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PMID:15613488
| Citation |
Oakes, SA, Scorrano, L, Opferman, JT, Bassik, MC, Nishino, M, Pozzan, T and Korsmeyer, SJ (2005) Proapoptotic BAX and BAK regulate the type 1 inositol trisphosphate receptor and calcium leak from the endoplasmic reticulum. Proc. Natl. Acad. Sci. U.S.A. 102:105-10 |
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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. |
| Links |
PubMed PMC544078 Online version:10.1073/pnas.0408352102 |
| Keywords |
Animals; Apoptosis/physiology; Calcium/metabolism; Calcium Channels/metabolism; Calcium-Transporting ATPases/antagonists & inhibitors; Endoplasmic Reticulum/drug effects; Endoplasmic Reticulum/metabolism; Inositol 1,4,5-Trisphosphate Receptors; Membrane Proteins/genetics; Membrane Proteins/metabolism; Mice; Phosphorylation; Proto-Oncogene Proteins c-bcl-2/genetics; Proto-Oncogene Proteins c-bcl-2/metabolism; Receptors, Cytoplasmic and Nuclear/metabolism; Thapsigargin/pharmacology; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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