Expression of the endoplasmic reticulum molecular chaperone (ORP150) rescues hippocampal neurons from glutamate toxicity.
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.
Kitao
Y
Y
Department of Neuroanatomy, Kanazawa University Medical School, Kanazawa City, Ishikawa, Japan. kitao@nanat.m.kanazawa-u.ac.jp
Ozawa
K
K
Miyazaki
M
M
Tamatani
M
M
Kobayashi
T
T
Yanagi
H
H
Okabe
M
M
Ikawa
M
M
Yamashima
T
T
Stern
D M
DM
Hori
O
O
Ogawa
S
S
D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D018698:Glutamic Acid / Q000633:toxicity*; D018840:HSP70 Heat-Shock Proteins; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D011506:Proteins; C050087:oxygen-regulated proteins; D018698:Glutamic Acid