Expression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity

A series of events initiated by glutamate-receptor interaction perturbs cel lular homeostasis resulting in elevation of intracellular free calcium and cell death. Cells subject to such environmental change express stress prote ins, which contribute importantly to maintenance of metabolic homeostasis a nd viability. We show that an inducible chaperone present in endoplasmic re ticulum (ER), the 150-kDa oxygen-regulated protein (ORP150), is expressed b oth in the human brain after seizure attack and in mouse hippocampus after kainate administration. Using mice heterozygous for ORP150 deficiency, expo sure to excitatory stimuli caused hippocampal neurons to display exaggerate d elevation of cytosolic calcium accompanied by activation of mu -calpain a nd cathepsin B, as well as increased vulnerability to glutamate-induced cel l death in vitro and decreased survival to kainate in vivo. In contrast, ta rgeted neuronal overexpression of ORP150 suppressed each of these events an d enhanced neuronal and animal survival in parallel with diminished seizure intensity. Studies using cultured hippocampal neurons showed that ORP150 r egulates cytosolic free calcium and activation of proteolytic pathways caus ing 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 ne uronal survival.