Blockade of NMDA receptor-mediated mobilization of intracellular Ca 2+ prevents neurotoxicity

Abstract

NMDA receptor activation leads to elevated Ca 2+ in cultured rat cortical and retinal ganglion cell neurons. If excessive, this Ca 2+ response in associated with delayed neurotoxicity. We used dantrolene and ionomycin to test if the Ca 2+ response to NMDA was due to mobilization of intracellular Ca 2+ stores rather than merely to Ca 2+ influx. In the presence of EGTA, ionomycin resulted in release and subsequent depletion of intracellular Ca 2+ stores. Henceforth, despite normal extracellular Ca 2+, NMDA elicited only about half of its former Ca 2+ response. Similarly, when dantrolene was used to block Ca 2+ release from intracellular stores, we observed > 50% smaller NMDA-evoked Ca 2+ responses. These results quite surprisingly indicate that at least half the Ca 2+ response to NMDA is due to release of intracellular Ca 2+, a process triggered by influx of extracellular Ca 2+. Dantrolene also protected neurons from NMDA receptor-mediated neurotoxicity. Release of intracellular Ca 2+ may therefore be a necessary step in the cascade leading to neuronal damage induced by excessive NMDA receptor stimulation and may be amenable to pharmacological intervention.