Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling.

Members of the Bcl-2 protein family play a central role in the regulation of apoptosis. An interaction between anti-apoptotic Bcl-xL and the endoplasmic reticulum (ER)-localized inositol trisphosphate receptor Ca2+ release channel (InsP3R) enables Bcl-xL to be fully efficacious as an anti-apoptotic mediator (White, C., Li, C., Yang, J., Petrenko, N. B., Madesh, M., Thompson, C. B., and Foskett, J. K. (2005) Nat. Cell Biol. 7, 1021–1028). Physiologically, Bcl-xL binds to the InsP3R to enhance its gating and Ca2+ signaling. Here we have discovered that structurally related proteins Bcl-2 and Mcl-1 function similarly. Bcl-2, Mcl-1 and Bcl-xL bind with comparable affinity to the carboxyl termini of all three mammalian InsP3R isoforms with important functional consequences. Stable expression of Bcl-2 or Mcl-1 lowered ER Ca2+ content and enhanced the rate of InsP3-mediated Ca2+ release in response to submaximal InsP3 stimulation in permeabilized wild-type DT40 cells but not in cells lacking InsP3R. In addition, expression of either Bcl-2 or Mcl-1 enhanced spontaneous InsP3R-dependent Ca2+ oscillations and spiking in intact cells in the absence of agonist stimulation. Bcl-2- and Mcl-1-mediated protection from apoptosis induced by staurosporine or etoposide was enhanced in cells expressing InsP3R, demonstrating that their interactions with InsP3R enable Bcl-2 and Mcl-1 to be fully efficacious anti-apoptotic mediators. Our data suggest a molecular mechanism that is shared by several anti-apoptotic Bcl-2 proteins that provides apoptosis resistance by direct interactions at the ER with the InsP3R that impinges on cellular Ca2+ homeostasis.