Bcl-2 proteins and calcium signaling: complexity beneath the surface

Antiapoptotic Bcl-2-family members are well known for their 'mitochondrial' functions as critical neutralizers of proapoptotic Bcl-2-family members, including the executioner multidomain proteins Bax and Bak and the BH3-only proteins. It has been clear for more than 20 years that Bcl-2 proteins can impact intracellular Ca2+ homeostasis and dynamics. Moreover, altered Ca2+ signaling is increasingly linked to oncogenic behavior. Specifically targeting the Ca2+-signaling machinery may thus prove to be a valuable strategy for cancer treatment. Over 10 years ago a major controversy was recognized concerning whether or not Bcl-2 proteins exerted their antiapoptotic functions via Ca2+ signaling through lowering the filling state of the endoplasmic reticulum (ER) Ca2+ stores or by suppressing Ca2+ release from the ER without affecting the filling state of this Ca2+ store. Further research from different laboratories indicated a wide variety of mechanisms by which Bcl-2-family members can impact Ca2+ signaling. In this review, we propose that antiapoptotic Bcl-2-family members are multimodal regulators of intracellular Ca2+-signaling events in cell survival and cell death. We will discuss how different Bcl-2-family members impact cell survival and cell death by regulating Ca2+ transport systems at the ER, mitochondria and plasma membrane and by impacting the organization of organelles and how these insights can be exploited for causing cell death in cancer cells. Finally, we propose that the existing controversy reflects the diversity of links between Bcl-2 proteins and Ca2+ signaling, as certainly not all targets or mechanisms will be operative in every cell type and every condition.