biostudies-literatureRosa NOnderzoeksraad, KU LeuvenNIDCR NIH HHSU.S. Department of Health &amp; Human Services | NIH | National Institute of Dental and Craniofacial ResearchFederaal WetenschapsbeleidFonds Wetenschappelijk OnderzoekCentral European Leuven Strategic Alliance - CELSA/18/040Gouvernement du Canada | Canadian Institutes of Health ResearchCIHR788-805https://www.ebi.ac.uk/biostudies/studies/S-EPMC8990011biostudies-literatureUnknown29(4)Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca²⁺ dynamics by controlling IP₃ receptor (IP₃R) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IP₃Rs and preventing pro-apoptotic Ca²⁺ release and Bcl-xL sensitizing IP₃Rs to low [IP₃] and promoting pro-survival Ca²⁺ oscillations. We here demonstrate that Bcl-xL too inhibits IP₃R-mediated Ca²⁺ release by interacting with the same IP₃R regions as Bcl-2. Via in silico superposition, we previously found that the residue K87 of Bcl-xL spatially resembled K17 of Bcl-2, a residue critical for Bcl-2's IP<sub>3</sCell death and differentiationBcl-xL acts as an inhibitor of IP₃R channels, thereby antagonizing Ca²⁺-driven apoptosis.PMC8990011G0H1716NR01 DE014756FDN143312AKUL/19/34R56 DE014756AKUL/15/34OT14/101DE014756C14/19/099IAP-P7/13G.0901.18NW0.019.17N12P0919NC14/19/101Karamanou SYule DIBultynck GHamada KSchymkowitz JRousseau FRosa NLa Rovere RLemmens IVandermarliere EAndo HAndrews DWShabardina VEconomou AWagner LEWelkenhuyzen KIvanova HTavernier JLouros NKale JParys JBMikoshiba KfalseBcl-xL acts as an inhibitor of IP₃R channels, thereby antagonizing Ca²⁺-driven apoptosis.Anti-apoptotic Bcl-2-family members not only act at mitochondria but also at the endoplasmic reticulum, where they impact Ca²⁺ dynamics by controlling IP₃ receptor (IP₃R) function. Current models propose distinct roles for Bcl-2 vs. Bcl-xL, with Bcl-2 inhibiting IP₃Rs and preventing pro-apoptotic Ca²⁺ release and Bcl-xL sensitizing IP₃Rs to low [IP₃] and promoting pro-survival Ca²⁺ oscillations. We here demonstrate that Bcl-xL too inhibits IP₃R-mediated Ca²⁺ release by interacting with the same IP₃R regions as Bcl-2. Via in silico superposition, we previously found that the residue K87 of Bcl-xL spatially resembled K17 of Bcl-2, a residue critical for Bcl-2's IP<sub>3</s2022-01-01T00:00:00Z2022 Apr2025-04-04T08:24:03.239Z2025-04-04T08:24:03.239ZS-EPMC89900113475053810.1038/s41418-021-00894-w