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 ζ1ε1 or ζ1ε2 NMDA receptor subunits, Pb++ inhibited glutamate-activated currents with IC50 values of 0.87 ± 0.25 and 1.21 ± 0.22 μM, respectively, and NMDA- activated currents with IC50 values of 1.37 ± 0.47 and 1.11 ± 0.33 μM, respectively. In oocytes expressing ζ1ε1ε2 subunits, the IC50 values for Pb++ blockade of NMDA-or glutamate-activated currents were significantly larger when compared to ζ1ε1 or ζ1ε2 combinations. Pb ++ concentrations greater than 1 μM inhibited glutamate-activated currents with an IC50 of 6.1 ± 1.22 μM and NMDA-activated currents with an IC50 of 6.64 ± 3.34 μM. Pb++ reduced the maximal current amplitude consistent with a noncompetitive block. ζ1ε1ε2 NMDA receptors were potentiated by low concentrations of Pb+ (<1.0 μM). These data suggest that brain regions with ζ1ε1 or ζ1ε2 NMDA receptors subunits would be more vulnerable to Pb ++ toxicity than those with ζ1ε1ε2 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.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jul 1 1996|
ASJC Scopus subject areas
- Molecular Medicine