockade of NMDA- or glutamate-activated currents were significantly larger when compared to zeta 1 epsilon 1 or zeta 1 epsilon 2 combinations. Pb+2 concentrations greater than 1 microM inhibited glutamate-activated currents with an IC50 of 6.1 +/- 1.22 microM and NMDA-activated currents with an IC50 of 6.64 +/- 3.34 microM. Pb+2 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+2 ( < 1.0 microM). 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+2 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+2 during development.
Omelchenko
I A
IA
Center for Research on Environmental and Occupational Toxicology, Oregon Health Sciences University, Portland, USA.
Nelson
C S
CS
Marino
J L
JL
Allen
C N
CN
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology*; D007854:Lead / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D009865:Oocytes; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D014982:Xenopus laevis
D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D018698:Glutamic Acid; D016202:N-Methylaspartate