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Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex.
Mol Pharmacol 1987; 32(6):820-30MP

Abstract

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.

Authors+Show Affiliations

Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

2892125

Citation

Loo, P S., et al. "Interaction of L-glutamate and Magnesium With Phencyclidine Recognition Sites in Rat Brain: Evidence for Multiple Affinity States of the phencyclidine/N-methyl-D-aspartate Receptor Complex." Molecular Pharmacology, vol. 32, no. 6, 1987, pp. 820-30.
Loo PS, Braunwalder AF, Lehmann J, et al. Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. Mol Pharmacol. 1987;32(6):820-30.
Loo, P. S., Braunwalder, A. F., Lehmann, J., Williams, M., & Sills, M. A. (1987). Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. Molecular Pharmacology, 32(6), pp. 820-30.
Loo PS, et al. Interaction of L-glutamate and Magnesium With Phencyclidine Recognition Sites in Rat Brain: Evidence for Multiple Affinity States of the phencyclidine/N-methyl-D-aspartate Receptor Complex. Mol Pharmacol. 1987;32(6):820-30. PubMed PMID: 2892125.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. AU - Loo,P S, AU - Braunwalder,A F, AU - Lehmann,J, AU - Williams,M, AU - Sills,M A, PY - 1987/12/1/pubmed PY - 1987/12/1/medline PY - 1987/12/1/entrez SP - 820 EP - 30 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 32 IS - 6 N2 - Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/2892125/Interaction_of_L_glutamate_and_magnesium_with_phencyclidine_recognition_sites_in_rat_brain:_evidence_for_multiple_affinity_states_of_the_phencyclidine/N_methyl_D_aspartate_receptor_complex_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2892125 DB - PRIME DP - Unbound Medicine ER -