Abstract
Cells subject to environmental change express stress proteins, which contribute importantly to maintenance of metabolic homeostasis and viability. As the most abundant cell type in the central nervous system, astrocytes show a phenotype resistant to environmental alterations. Based upon this ability of astrocytes, we have purified and cloned a novel stress protein, ORP150, a 150-kDa oxygen regulated protein. We have shown that ORP150 is an inducible chaperone present in endoplasmic reticulum (ER), which regulates cytosolic free calcium and activation of proteolytic pathways causing cell death in neurons subject to excitatory stress. Using mice heterozygous for ORP150 deficiency, exposure to excitatory stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic calcium accompanied by an 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. Our data underscore a pivotal role for ER stress in glutamate toxicity and pinpoint a key ER chaperone, ORP150, which orchestrates the protective stress response critical for neuronal survival.
