Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity
Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity
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DOI：
10.1016/j.cell.2004.11.049
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发表时间：
2005-01-28
期刊：
影响因子：
64.5
通讯作者：
Nicotera, P
中科院分区：
文献类型：
--
作者：
Bano, D;Young, KW;Nicotera, P
在脑缺血中，突触后谷氨酸受体和其他膜通道的门控触发细胞内Ca2+过载和细胞死亡。在兴奋性中毒的情况下，通过谷氨酸受体的初始Ca2+内流随后是第二次不受控制的Ca2+增加，导致神经元死亡。在这里，我们报道了主要的质膜Ca2+挤出系统，Na+/Ca2+交换器（NCX），在脑缺血和神经元经历兴奋毒性时被劈裂。Ca2+活化蛋白酶（calpain）通过过表达其内源性抑制剂蛋白calpastatin或未被calpain切割的NCX亚型的表达来抑制，可以防止Ca2+过载并拯救神经元免于兴奋性毒性死亡。相反，siRNA对NCX的下调损害了神经元对Ca2+的处理，将非兴奋性谷氨酸浓度引起的Ca2+瞬间转化为致命的Ca2+过载。因此，ncx驱动的神经元Ca2+挤压的蛋白水解激活是延迟兴奋性Ca2+解除管制和神经元死亡的原因。
In brain ischemia, gating of postsynaptic glutamate receptors and other membrane channels triggers intracellular Ca2+ overload and cell death. In excitotoxic settings, the initial Ca2+ influx through glutamate receptors is followed by a second uncontrolled Ca2+ increase that leads to neuronal demise. Here we report that the major plasma membrane Ca2+ extruding system, the Na+/Ca2+ exchanger (NCX), is cleaved during brain ischemia and in neurons undergoing excitotoxicity. Inhibition of Ca2+-activated proteases (calpains) by overexpressing their endogenous inhibitor protein, calpastatin or the expression of an NCX isoform not cleaved by calpains, prevented Ca2+ overload and rescued neurons from excitotoxic death. Conversely, down-regulation of NCX by siRNA compromised neuronal Ca2+ handling, transforming the Ca2+ transient elicited by non-excitotoxic glutamate concentrations into a lethal Ca2+ overload. Thus, proteolytic in,activation of NCX-driven neuronal Ca2+ extrusion is responsible for the delayed excitotoxic Ca2+ deregulation and neuronal death.