The endoplasmic reticulum gateway to apoptosis by Bcl-X_L modulation of the InsP₃R

Members of the Bcl-2 protein family modulate outer mitochondrial membrane permeability to control apoptosis. However, these proteins also localize to the endoplasmic reticulum (ER), the functional significance of which is controversial. Here we provide evidence that anti-apoptotic Bcl-2 proteins regulate the inositol 1,4,5-trisphosphate receptor (InsP₃R) ER Ca²⁺ release channel resulting in increased cellular apoptotic resistance and enhanced mitochondrial bioenergetics. Anti-apoptotic Bcl-X_L interacts with the carboxyl terminus of the InsP₃R and sensitizes single InsP₃R channels in ER membranes to low [InsP₃], enhancing Ca²⁺ and InsP₃-dependent regulation of channel activity in vitro and in vivo, reducing ER Ca²⁺ content and stimulating mitochondrial energetics. The pro-apoptotic proteins Bax and tBid antagonize this effect by blocking the biochemical interaction of Bcl-X_L with the InsP₃R. These data support a novel model in which Bcl-X_L is a direct effector of the InsP₃R, increasing its sensitivity to InsP₃ and enabling ER Ca²⁺ release to be more sensitively coupled to extracellular signals. As a consequence, cells are protected against apoptosis by a more sensitive and dynamic coupling of ER to mitochondria through Ca²⁺-dependent signal transduction that enhances cellular bioenergetics and preserves survival.