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Molecular Pharmacology

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Research ArticleArticle

Putative Partial Agonist 1-Aminocyclopropanecarboxylic Acid Acts Concurrently as a Glycine-Site Agonist and a Glutamate-Site Antagonist at N-Methyl-d-aspartate Receptors

Rinat Nahum-Levy, Linda H. Fossom, Phil Skolnick and Morris Benveniste
Molecular Pharmacology December 1999, 56 (6) 1207-1218; DOI: https://doi.org/10.1124/mol.56.6.1207
Rinat Nahum-Levy
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Linda H. Fossom
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Phil Skolnick
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Morris Benveniste
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Abstract

1-Aminocyclopropanecarboxylic acid (ACPC) has been shown to protect against neuronal cell death after ischemic insult in vivo. Such results can be correlated with in vitro assays in which ACPC protected neurons against glutamate-induced neurotoxicity by reducing the activity ofN-methyl-d-aspartate (NMDA) channel activation. Electrophysiological studies have determined that ACPC inhibits NMDA receptor activity by acting as a glycine-binding site partial agonist. In this study, rapid drug perfusion combined with whole-cell voltage-clamp was used to elicit and measure the effects of ACPC on NMDA receptor-mediated responses from cultured hippocampal neurons and cerebellar granule cells. The ACPC steady-state dose-response curve had both stimulatory and inhibitory phases. Half-maximal activation by ACPC as a glycine-site agonist was 0.7 to 0.9 μM. Half-maximal inhibition by ACPC was dependent on NMDA concentration. Peak responses to a >100 μM ACPC pulse in the presence of 1 μM glutamate were similar to those of glycine but decayed to a steady-state amplitude below that of glycine. The removal of ACPC initially caused an increase in inward current followed by a subsequent decrease to baseline levels. This suggests that relief of low-affinity antagonism occurs before high-affinity agonist dissociation. Simulations of ACPC action by a two glutamate-binding site/two glycine-binding site model for NMDA channel activation in conjunction with the concurrent role of ACPC as a glycine-site full agonist and glutamate-site competitive antagonist were able to successfully approximate experimental results.

Footnotes

    • Received July 6, 1999.
    • Accepted August 28, 1999.
  • Send reprint requests to: Dr. Morris Benveniste, Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel. E-mail:morrisb{at}post.tau.ac.il

  • ↵1 Present address: Division of Neuropharmacological Drug Products, CDER/FDA, HFD-120, 5600 Fishers Lane, Rockville, MD 20857.

  • ↵2 Present address: Lilly Research Laboratories, Indianapolis, IN 46285.

  • This work was supported by Grant 96-00245 from the United States-Israel Binational Science Foundation (Jerusalem, Israel) and by Grant 3765 from the Israeli Ministry of Health.

  • U.S. Government
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Molecular Pharmacology: 56 (6)
Molecular Pharmacology
Vol. 56, Issue 6
1 Dec 1999
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Research ArticleArticle

Putative Partial Agonist 1-Aminocyclopropanecarboxylic Acid Acts Concurrently as a Glycine-Site Agonist and a Glutamate-Site Antagonist at N-Methyl-d-aspartate Receptors

Rinat Nahum-Levy, Linda H. Fossom, Phil Skolnick and Morris Benveniste
Molecular Pharmacology December 1, 1999, 56 (6) 1207-1218; DOI: https://doi.org/10.1124/mol.56.6.1207

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Research ArticleArticle

Putative Partial Agonist 1-Aminocyclopropanecarboxylic Acid Acts Concurrently as a Glycine-Site Agonist and a Glutamate-Site Antagonist at N-Methyl-d-aspartate Receptors

Rinat Nahum-Levy, Linda H. Fossom, Phil Skolnick and Morris Benveniste
Molecular Pharmacology December 1, 1999, 56 (6) 1207-1218; DOI: https://doi.org/10.1124/mol.56.6.1207
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