Subunit specificity and mechanism of action of NMDA partial agonist D-cycloserine

Recently, we have shown that 1-aminocyclopropanecarboxylic acid (ACPC) acts simultaneously as a high affinity full glycine agonist and a low affinity glutamate site competitive antagonist for NMDA receptor channels. In this paper, we have attempted to determine the subunit specificity and mechanism of action of a different putative cyclic partial agonist, D-cycloserine (DCS). NMDA receptor currents were measured utilizing the two-electrode voltage clamp technique on Xenopus oocytes injected with NR1-1a cRNA and either NR2A, NR2B or NR2C cRNA. Efficacies of DCS were 35-68% of glycine controls for channels containing NR1-1a and NR2A or NR2B subunits, but channels containing NR2C subunits had efficacies greater than glycine controls (192%). Unlike ACPC, DCS efficacy does not increase with increasing NMDA concentration; however, the lowered efficacy elicited by DCS results solely through its interaction with the glycine binding site. The efficacy of DCS was pH sensitive for NR2A or NR2B-containing channels, but not for channels containing NR2C. From this, we suggest that the protonated and deprotonated forms of DCS when bound, probably open NMDA channels with different efficiency. Two models compatible with these results are presented.