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Bcl-2 binds to and inhibits ryanodine receptors

(2014) JOURNAL OF CELL SCIENCE. 127(12). p.2782-2792
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Abstract
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.
Keywords
Ryanodine receptor, Ca2+ signaling, Hippocampus, Bcl-2, INOSITOL 1, 4, 5-TRISPHOSPHATE RECEPTORS, ENDOPLASMIC-RETICULUM STRESS, KDA FK506-BINDING PROTEIN, CA2+ RELEASE CHANNELS, CALCIUM-RELEASE, IP3 RECEPTOR, CELL-DEATH, ANTIAPOPTOTIC ACTIVITY, SKELETAL-MUSCLE, CENTRAL DOMAIN

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Citation

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Chicago
Vervliet, Tim, Elke Decrock, Jordi Molgó, Vincenzo Sorrentino, Ludwig Missiaen, Luc Leybaert, Humbert De Smedt, Nael Nadif Kasri, Jan B Parys, and Geert Bultynck. 2014. “Bcl-2 Binds to and Inhibits Ryanodine Receptors.” Journal of Cell Science 127 (12): 2782–2792.
APA
Vervliet, T., Decrock, E., Molgó, J., Sorrentino, V., Missiaen, L., Leybaert, L., De Smedt, H., et al. (2014). Bcl-2 binds to and inhibits ryanodine receptors. JOURNAL OF CELL SCIENCE, 127(12), 2782–2792.
Vancouver
1.
Vervliet T, Decrock E, Molgó J, Sorrentino V, Missiaen L, Leybaert L, et al. Bcl-2 binds to and inhibits ryanodine receptors. JOURNAL OF CELL SCIENCE. 2014;127(12):2782–92.
MLA
Vervliet, Tim, Elke Decrock, Jordi Molgó, et al. “Bcl-2 Binds to and Inhibits Ryanodine Receptors.” JOURNAL OF CELL SCIENCE 127.12 (2014): 2782–2792. Print.
@article{5829833,
  abstract     = {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.},
  author       = {Vervliet, Tim and Decrock, Elke and Molg{\'o}, Jordi and Sorrentino, Vincenzo and Missiaen, Ludwig and Leybaert, Luc and De Smedt, Humbert and Kasri, Nael Nadif and Parys, Jan B and Bultynck, Geert},
  issn         = {0021-9533},
  journal      = {JOURNAL OF CELL SCIENCE},
  language     = {eng},
  number       = {12},
  pages        = {2782--2792},
  title        = {Bcl-2 binds to and inhibits ryanodine receptors},
  url          = {http://dx.doi.org/10.1242/jcs.150011},
  volume       = {127},
  year         = {2014},
}

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