期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：5
页码：2842-2847
DOI：10.1073/pnas.0438041100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Estrogens are neuroprotective against glutamate excitotoxicity caused by an excessive rise in intracellular calcium ([Ca2+]i). In this study, we demonstrate that 17{beta}-estradiol (E2) treatment of hippocampal neurons attenuated the excitotoxic glutamate-induced rise in bulk-free [Ca2+]i despite potentiating the influx of Ca2+ induced by glutamate. E2-induced attenuation of bulk-free [Ca2+]i depends on mitochondrial sequestration of Ca2+, which is blocked in the presence of the combination of rotenone and oligomycin or in the presence of antimycin, which collapse the mitochondrial membrane potential, thereby preventing mitochondrial Ca2+ transport. Release of mitochondrial Ca2+ by carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) after excitotoxic glutamate treatment resulted in a greater [Ca2+]i in E2-treated cells, indicating an E2-induced increase in the mitochondrial calcium ([Ca2+]m) load. The increased [Ca2+]m load was accompanied by increased expression of Bcl-2, which can promote mitochondrial Ca2+ load tolerance. These findings provide a mechanism of E2-induced neuronal survival by attenuation of excitotoxic glutamate [Ca2+]i rise via increased mitochondrial sequestration of cytosolic Ca2+ coupled with an increase in Bcl-2 expression to sustain mitochondrial Ca2+ load tolerance and function.
