AN ENDOGENOUS METAL APPEARS TO REGULATE NMDA RECEPTOR MEDIATED CA-45 INFLUX AND TOXICITY IN CULTURED CEREBELLAR GRANULE CELLS

Glutamate induced Ca-45 influx and toxicity were enhanced 2-10 fold by EDTA. A chelator concentration of 10-mu-M, which was equivalent to less than 1% of the Mg2+ and Ca2+ concentration in the medium, was effective. The chelator revealed no activity on its own and caused potentiation only when present simultaneously with the agonist of the NMDA receptor. Cysteine, which is known to bind certain metals tightly through its sulfhydryl group, and another chelator, O-phenanthroline, produced the same effect as EDTA. The findings indicate that when the N-methyl-D-aspartate receptor is activated, an endogenous metal can become bound to a chelator or to a physiological metal binding agent, such as cysteine, leading to enhanced Ca2+ influx into the neuron and toxicity.