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Suppression of calcium release from inositol 1,4,5-trisphosphate-sensitive stores mediates the anti-apoptotic

Simonetta Camandola1, Roy G Cutler, Devin S Gary

  • 1Laboratory of Neurosciences, National Institute on Aging/NIH, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA. camandolasi@grc.nia.nih.gov

The Journal of Biological Chemistry
|April 9, 2005
PubMed

Insights

Nuclear factor-kappaB (NF-kappaB) prevents cell death by regulating calcium signaling. NF-kappaB activation decreases calcium release via inositol trisphosphate (IP3) receptors, promoting cell survival.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Nuclear factor-kappaB (NF-kappaB) activation by various stimuli confers resistance to apoptosis.
  • The precise molecular mechanisms underlying NF-kappaB's anti-apoptotic function remain largely unknown.
  • Calcium signaling is implicated in cellular stress responses and apoptosis.

Purpose of the Study:

  • To elucidate the mechanism by which NF-kappaB activation prevents apoptosis.
  • To investigate the role of calcium signaling in NF-kappaB-mediated cell survival.
  • To identify specific targets of NF-kappaB involved in regulating calcium homeostasis.

Main Methods:

  • Utilized embryonic fibroblasts deficient in the RelA (p65) subunit of NF-kappaB.
  • Measured inositol 1,4,5-trisphosphate (IP(3)) receptor-mediated calcium release from the endoplasmic reticulum (ER).
  • Assessed apoptosis sensitivity, ER calcium pool size, and IP(3) receptor levels under varying NF-kappaB activity conditions.
  • Investigated the effects of IP(3) receptor antagonism and Bcl-2 overexpression.

Main Results:

  • RelA-deficient cells showed increased IP(3) receptor-mediated calcium release and apoptosis sensitivity.
  • NF-kappaB activation decreased ER calcium pool size and IP(3) receptor levels.
  • Blocking IP(3) receptors prevented apoptosis in RelA-deficient cells.
  • Overexpression of Bcl-2 restored ER calcium homeostasis and prevented apoptosis.

Conclusions:

  • NF-kappaB exerts its anti-apoptotic function by modulating calcium signaling pathways.
  • The endoplasmic reticulum calcium channel, specifically the type 1 IP(3) receptor, is a key target of NF-kappaB.
  • NF-kappaB-mediated regulation of ER calcium homeostasis is crucial for cell survival.

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