Article Dans Une Revue Journal of Cell Science Année : 2014

Bcl-2 binds to and inhibits ryanodine receptors.

Résumé

The anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein not only counteracts apoptosis at the mitochondria by scaffolding pro-apoptotic Bcl-2-family members, but also acts at the endoplasmic reticulum, thereby controlling intracellular Ca(2+) dynamics. Bcl-2 inhibits Ca(2+) release by targeting the inositol 1,4,5-trisphosphate receptor (IP3R). Sequence analysis has revealed that the Bcl-2-binding site on the IP3R displays strong similarity with a conserved sequence present in all three ryanodine receptor (RyR) isoforms. We now report that Bcl-2 co-immunoprecipitated with RyRs in ectopic expression systems and in native rat hippocampi, indicating that endogenous RyR-Bcl-2 complexes exist. Purified RyR domains containing the putative Bcl-2-binding site bound full-length Bcl-2 in pulldown experiments and interacted with the BH4 domain of Bcl-2 in surface plasmon resonance (SPR) experiments, suggesting a direct interaction. Exogenous expression of full-length Bcl-2 or electroporation loading of the BH4 domain of Bcl-2 dampened RyR-mediated Ca(2+) release in HEK293 cell models. Finally, introducing the BH4-domain peptide into hippocampal neurons through a patch pipette decreased RyR-mediated Ca(2+) release. In conclusion, this study identifies Bcl-2 as a new inhibitor of RyR-based intracellular Ca(2+)-release channels.

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hal-01178836 , version 1 (06-01-2025)

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Tim Vervliet, Elke Decrock, Jordi Molgó, Vincenzo Sorrentino, Ludwig Missiaen, et al.. Bcl-2 binds to and inhibits ryanodine receptors.. Journal of Cell Science, 2014, 127 (Pt 12), pp.2782-92. ⟨10.1242/jcs.150011⟩. ⟨hal-01178836⟩
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