Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor
Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor
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DOI：
10.1016/j.neuron.2010.11.010
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发表时间：
2010-12-09
期刊：
影响因子：
16.2
通讯作者：
Mikoshiba, Katsuhiko
中科院分区：
文献类型：
--
作者：
Higo, Takayasu;Hamada, Kozo;Mikoshiba, Katsuhiko
紊乱的Ca2+信号和异常蛋白的积累引起内质网（ER）应激，这是许多神经退行性疾病中涉及的细胞死亡的标志。然而，潜在的机制是难以捉摸的。在这里，我们报告了内质网内Ca2+通道肌醇1,4,5-三磷酸受体（IP3R）的功能障碍，促进内质网应激时细胞死亡。杂合敲除脑显性1型IP3R （IP(3)R1）导致体内神经元对内质网应激的易感性，IP(3)R1敲除增强内质网应激诱导的培养细胞线粒体凋亡。IP(3)R1四聚体组装以能量依赖的方式受到ER伴侣GRP78的正调控。内质网应激通过受损的IP(3)R1- grp78相互作用诱导IP(3)R1功能障碍，这在亨廷顿病模型小鼠的大脑中也有观察到。这些结果表明，IP(3)R1通过GRP78感知内质网应激，改变Ca2+信号，促进与神经退行性疾病有关的神经元细胞死亡。
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.