Strychnine-insensitive glycine receptors in embryonic chick retina: characteristics and modulation of NMDA neurotoxicity.
In the mammalian brain, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is coupled to a cation channel and a strychnine-insensitive glycine receptor. The present paper demonstrates the presence of NMDA receptor-coupled strychnine-insensitive glycine receptors in embryonic chick retina. Both glycine and 1-aminocyclopropanecarboxylic acid (ACPC) exhibited similar potencies (271 +/- 39 vs 247 +/- 39 nM, respectively) as inhibitors of strychnine-insensitive [3H]glycine binding to retinal membranes. Moreover, glycine and ACPC enhanced [3H]MK-801 binding to sites within the NMDA-coupled cation channel in retinal membranes with potencies comparable to those reported in rat brain. While the potency of ACPC was significantly higher than glycine (EC50 54 +/- 12 vs 256 +/- 57 nM, P < 0.02) in this measure, there were no significant differences in the maximum enhancement (efficacy) of [3H]MK-801 binding by these compounds. Since glycine appears to be required for the operation of NMDA-coupled cation channels, we examined the effects of glycine and ACPC on NMDA-induced acute excytotoxicity in the 14-day embryonic chick retina. Histological evaluation of retina revealed that either ACPC (10-100 microM) or glycine (200 microM) attenuated NMDA-induced (200 microM) retinal damage and a combination of these agents produced an enhanced protection against acute NMDA toxicity. ACPC (100 microM), but not MK-801 (1 microM) also afforded a modest protection against kainate-induced (25 microM) retinal damage. These findings demonstrate that while strychnine-insensitive glycine receptors are present in embryonic chick retina, occupation of these sites does not augment the cytotoxic actions of NMDA. Moreover, the ability of ACPC and glycine to attenuate NMDA-induced cytotoxicity does not appear to be mediated through occupation of these sites.
Boje
K M
KM
Laboratory of Neuroscience, NIDDK, National Institutes of Health, Bethesda, MD 20892.
Skolnick
P
P
Raber
J
J
Fletcher
R T
RT
Chader
G
G
D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D002642:Chick Embryo; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004351:Drug Resistance; D016202:N-Methylaspartate / Q000633:toxicity*; D009498:Neurotoxins / Q000494:pharmacology*; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D013331:Strychnine / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D009498:Neurotoxins; D018009:Receptors, Glycine; D017981:Receptors, Neurotransmitter; C023863:1-aminocyclopropane-1-carboxylic acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D013331:Strychnine