2010年12月
Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor
NEURON
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- 巻
- 68
- 号
- 5
- 開始ページ
- 865
- 終了ページ
- 878
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1016/j.neuron.2010.11.010
- 出版者・発行元
- CELL PRESS
Deranged Ca2+ signaling and an accumulation of aberrant proteins cause endoplasmic reticulum (ER) stress, which is a hallmark of cell death implicated in many neurodegenerative diseases. However, the underlying mechanisms are elusive. Here, we report that dysfunction of an ER-resident Ca2+ channel, inositol 1,4,5-trisphosphate receptor (IP3R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP3R (IP(3)R1) resulted in neuronal vulnerability to ER stress in vivo, and IP(3)R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP(3)R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP(3)R1 dysfunction through an impaired IP(3)R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP(3)R1 senses ER stress through GRP78 to alter the Ca2+ signal to promote neuronal cell death implicated in neurodegenerative diseases.
- リンク情報
- ID情報
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- DOI : 10.1016/j.neuron.2010.11.010
- ISSN : 0896-6273
- PubMed ID : 21145001
- Web of Science ID : WOS:000285664900009