Biochemical evidence of an interaction of lead at the zinc allosteric sites of the NMDA receptor complex: effects of neuronal development.
Electrophysiological and biochemical studies have shown that Pb2+ inhibits the activation of the N-Methyl-D-Aspartate (NMDA) receptor complex, an excitatory amino acid receptor subtype known to play an important role in neuronal development and cognitive function. In the present study we have provided biochemical evidence that Pb2+ may inhibit NMDA receptor function via an interaction at the Zn2+ allosteric sites. Binding of [3H]-MK-801 to the NMDA receptor ion channel was used as a biochemical indicator of receptor function. The initial experiments indicated that Zn2+ inhibited [3H]-MK-801 binding via high and low affinity sites in PN14 membranes with potencies of 0.77 +/- 0.05 and 57.4 +/- 6.9 microM, respectively. Similar effects were present in neuronal membranes from adult rats, but Zn2+ was significantly less potent (IC50: 153 +/- 21; p < 0.025) in inhibiting [3H]-MK-801 via the low affinity site than in PN14 membranes. The addition of Pb2+ to Zn2+/[3H]-MK-801 displacement curves significantly altered the inhibition of [3H]-MK-801 binding by Zn2+. IN PN14 membranes, Pb2+ increased the potency of Zn2+ inhibition at the high affinity site and decreased the Zn2+ potency at the low affinity site suggestive of a competitive interaction. In adult membranes, Pb2+ did not alter the potency of Zn2+ inhibition of [3H]-MK-801 binding at either site in concentrations up to 40 microM. These findings suggest that the Zn2+ allosteric sites are more sensitive to Pb2+ effects in immature brain tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Guilarte
T R
TR
Department of Environmental Health Sciences, Johns Hopkins University, School of Hygiene and Public Health, Baltimore, Maryland USA.
Miceli
R C
RC
Jett
D A
DA
D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D007854:Lead / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D010713:Phosphatidylcholines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D015032:Zinc / Q000494:pharmacology*
D010713:Phosphatidylcholines; D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead; D016291:Dizocilpine Maleate; C017251:1,2-oleoylphosphatidylcholine; D008274:Magnesium; D015032:Zinc