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 Ca 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 Ca -dependent processes, independent of cell death. Among them Bcl-xL has been proposed to promote IPR1 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 Ca 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 Ca trafficking through IP 3 R channels.