Bcl-2 binds to and inhibits ryanodine receptors

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Updated: Apr 30, 2026

Functional Characterization of Endogenously Expressed Human RYR1 Variants
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Functional Characterization of Endogenously Expressed Human RYR1 Variants

Published on: June 9, 2021

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Tim Vervliet1, Elke Decrock2, Jordi Molgó3

  • 1KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, B-3000 Leuven, Belgium.

Journal of Cell Science
|April 26, 2014
PubMed

Insights

B-cell lymphoma-2 (Bcl-2) inhibits calcium release channels called ryanodine receptors (RyRs). This study reveals Bcl-2 directly binds RyRs, dampening calcium release in cellular models and neurons.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • B-cell lymphoma-2 (Bcl-2) is an anti-apoptotic protein regulating mitochondrial function and intracellular calcium (Ca2+) dynamics.
  • Bcl-2 inhibits Ca2+ release by targeting the inositol 1,4,5-trisphosphate receptor (IP3R) at the endoplasmic reticulum.

Purpose of the Study:

  • To investigate if Bcl-2 interacts with ryanodine receptors (RyRs), another class of intracellular Ca2+-release channels.
  • To determine if Bcl-2 modulates RyR activity and Ca2+ release.

Main Methods:

  • Co-immunoprecipitation assays to detect Bcl-2 and RyR complexes in vitro and in native rat hippocampi.
  • Pulldown and surface plasmon resonance (SPR) experiments to analyze direct binding between Bcl-2 and purified RyR domains.
  • Functional assays in HEK293 cells and primary hippocampal neurons to assess the impact of Bcl-2 on RyR-mediated Ca2+ release.

Main Results:

  • Endogenous Bcl-2 and RyR proteins form complexes in rat hippocampi.
  • The BH4 domain of Bcl-2 directly binds to specific RyR domains.
  • Bcl-2 and its BH4 domain peptide significantly inhibit RyR-mediated Ca2+ release in cellular models and neurons.

Conclusions:

  • Bcl-2 acts as a novel inhibitor of RyR-based Ca2+-release channels.
  • This interaction provides a new mechanism for regulating intracellular Ca2+ signaling by Bcl-2.
  • The findings open new avenues for understanding Bcl-2's role beyond apoptosis and in calcium channel regulation.
Keywords:
Bcl-2Ca2+ signalingHippocampusRyanodine receptor

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