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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.
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Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum.

机译：促凋亡的BAX和BAK调节1型肌醇三磷酸受体和钙从内质网泄漏。

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摘要

Proapoptotic BCL-2 family members BAX and BAK are required for the initiation of mitochondrial dysfunction during apoptosis and for maintaining the endoplasmic reticulum (ER) Ca(2+) stores necessary for Ca(2+)-dependent cell death. Conversely, antiapoptotic BCL-2 has been shown to decrease Ca(2+) concentration in the ER. We found that Bax(-/-)Bak(-/-) double-knockout (DKO) cells have reduced resting ER Ca(2+) levels because of increased Ca(2+) leak and an increase in the Ca(2+)-permeable, hyperphosphorylated state of the inositol trisphosphate receptor type 1 (IP3R-1). The ER Ca(2+) defect of DKO cells is rescued by RNA interference reduction of IP3R-1, supporting the argument that this channel regulates the increased Ca(2+) leak in these cells. BCL-2 and IP3R-1 physically interact at the ER, and their binding is increased in the absence of BAX and BAK. Moreover, knocking down BCL-2 decreases IP3R-1 phosphorylation and ER Ca(2+) leak rate in the DKO cells. These findings support a model in which BCL-2 family members regulate IP3R-1 phosphorylation to control the rate of ER Ca(2+) leak from intracellular stores.
机译：凋亡的BCL-2家族成员BAX和BAK在细胞凋亡期间引发线粒体功能障碍和维持Ca（2+）依赖性细胞死亡所必需的内质网（ER）Ca（2+）存储所需。相反，已显示抗凋亡BCL-2可以降低ER中的Ca（2+）浓度。我们发现Bax（-/-）Bak（-/-）双敲除（DKO）细胞减少了静息ER Ca（2+）水平，因为增加了Ca（2+）泄漏并增加了Ca（2+ 1型肌醇三磷酸受体（IP3R-1）的可渗透性，高磷酸化状态。 DKO细胞的ER Ca（2+）缺陷可以通过IP3R-1的RNA干扰减少来挽救，支持这种通道调节这些细胞中增加的Ca（2+）泄漏的说法。 BCL-2和IP3R-1在ER处进行物理相互作用，并且在不存在BAX和BAK的情况下增加了它们的结合。此外，敲低BCL-2减少DKO细胞中IP3R-1磷酸化和ER Ca（2+）泄漏率。这些发现支持一个模型，其中BCL-2家族成员调节IP3R-1磷酸化，以控制从细胞内存储的ER Ca（2+）泄漏的速率。

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