Sustained exposure to 1-aminocyclopropanecarboxylic acid, a glycine partial agonist, alters N-methyl-D-aspartate receptor function and subunit composition

Partial agonists at the strychnine-insensitive glycine sites coupled to N-methyl-D-aspartate (NMDA) receptors reduce both glutamate-induced neurotoxicity in vitro and ischemia-induced neurodegeneration in vivo. Paradoxically, sustained exposure of cultured cerebellar granule cell neurons to glycinergic ligands, including glycine and the glycine partial agonists (+/-)-3-amino-1 -hydroxy-2-pyrrolidone, 1-aminocyclopropanecarboxylic acid (ACPC), and D-cycloserine, attenuates the neuroprotective effects of (+/-)-3-amino-1-hydroxy-2-pyrrolidone and ACPC. In the present study, we investigated the mechanisms responsible for this attenuated neuroprotection. Three NMDA receptor-mediated responses were examined after sustained exposure to ACPC: glutamate-induced neurotoxicity, NMDA-stimulated increases in cGMP levels, and NMDA-stimulated increases in [Ca+2](i). Consistent with previous findings, coincubation with ACPC blocked glutamate-induced neurotoxicity, whereas sustained (24 hr) exposure to ACPC attenuated its protective effects. Moreover, sustained exposure to ACPC caused an apparent similar to 2-fold increase in the potency of both glutamate to act as a neurotoxin and NMDA to stimulate cGMP formation. Sustained exposure to ACPC also increased NMDA-stimulated [Ca+2](i) similar to 3-fold compared with control granule cell cultures but did not affect basal [Ca+2](i). This apparent increase in glutamate sensitivity may be attributable to a change in NMDA receptor subunit composition as sustained ACPC exposure resulted in a similar to 2.5-fold increase in NMDA receptor 2C RNA levels, without concomitant changes in the amounts of RNA encoding the NMDA receptor 2A, 2B, or I subunit. This is the first demonstration that sustained exposure to a glycinergic ligand can alter the expression of RNAs encoding NMDA receptor subunits. Because glycinergic ligands are potential clinical candidates, these results may have important implications for the treatment of neurodegenerative disorders.