Blockade of NMDA receptor-mediated mobilization of intracellular Ca2+ prevents neurotoxicity.
NMDA receptor activation leads to elevated Ca2+ in cultured rat cortical and retinal ganglion cell neurons. If excessive, this Ca2+ response is associated with delayed neurotoxicity. We used dantrolene and ionomycin to test if the Ca2+ response to NMDA was due to mobilization of intracellular Ca2+ stores rather than merely to Ca2+ influx. In the presence of EGTA, ionomycin resulted in release and subsequent depletion of intracellular Ca2+ stores. Henceforth, despite normal extracellular Ca2+, NMDA elicited only about half of its former Ca2+ response. Similarly, when dantrolene was used to block Ca2+ release from intracellular stores, we observed > 50% smaller NMDA-evoked Ca2+ responses. These results quite surprisingly indicate that at least half the Ca2+ response to NMDA is due to release of intracellular Ca2+, a process triggered by influx of extracellular Ca2+. Dantrolene also protected neurons from NMDA receptor-mediated neurotoxicity. Release of intracellular Ca2+ 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.
Lei
S Z
SZ
Department of Neurology, Children's Hospital, Boston, MA.
Zhang
D
D
Abele
A E
AE
Lipton
S A
SA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D003620:Dantrolene / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012165:Retinal Ganglion Cells / Q000187:drug effects*
D016194:Receptors, N-Methyl-D-Aspartate; D015759:Ionomycin; D003620:Dantrolene; D002118:Calcium