Induction of astrocyte glutamine synthetase activity by the Lathyrus toxin beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP).
beta-N-Oxalyl-L-alpha,beta-diaminopropionic acid (beta-L-ODAP) is thought to be the causative agent in lathyrism due to its neuroexcitatory and neurotoxic properties. We have recently reported that beta-L-ODAP is also gliotoxic at high concentrations (Bridges et al.: Brain Res 561:262, 1991). Evidence is now presented that low, subgliotoxic concentrations of beta-L-ODAP may alter the ability of astrocytes to regulate glutamate concentrations in the CNS by increasing astrocyte glutamine synthetase activity. When astrocytes cultured from rat cortex were exposed to 100 microM beta-L-ODAP for 24 h, the resulting glutamine synthetase activity was 155% of control levels. This effect was enantiomer- and isomer-specific, dose-dependent, and required protein translation as the induction was blocked with cycloheximide. The effect of beta-L-ODAP on glutamine synthetase was not mimicked by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) or kainate, suggesting that the induction was not transduced solely through activation of cell surface non-N-methyl-D-aspartate (NMDA) glutamate receptors. An intracellular site of action of beta-L-ODAP is proposed because its effect on glutamine synthetase activity could be blocked by the amino acid uptake blocker dihydrokainate.
Miller
S
S
Department of Psychobiology, University of California, Irvine 92717.
Nunn
P B
PB
Bridges
R J
RJ
D000599:Amino Acids, Diamino / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis* / Q000378:metabolism; D007051:Ibotenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D016202:N-Methylaspartate / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
D000599:Amino Acids, Diamino; D009498:Neurotoxins; D003609:Dactinomycin; C100126:oxalyldiaminopropionic acid; D007051:Ibotenic Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid