Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum

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Abstract
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.