Potentiation of 45Ca Uptake and Acute Toxicity Mediated by the N‐Methyl‐D‐Aspartate Receptor: The Effect of Metal Binding Agents and Transition Metal Ions

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Abstract
The activities mediated by the N-methyl-D-aspartate (NMDA) receptor were studied in cultured rat cerebellar granule cells. Micromolar concentrations of the metal binding compounds, EDTA, cysteine, and histidine, as well as serum albumin strongly potentiated receptor activity in the presence of millimolar concentrations of Ca2+ and Mg2+. The findings indicated that these agents remove an endogenous metal, probably Zn2+, which attenuates NMDA receptor-mediated 45Ca uptake and toxicity. Several added metal ions were therefore tested at low micromolar concentrations. Zn2+ was found to be the most potent inhibitor of NMDA-induced 45Ca uptake, followed by Cu2+ and Fe2+.Co2+, Cd2+, Fe3+, and Al3+ had no significant effect, whereas Ni2+ potentiated the 45Ca uptake but inhibited at much higher concentrations. The potentiating agents that remove the endogenous metal had a particularly dramatic effect in the presence of Mg2+, the voltage-dependent suppressor of the NMDA receptor. Mg2+ also played an important role in the inhibitory effect of added Zn2+. Much lower concentrations of Zn2+ were needed to achieve inhibition of NMDA-induced 45Ca uptake in the presence of Mg2+. Under a variety of conditions, a very good correlation was found between NMDA receptor-mediated 45Ca uptake and the magnitude of acute neurotoxicity.