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Apoptosis protection by Mcl-1 and Bcl-2 modulation of inositol 1,4,5-trisphosphate receptor-dependent Ca2+ signaling

Emily F Eckenrode1, Jun Yang, Gopal V Velmurugan

  • 1Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.

The Journal of Biological Chemistry
|March 2, 2010
PubMed

Insights

Several Bcl-2 family proteins, including Bcl-2 and Mcl-1, interact with the inositol trisphosphate receptor (InsP3R) to regulate calcium (Ca2+) signaling and enhance apoptosis resistance. This interaction is crucial for their anti-apoptotic functions.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Bcl-2 protein family is critical for regulating apoptosis (programmed cell death).
  • The anti-apoptotic protein Bcl-x(L) interacts with the endoplasmic reticulum (ER) inositol trisphosphate receptor (InsP3R) to enhance its function and mediate anti-apoptotic effects.
  • This interaction modulates calcium (Ca2+) signaling, a key cellular process.

Purpose of the Study:

  • To investigate whether other Bcl-2 family members, specifically Bcl-2 and Mcl-1, interact with the InsP3R.
  • To determine if these interactions affect InsP3R function and contribute to anti-apoptotic activity.
  • To elucidate the role of InsP3R interaction in the efficacy of Bcl-2 and Mcl-1 as anti-apoptotic mediators.

Main Methods:

  • Studied the binding affinity of Bcl-2, Mcl-1, and Bcl-x(L) to the carboxyl termini of InsP3R isoforms.
  • Assessed the impact of Bcl-2 and Mcl-1 expression on ER Ca2+ content and InsP3-mediated Ca2+ release in permeabilized and intact cells.
  • Evaluated the anti-apoptotic effects of Bcl-2 and Mcl-1 in cells with and without InsP3R expression.

Main Results:

  • Bcl-2, Mcl-1, and Bcl-x(L) bind to InsP3R with comparable affinities.
  • Expression of Bcl-2 or Mcl-1 reduced ER Ca2+ content and accelerated InsP3-induced Ca2+ release.
  • Bcl-2 and Mcl-1 enhanced spontaneous Ca2+ oscillations and spiking, and their anti-apoptotic protection was augmented in InsP3R-expressing cells.

Conclusions:

  • Bcl-2 and Mcl-1, similar to Bcl-x(L), interact with the InsP3R to modulate Ca2+ homeostasis.
  • These interactions are essential for the full anti-apoptotic efficacy of Bcl-2 and Mcl-1.
  • A shared molecular mechanism involving ER Ca2+ regulation by anti-apoptotic Bcl-2 proteins contributes to apoptosis resistance.

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