Bcl-xL and IP3R interaction: Intimate relationship with an uncertain outcome

Bcl-2 family proteins are major apoptosis regulators. They control a key step in apoptosis execution referred to as the mitochondrial outer membrane permeabilization. Several Bcl-2 homologs were also reported to act at the level of the endoplasmic reticulum (ER) where they control intracellular Ca²⁺ trafficking. There is an increasing body of evidence that, in addition to their conventional role as MOMP regulators, several Bcl-2 family members, including Bcl-xL, are linked to Ca²⁺ -dependent processes, independent of cell death. Among them Bcl-xL has been proposed to promote IP₃R1 channel opening and sustain mitochondrial bioenergetics. A recent article by Rosa and colleagues in Cell Death & Differentiation challenges this model and support the notion that Bcl-xL acts more as a repressor than as a sensitizer of IP3R1 opening. They suggest the existence of intrafamilial competition among the Bcl-2 family of protein with respect to their effect on IP3R Ca²⁺ permeability, which might be important regarding their respective non-canonical functions. In this regard, the results by Rosa and colleagues open exciting avenues regarding the biological process by which Bcl-xL affects Ca²⁺ trafficking through IP 3 R channels.