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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 …