Sustained exposure to a glycine receptor partial agonist differentially alters NMDA receptor agonist and antagonist potencies in cultured spinal cord neurons.
Sustained (20 h) exposure to the glycine partial agonist 1-aminocyclopropanecarboxylic acid (ACPC) significantly reduced N-methyl-D-aspartate (NMDA)-induced neurotoxicity in cultured spinal cord neurons when the NMDA (25 and 100 microM) was added to the cultures 30 min after removal of the ACPC (1 mM). In contrast, ACPC preexposure failed to protect against kainate-induced neuronal injury. The magnitude of neuronal protection against NMDA (100 microM) was further enhanced if the neurons pretreated with ACPC were reexposed to this drug during the NMDA challenge. In addition, the potencies of both the competitive NMDA antagonist AP5 and the noncompetitive antagonist dizocilpine to block NMDA toxicity were significantly increased following ACPC preexposure, while the potency of the competitive glycine receptor antagonist 7-chlorokynurenate (7-CK) was unchanged. Analysis of Northern blots suggest that ACPC-induced changes in NMDA receptor function were not associated with alterations in the levels of the mRNAs encoding the NMDAR-1, -2A, -2B, or -2C subunits. These results indicate that sustained exposure to ACPC modifies NMDA receptors in a manner that diminishes NMDA receptor-mediated neurotoxicity while selectively enhancing the potencies of several NMDA receptor antagonists. These effects do not appear to be related to changes in expression of specific NMDA receptor subunits, and may instead involve a post-translational modification of one or more subunit proteins.
Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Y
Y
Lin
L H
LH
Fossom
P
P
Skolnick
J B
JB
Long
D015763:2-Amino-5-phosphonovalerate / Q000633:toxicity; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003515:Cycloleucine / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects*
D018690:Excitatory Amino Acid Agonists; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D003515:Cycloleucine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate