Increased Na+/Ca2+ exchanger activity promotes resistance to excitotoxicity in cortical neurons of the ground squirrel(a hibernator)

【作者】 柴真； 赵娟娟； 高珊； 景军展； 朱明月； 周辰； 魏军；

【机构】 北京大学生命科学学院/柴真实验室；

【摘要】 Ground squirrel,a hibernating mammalian species,is more resistant to ischemic brain stress than rat.Gaining insight into the adaptive mechanism of ground squirrels may help us design treatment strategies to reduce brain damage in patients suffering ischemic stroke.To understand the anti-stress mechanism in ground squirrel neurons,we studied glutamate toxicity in primary cultured neurons of the Daurian ground squirrel(Spermophilus dauricus).At the neuronal level,for the first time,we found that ground squirrel was more resistant to glutamate excitotoxicity than rat.Mechanistically,ground squirrel neurons displayed a similar calcium influx to the rat neurons in response to glutamate or N-methyl-D-aspartate(NMDA)perfusion.However,the rate of calcium removal in ground squirrel neurons was markedly faster than in rat neurons.This allows ground squirrel neurons to maintain lower level of intracellular calcium concentration([Ca2+]i)upon glutamate insult.Moreover,we found that Na+/Ca2+exchanger(NCX)activity was higher in ground squirrel neurons than in rat neurons.We also proved that overexpression of ground squirrel NCX2,rather than NCX1 or NCX3,in rat neurons promoted neuron survival against glutamate toxicity.Taken together,our results indicate that ground squirrel neurons are better at maintaining calcium homeostasis than rat neurons and this is likely achieved through the activity of ground squirrel NCX2.Our findings not only reveal an adaptive mechanisms of mammalian hibernators atthe cellular level,but also suggest that NCX2 of ground squirrel may have therapeutic value for suppressing brain ischemic damage.更多还原

【Abstract】 Ground squirrel,a hibernating mammalian species,is more resistant to ischemic brain stress than rat.Gaining insight into the adaptive mechanism of ground squirrels may help us design treatment strategies to reduce brain damage in patients suffering ischemic stroke.To understand the anti-stress mechanism in ground squirrel neurons,we studied glutamate toxicity in primary cultured neurons of the Daurian ground squirrel(Spermophilus dauricus).At the neuronal level,for the first time,we found that ground squirrel was more resistant to glutamate excitotoxicity than rat.Mechanistically,ground squirrel neurons displayed a similar calcium influx to the rat neurons in response to glutamate or N-methyl-D-aspartate(NMDA) perfusion.However,the rate of calcium removal in ground squirrel neurons was markedly faster than in rat neurons.This allows ground squirrel neurons to maintain lower level of intracellular calcium concentration([Ca2+]i) upon glutamate insult.Moreover,we found that Na+/Ca2+ exchanger(NCX) activity was higher in ground squirrel neurons than in rat neurons.We also proved that overexpression of ground squirrel NCX2,rather than NCX1 or NCX3,in rat neurons promoted neuron survival against glutamate toxicity.Taken together,our results indicate that ground squirrel neurons are better at maintaining calcium homeostasis than rat neurons and this is likely achieved through the activity of ground squirrel NCX2.Our findings not only reveal an adaptive mechanisms of mammalian hibernators atthe cellular level,but also suggest that NCX2 of ground squirrel may have therapeutic value for suppressing brain ischemic damage.更多还原