GLYCINE MODULATES ETHANOL INHIBITION OF HETEROMERIC N-METHYL-D-ASPARTATE RECEPTORS EXPRESSED IN XENOPUS OOCYTES

Ethanol inhibits N-methyl-D-aspartate (NMDA) receptor-mediated respons es at pharmacologically relevant concentrations, suggesting that inhib ition of NMDA receptors may underlie some of the actions of ethanol in the central nervous system. We examined the ability of glycine to mod ulate ethanol inhibition of four recombinant heteromeric NMDA receptor s (NR1a/NR2A through NR2D) expressed in Xenopus oocytes. Ethanol dose- response analysis revealed enhanced inhibitory efficacy of ethanol in the presence of subsaturating glycine concentrations at the NR1/NR2A, NR1/NR2C, and NR1/NR2D receptors. When assayed over a range of glycine concentrations, ethanol exhibited both glycine-reversible and glycine -independent inhibition of NMDA receptors. In contrast, ethanol inhibi tion of recombinant NMDA receptors was independent of NMDA concentrati on. Glycine reversal of ethanol inhibition suggested that ethanol migh t lower the affinity of glycine for the NMDA receptor and thereby decr ease response magnitude. Consistent with this hypothesis, ethanol sign ificantly reduced glycine affinity at NR1/NR2A and NR1/NR2C receptors. Evaluation of the glycine-independent component of ethanol inhibition demonstrated that in the presence of saturating concentrations of gly cine, the NR1/NR2A and NR1/NR2B receptors were more sensitive to ethan ol than the NR1/NR2C and NR1/NR2D receptors. Activation of the NR1/NR2 D heteromers by NMDA and low concentrations of glycine elicited respon ses characterized by an initial peak followed by a lower-amplitude pla teau response, which is consistent with glycine-sensitive desensitizat ion as previously described for native NMDA receptors. In addition, no ndesensitizing NR1/NR2B responses elicited in the presence of subsatur ating concentrations of glycine were frequently converted into desensi tizing responses by the addition of ethanol, an effect that was revers ed with increasing glycine concentrations. The ability of ethanol to p romote glycine-sensitive desensitization further suggests an interacti on between glycine and ethanol inhibition of the NMDA receptor. Taken together, the results of the present report demonstrate that ethanol i nhibition of NMDA receptors has both glycine-reversible and glycine-in dependent components, suggesting two distinct molecular mechanisms for ethanol inhibition of NMDA receptors.