Abstract:The neurotoxic properties of the dietary excitotoxins /3-N-methylamino-L-alanine and~3-N-oxalylamino-L-alanine have been studied in rat cerebellar granule cells and compared with those of glutamate. Glutamate caused dose-dependent death of cerebellar granule cells after a 30-min exposure when viability was assessed 24 h later. ß-N-Methylamino-L-alanine and /3-N-oxalylamino-L-alanine, however, were toxic only after 24 or 48 h of exposure. The neurotoxic effects of ß-N-methylaminO-L-alanine were blocked by D(-)-2-amino-5-phosphonopentanoic acid, and those of ß-N-oxalylamino-Lalanine were blocked by kynurenic acid, which demonstrated that these excitotoxins caused cerebellar granule cell death through the activation of glutamate receptors.

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Abstract:The neuronal effects of the metabotropic glutamate receptor agonist (1 S,3R)-aminocyclopentane-1 ,3-dicarboxylic acid have been studied in cultured rat cerebellar granule cells, and compared with those of the endogenous excitotoxin glutamate, and the dietary excitotoxin /3-N-methylamino-L-alanine. Glutamate,~3-N-methylamino-L-alanine, and (1 S ,3R) -aminocyclopentane-1 ,3-dicarboxylic acid all caused concentration-dependent cerebellar granule cell death over a 24-h exposure period. The metabotropic antagonist (RS) -a-methyl-4-carboxyphenylglycine reduced glutamate-, /3-N-methylamino-L-alanine-, and (1 S ,3R)-aminocyclopentane-1 ,3-dicarboxylic acid-induced death by 50, 37, and 90%, respectively. (1 S ,3R) -Aminocyclopentane-1 ,3-dicarboxylic acid-induced death was unaffected by the group I antagonist (RS)-1 -aminoindan-1 ,5-dicarboxylic acid, increased by the group II antagonist ethylglutamic acid, and markedly decreased by the group Ill antagonist (RS) -amethylserine-O-phosphate. Neither (1 S ,3R) -aminocyclopentane-1 ,3-dicarboxylic acid nor the group I agonist (RS)-3,5-dihydroxyphenylglycine caused an increase in intracellular free calcium levels. The group Ill agonist L-(+)-2-amino-4-phosphonobutyric acid also induced concentration-dependent cerebellar granule cell death, and so it was suggested that the group Ill metabotropic glutamate receptors were responsible for (1 S,3R)-aminocyclopentane-1 ,3-dicarboxylic acid-induced death. Blocking these receptors with (RS) -a-methylserine-O-phosphate also prevented a proportion of glutamate-and /3-N-methylamino-L-alanineinduced death. Key Words: (1 S,3R)-Aminocyclopentane-1 ,3-dicarboxylic acid-/3-N-Methylamino-L-alanine-Rat cerebellar granule cells-Glutamate. J. Neurochem. 71, 1280Neurochem. 71, -1288Neurochem. 71, (1998.Glutamate is the principal excitatory neurotransmitter in the mammalian brain, where it activates both ionotropic glutamate receptors and metabotropic glutamate receptors (mGluRs). Tonotropic glutamate receptors are ligand-gated ion channels that comprise NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) kainate subtypes (Monaghan et al., 1989). Overactivation of ionotropic receptors results in neuronal death via excitotoxicity , and some of the intracellular events that lead to death can be influenced by mGluRs (Pin and Duvoisin, 1995).mGluRs are coupled to U proteins, and this family of glutamate receptors comprises eight subtypes, to date, that are divided into three groups, based on their second messenger coupling, sequence similarity, and ligand selectivities (Pin and Duvoisin, 1995). Group I includes mGluRi and mGluR5, which are coupled to polyphosphoinositide (PPI) hydrolysis. mGluRs from groups II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7, and mGluR8) are negatively coupled to adenylate cyclase activity. In addition, an mGluR receptor coupled to phospholipase D has been identified in the hippocampus (Pellegrini-Giampetro et al., 1996). This coupling to disparate transduction pathways may underlie th...

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