Modulation of Mg(2+)-dependent [3H]TCP binding by L-glutamate, glycine, and guanine nucleotides in rat cerebral cortex.
Biochemical and electrophysiological studies have demonstrated that phencyclidine (PCP) recognition site exists in the ion channel of the N-methyl-D-aspartate (NMDA) receptor ion channel complex. Using an extensively washed rat cortical membrane preparation, the effects of Mg2+ and guanylylimidodiphosphate (GppNHp) were examined on the binding of [3H]-N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP). Low concentrations of Mg2+ (EC50 = 11 microM) stimulated [3H]TCP binding under the basal condition and high concentrations of Mg2+ (IC50 = 1 mM) inhibited it. In the presence of 10 microM L-glutamate and 10 microM glycine, their EC50 values for Mg2+ enhancement of [3H]TCP binding were markedly reduced (to 1.9 microM or 8.4 microM), respectively. By contrast, the IC50 values for Mg2+ inhibition of [3H]TCP binding were reduced in the presence of L-glutamate, but not glycine. Furthermore, a stimulatory effect of Mg2+ on [3H]TCP binding was additional to the [3H]TCP binding stimulated by a maximally effective concentration of L-glutamate (10 microM) or glycine (10 microM). In the kinetic study, 300 microM Mg2+ produced an increase in the rates of both association and dissociation of [3H]TCP. Similar results were obtained with L-glutamate (10 microM) and glycine (10 microM); 10 mM Mg2+ also caused an acceleration of the association rate but strongly decreased [3H]TCP binding at equilibrium. Compared with [3H]TCP binding under the basal condition, K+ (10 mM) alone decreased the maximal binding without producing any change in the association rate; 10 mM K+ also significantly decreased Mg(2+)-stimulated [3H]TCP binding but caused no change in the acceleration of the association rate caused by Mg2+.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Psychopharmacology, Psychiatric Research Institute of Tokyo, Japan.
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Hori
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Yamamoto
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Moroji
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D005998:Glycine / Q000494:pharmacology*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology*; D013287:Illicit Drugs; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D013570:Synaptic Membranes / Q000378:metabolism*; D014316:Tritium
D005971:Glutamates; D013287:Illicit Drugs; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D014316:Tritium; D006165:Guanylyl Imidodiphosphate; D018698:Glutamic Acid; C012058:tenocyclidine; D008274:Magnesium; D010622:Phencyclidine; D011188:Potassium; D005998:Glycine