TY - JOUR
T1 - The sensitivity of N-methyl-D-aspartate receptors to lead inhibition is dependent on the receptor subunit composition
AU - Omelchenko, Irina A.
AU - Nelson, Cole S.
AU - Marino, Jennifer L.
AU - Allen, Charles N.
PY - 1996/7
Y1 - 1996/7
N2 - 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.
AB - 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.
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M3 - Article
C2 - 8764330
AN - SCOPUS:0030426276
SN - 0022-3565
VL - 278
SP - 15
EP - 20
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -