Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum

The antiapoptotic protein Bcl-2 localizes not only to mitochondria but also to the endoplasmic reticulum (ER), However, the function of Bcl-2 at the l evel of the ER is poorly understood. In this study, we have investigated th e effects of Bcl-2 expression on Ca2+ storage and release by the ER. The ex pression of Bcl-2 decreased the amount of Ca2+ that could be released from intracellular stores, regardless of the mode of store depletion, the cell t ype, or the species from which Bcl-2 was derived. Bcl-2 also decreased cell ular Ca2+ store content in the presence of mitochondrial inhibitors, sugges ting that its effects were not mediated through mitochondrial Ca2+ uptake. Direct measurements with ER-targeted Ca2+-sensitive fluorescent "cameleon" proteins revealed that Bcl-2 decreased the free Ca2+ concentration within t he lumen of the ER, [Ca2+](ER). Analysis of the kinetics of Ca2+ store depl etion in response to the Ca2+-ATPase inhibitor thapsigargin revealed that B cl-2 increased the permeability of the ER membrane. These results suggest t hat Bcl-2 decreases the free Ca2+ concentration within the ER lumen by incr easing the Ca2+ permeability of the ER membrane. The increased ER Ca2+ perm eability conferred by Bcl-2 would be compatible with an ion channel functio n of Bcl-2 at the level of the ER membrane.