Hanson, C. Jane; Bootman, Martin D.; Distelhorst, Clark W.; Wojcikiewicz, Richard J. H. and Roderick, H. Llewelyn
Bcl-2 suppresses Ca2+ release through inositol 1,4,5-trisphosphate receptors and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content.
Cell Calcium, 44(3),
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Cell survival is promoted by the oncoprotein Bcl-2. Previous studies have established that one of the pro-survival actions of Bcl-2 is to reduce cellular fluxes of Ca2+ within cells. In particular, Bcl-2 has been demonstrated to inhibit the release of Ca2+ from the endoplasmic reticulum. However, the mechanism by which Bcl-2 causes reduced Ca2+ release is unclear. In the accompanying paper [C.J. Hanson, M.D. Bootman, C.W. Distelhorst, T. Maraldi, H.L. Roderick, The cellular concentration of Bcl-2 determines its pro- or anti-apoptotic effect, Cell Calcium (2008)], we described that only stable expression of Bcl-2 allowed it to work in a pro-survival manner whereas transient expression did not. In this study, we have employed HEK-293 cells that stably express Bcl-2, and which are, therefore, protected from pro-apoptotic stimuli, to examine the effect of Bcl-2 on Ca2+ homeostasis and signalling. We observed that Bcl-2 expression decreased the Ca2+ responses of cells induced by application of submaximal agonist concentrations. Whereas, decreasing endogenous Bcl-2 concentration using siRNA potentiated Ca2+ responses. Furthermore, we found that Bcl-2 expression reduced mitochondrial Ca2+ uptake by raising the threshold cytosolic Ca2+ concentration required to activate sequestration. Using a number of different assays, we did not find any evidence for reduction of endoplasmic reticulum luminal Ca2+ in our Bcl-2-expressing cells. Indeed, we observed that Bcl-2 served to preserve the content of the agonist-sensitive Ca2+ pool. Endogenous Bcl-2 was found to interact with inositol 1,4,5-trisphosphate receptors (InsP3Rs) in our cells, and to modify the profile of InsP3R expression. Our data suggest that the presence of Bcl-2 in the proteome of cells has multiple effects on agonist-mediated Ca2+ signals, and can abrogate responses to submaximal levels of stimulation through direct control of InsP3Rs.
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Bcl-2 suppresses Ca2+ release through inositol 1,4,5-trisphosphate receptors and inhibits Ca2+ uptake by mitochondria without affecting ER calcium store content. (deposited 20 Nov 2012 11:46)
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