Putative partial agonist 1-aminocyclopropanecarboxylic acid acts concurrently as a glycine-site agonist and a glutamate-site antagonist at N-methyl-D-aspartate receptors

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