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首页> 外文期刊>Neuron >Mechanism of ER stress-induced brain damage by IP(3) receptor.
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Mechanism of ER stress-induced brain damage by IP(3) receptor.

机译：IP（3）受体的内质网应激诱发脑损伤的机制。

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摘要

Deranged Ca(2+) 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 Ca(2+) channel, inositol 1,4,5-trisphosphate receptor (IP(3)R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP(3)R (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 Ca(2+) signal to promote neuronal cell death implicated in neurodegenerative diseases.
机译：紊乱的Ca（2+）信号传导和异常蛋白的积累引起内质网（ER）压力，这是许多神经退行性疾病中所涉及的细胞死亡的标志。但是，潜在的机制是难以捉摸的。在这里，我们报告功能障碍的居民驻地的Ca（2+）通道，肌醇1,4,5-三磷酸受体（IP（3）R），​​促进细胞内质网应激期间死亡。脑优势型1型IP（3）R（IP（3）R1）的杂合敲除导致神经元在体内对ER应激具有脆弱性，而IP（3）R1敲低则通过线粒体增强了ER应激诱导的细胞凋亡。 IP（3）R1四聚体组装受到ER伴侣GRP78的能量依赖性正调控。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，这也在亨廷顿病模型小鼠的大脑中观察到。这些结果表明IP（3）R1通过GRP78感应ER应激，以改变Ca（2+）信号，从而促进神经退行性疾病中涉及的神经元细胞死亡。

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