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

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.
Mesh Terms:
Animals, Apoptosis, Calcium, Calcium Channels, Calcium-Transporting ATPases, Endoplasmic Reticulum, Inositol 1,4,5-Trisphosphate Receptors, Membrane Proteins, Mice, Phosphorylation, Proto-Oncogene Proteins c-bcl-2, Receptors, Cytoplasmic and Nuclear, Thapsigargin, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein
Proc. Natl. Acad. Sci. U.S.A.
Date: Jan. 04, 2005
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