Recent work has shown that Bcl-2 and other anti-apoptotic proteins partially deplete the endoplasmic reticulum (EB) Ca2+ store and that this alteration of Ca2+ signaling reduces cellular sensitivity to apoptotic stimuli. We expressed in HeLa cells Bcl-2, Bax, and Bcl-2/Bax chimeras in which the putative pore-forming domains of the two proteins (α5-α6) were mutually swapped, comparing the effects on Ca 2+ signaling of the two proteins and relating them to defined molecular domains. The results showed that only Bcl-2 reduces ER Ca2+ levels and that this effect does not depend on the α5-α6 helices of this oncoprotein. Soon after its expression, Bax increased ER Ca2+ loading, with ensuing potentiation of mitochondrial Ca2+ responses. Then the cells progressed into an apoptotic plienotype (which included drastic reductions of cytosolic and mitochondrial Ca2+ responses and alterations of organelle morphology). These results provide a coherent scenario that highlights a primary role of Ca2+ signals in deciphering apoptotic stimuli.
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