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 microM, 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 microM), the IC50 value was 8.19 microM, whereas at 3 microM glutamate, the IC50 value was 3.39 microM. Pb2+ was a noncompetitive inhibitor of NR1b-2A, NR1b-2C and NR1b-2D NMDA receptors. At low concentrations (<1 microM) 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.
Omelchenko
I A
IA
Center for Research on Environmental and Occupational Toxicology, Oregon Health Sciences University, Portland 97201-3098, USA.
Nelson
C S
CS
Allen
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CN
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D007854:Lead / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014982:Xenopus laevis
D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D018698:Glutamic Acid