ROLE OF GROUP-III METABOTROPIC GLUTAMATE RECEPTORS IN EXCITOTOXIN-INDUCED CEREBELLAR GRANULE CELL-DEATH

The neuronal effects of the metabotropic glutamate receptor agonist(1S ,3R) -aminocyclopentane-1,3-dicarboxylic acid have been studied in cul tured rat cerebellar granule cells, and compared with those of the end ogenous excitotoxin glutamate, and the dietary excitotoxin beta-N-meth ylamino-L-alanine. Glutamate, beta-N-methylamino-L-alanine, and (1S,3R )-aminocyclopentane-1,3-dicarboxylic acid all caused concentration-dep endent cerebellar granule cell death over a 24-h exposure period. The metabotropic antagonist (RS)-alpha-methyl-4-carboxyphenylglycine reduc ed glutamate-, beta-N-methylamino-L-alanine-, and (1S,3R)-aminocyclope ntane-1,3-dicarboxylic acid-induced death by 50, 37, and 90%, respecti vely. (1S,3R) -Aminocyclopentane-1,3-dicarboxylic acid-induced death w as unaffected by the group I antagonist (RS)-1 -aminoindan-1,5-dicarbo xylic acid, increased by the group II antagonist ethylglutamic acid, a nd markedly decreased by the group III antagonist (RS)-alpha-methylser ine-O-phosphate. Neither (1S,3R)-aminocyclopentane-1,3-dicarboxylic ac id nor the group I agonist (RS)-3,5-dihydroxyphenylglycine caused an i ncrease in intracellular free calcium levels. The group III agonist L- (+)-2-amino-4-phosphonobutyric acid also induced concentration-depende nt cerebellar granule cell death, and so it was suggested that the gro up III metabotropic glutamate receptors were responsible for (1S,3R) - aminocyclopentane-1,3-dicarboxylic acid-induced death. Blocking these receptors with (RS)-alpha-methylserine-O-phosphate also prevented a pr oportion of glutamate- and beta-N-methylamino-L-alanine-induced death.