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J Cell Sci. 2014 Jun 15;127(Pt 12):2782-92. doi: 10.1242/jcs.150011. Epub 2014 Apr 24.

Bcl-2 binds to and inhibits ryanodine receptors.

Author information

1
KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium.
2
University of Ghent, Physiology Group, Department Basic Medical Sciences, B-9000 Ghent, Belgium.
3
Institut de Neurobiologie Alfred Fessard, CNRS, Laboratoire de Neurobiologie et Développement, 91198 Gif sur Yvette cedex, France.
4
University of Siena, Molecular Medicine Section, Department of Molecular and Developmental Medicine, and Interuniversitary Institute of Myology, 53100 Siena, Italy.
5
Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, 6500HB Nijmegen, The Netherlands.
6
KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium geert.bultynck@med.kuleuven.be.

Abstract

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.

KEYWORDS:

Bcl-2; Ca2+ signaling; Hippocampus; Ryanodine receptor

PMID:
24762814
DOI:
10.1242/jcs.150011
[Indexed for MEDLINE]
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