Vol. 56, Issue 6, 1207-1218, December 1999

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,¹ Phil Skolnick,² and Morris Benveniste

Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel (R.N.-L., M.B.); and Laboratory of Neuroscience, National Institute of Diabetes and Diseases of the Kidney, National Institutes of Health, Bethesda, Maryland (L.H.F., P.S.)

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 of N-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.