High concentrations of neutral amino acids activate NMDA receptor currents in rat hippocampal neurons

High concentrations (30 microM-5 mM) of the neutral amino acids L-serine, L-cysteine, L-alanine, L-proline and glycine elicited inward current responses when applied to hippocampal neurons patch clamped at -60 mV in the presence of 1-10 microM glycine and 1 microM strychnine. The amplitude of the response to L-serine increased in a concentration-dependent fashion within the range 0.1-10 mM (EC50, 2.6 mM). L-Serine (1 mM) currents were attenuated by Mg2+ (100 microM) and completely blocked by the competitive N-methyl-D-aspartate (NMDA) antagonist 3-(2-carboxypiperazin-4-yl)-propyl-1- phosphonic acid (CPP) (30 microM). The CPP block could be overcome by raising the concentration of L-serine. We conclude that high concentrations of some neutral amino acids activate NMDA receptor-coupled ion channels by acting as agonists at the NMDA recognition site.