Bcl-2-Protein Family as Modulators of IP3 Receptors and Other Organellar Ca2+ Channels

The pro- and antiapoptotic proteins belonging to the B-cell lymphoma-2 (Bcl-2) family exert a critical control over cell-death processes by enabling or counteracting mitochondria! outer membrane permeabilization. Beyond this mitochondria! function, several Bcl-2 family members have emerged as critical modulators of intracellular Ca2+ homeostasis and dynamics, showing proapoptotic and antiapoptotic functions. Bcl-2 family proteins specifically target several intracellular Ca2+-transport systems, including organellar Ca2+ channels: inositol 1,4,5-trisphosphate receptors (IP(3)Rs) and ryanodine receptors (RyRs), Ca2+-release channels mediating Ca2+ flux from the endoasmic reticulum, as well as voltage-dependent anion channels (VDACs), which mediate Ca2+ flux across the mitochondria! outer membrane into the mitochondria. Although the formation of protein complexes between Bcl-2 proteins and these channels has been extensively studied, a major advance during recent years has been elucidating the complex interaction of Bcl-2 proteins with IP(3)Rs. Distinct interaction sites for different Bcl-2 family members were identified in the primary structure of IP(3)Rs. The unique molecular profiles of these Bcl-2 proteins may account for their distinct functional outcomes when bound to IP(3)Rs. Furthermore, Bcl-2 inhibitors used in cancer therapy may affect IP3R function as part of their proapoptotic effect and/or as an adverse effect in healthy cells.