Estrogen attenuates glutamate-induced cell death by inhibiting Ca²⁺ influx through L-type voltage-gated Ca²⁺ channels

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• 作者：Eric A. Sribnick ; Angelo M. Del Re ; Swapan K. Ray ; John J. Woodward ; Naren L. Banik
• 关键词：Apoptosis ; Calpain ; Ca²⁺ influx ; Caspase-3 ; Glutamate ; Motoneurons ; Nifedipine
• 刊名：Brain Research
• 出版年：2009
• 出版时间：18 June 2009
• 年：2009
• 卷：1276
• 期：Complete
• 页码：159-170
• 全文大小：1708 K

文摘

Estrogen-mediated neuroprotection is observed in neurodegenerative disease and neurotrauma models; however, determining a mechanism for these effects has been difficult. We propose that estrogen may limit cell death in the nervous system tissue by inhibiting increases in intracellular free Ca²⁺. Here, we present data using VSC 4.1 cell line, a ventral spinal motoneuron and neuroblastoma hybrid cell line. Treatment with 1 mM glutamate for 24 h induced apoptosis. When cells were pre-treated with 100 nM 17β-estradiol (estrogen) for 1 h and then co-treated with glutamate, apoptotic death was significantly attenuated. Estrogen also prevented glutamate-mediated changes in resting membrane potential and membrane capacitance. Treatment with either 17α-estradiol or cell impermeable estrogen did not mimic the findings seen with estrogen. Glutamate treatment significantly increased both intracellular free Ca²⁺ and the activities of downstream proteases such as calpain and caspase-3. Estrogen attenuated both the increases in intracellular free Ca²⁺ and protease activities. In order to determine the pathway responsible for estrogen-mediated inhibition of these increases in intracellular free Ca²⁺, cells were treated with several Ca²⁺ entry inhibitors, but only the L-type Ca²⁺ channel blocker nifedipine demonstrated cytoprotective effects comparable to estrogen. To expand these findings, cells were treated with the L-type Ca²⁺ channel agonist FPL 64176, which increased both cell death and intracellular free Ca²⁺, and estrogen inhibited both effects. From these observations, we conclude that estrogen limits glutamate-induced cell death in VSC 4.1 cells through effects on L-type Ca²⁺ channels, inhibiting Ca²⁺ influx as well as activation of the pro-apoptotic proteases calpain and caspase-3.