Kitao Y, Ozawa K, Miyazaki M, Tamatani M, Kobayashi T, Yanagi H, Okabe M, Ikawa M, Yamashima T, Stern D M, Hori O, Ogawa S
Department of Neuroanatomy, Kanazawa University Medical School, Kanazawa City, Ishikawa, Japan.
J Clin Invest. 2001 Nov;108(10):1439-50. doi: 10.1172/JCI12978.
A series of events initiated by glutamate-receptor interaction perturbs cellular homeostasis resulting in elevation of intracellular free calcium and cell death. Cells subject to such environmental change express stress proteins, which contribute importantly to maintenance of metabolic homeostasis and viability. We show that an inducible chaperone present in endoplasmic reticulum (ER), the 150-kDa oxygen-regulated protein (ORP150), is expressed both in the human brain after seizure attack and in mouse hippocampus after kainate administration. Using mice heterozygous for ORP150 deficiency, exposure to excitatory stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic calcium accompanied by activation of mu-calpain and cathepsin B, as well as increased vulnerability to glutamate-induced cell death in vitro and decreased survival to kainate in vivo. In contrast, targeted neuronal overexpression of ORP150 suppressed each of these events and enhanced neuronal and animal survival in parallel with diminished seizure intensity. Studies using cultured hippocampal neurons showed that ORP150 regulates cytosolic free calcium and activation of proteolytic pathways causing cell death in neurons subject to excitatory stress. Our data underscore a possible role for ER stress in glutamate toxicity and pinpoint a key ER chaperone, ORP150, which contributes to the stress response critical for neuronal survival.
由谷氨酸受体相互作用引发的一系列事件扰乱了细胞内稳态，导致细胞内游离钙升高和细胞死亡。遭受这种环境变化的细胞会表达应激蛋白，这些蛋白对维持代谢稳态和细胞活力起着重要作用。我们发现，内质网（ER）中存在的一种可诱导伴侣蛋白，即150 kDa的氧调节蛋白（ORP150），在癫痫发作后的人脑中以及在给予海藻酸后的小鼠海马体中均有表达。使用ORP150缺陷的杂合小鼠，暴露于兴奋性刺激会导致海马神经元胞质钙过度升高，同时伴有μ-钙蛋白酶和组织蛋白酶B的激活，以及在体外对谷氨酸诱导的细胞死亡的易感性增加和在体内对海藻酸的存活率降低。相反，靶向神经元过表达ORP150可抑制这些事件中的每一个，并增强神经元和动物的存活率，同时癫痫发作强度降低。使用培养的海马神经元进行的研究表明，ORP150调节胞质游离钙和导致兴奋性应激神经元细胞死亡的蛋白水解途径的激活。我们的数据强调了内质网应激在谷氨酸毒性中的可能作用，并确定了一种关键的内质网伴侣蛋白ORP150，它有助于对神经元存活至关重要的应激反应。
