期刊
JOURNAL OF CELL SCIENCE
卷 127, 期 12, 页码 2782-2792出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.150011
关键词
Ca2+ signaling; Bcl-2; Ryanodine receptor; Hippocampus
类别
资金
- Research Foundation-Flanders (FWO) [G.0571.12, G.0134.09N]
- Research Council of the KU Leuven (OT START) [STRT1/10/044]
- Interuniversity Attraction Poles Program [P7/13, P7/10]
- Donders Center for Neuroscience fellowship award of the Radboud University Nijmegen Medical Center
- FP7-Marie Curie International Reintegration Grant [277091]
- FWO travel grant [V42613N]
The anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein not only counteracts apoptosis at the mitochondria by scaffolding proapoptotic Bcl-2-family members, but also acts at the endoplasmic reticulum, thereby controlling intracellular Ca2+ dynamics. Bcl-2 inhibits Ca2+ 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 Ca2+ release in HEK293 cell models. Finally, introducing the BH4-domain peptide into hippocampal neurons through a patch pipette decreased RyR-mediated Ca2+ release. In conclusion, this study identifies Bcl-2 as a new inhibitor of RyR-based intracellular Ca2+-release channels.
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