RT Journal Article
SR Electronic
T1 Putative Partial Agonist 1-Aminocyclopropanecarboxylic Acid Acts Concurrently as a Glycine-Site Agonist and a Glutamate-Site Antagonist at N-Methyl-d-aspartate Receptors
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1207
OP 1218
DO 10.1124/mol.56.6.1207
VO 56
IS 6
A1 Rinat Nahum-Levy
A1 Linda H. Fossom
A1 Phil Skolnick
A1 Morris Benveniste
YR 1999
UL http://molpharm.aspetjournals.org/content/56/6/1207.abstract
AB 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.