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Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD

H G Wang1, N Pathan, I M Ethell

  • 1The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Science (New York, N.Y.)
|April 9, 1999
PubMed

Insights

Calcium-activated protein phosphatase calcineurin triggers apoptosis by dephosphorylating the pro-apoptotic protein BAD. This leads to BAD

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Calcineurin, a calcium-activated protein phosphatase, is known to induce apoptosis.
  • The precise molecular mechanisms by which calcineurin promotes programmed cell death remain largely unelucidated.

Purpose of the Study:

  • To investigate the role of calcineurin in apoptosis induction.
  • To identify the downstream targets and mechanisms regulated by calcineurin during apoptosis.

Main Methods:

  • Biochemical assays to assess protein dephosphorylation and heterodimerization.
  • Cellular localization studies using microscopy to track protein translocation.
  • Experiments in hippocampal neurons involving L-glutamate stimulation.
  • Inhibition studies using dominant-negative calcineurin mutants and pharmacological inhibitors.

Main Results:

  • Calcineurin dephosphorylates the pro-apoptotic protein BAD, a member of the Bcl-2 family.
  • Dephosphorylation enhances BAD's heterodimerization with Bcl-xL, promoting apoptosis.
  • Calcium-induced BAD dephosphorylation causes its dissociation from 14-3-3 proteins and translocation to mitochondria.
  • In hippocampal neurons, L-glutamate triggers BAD mitochondrial targeting and apoptosis, which are blocked by calcineurin inhibition.

Conclusions:

  • A novel calcium-inducible pathway for apoptosis induction involves calcineurin-mediated regulation of BAD phosphorylation.
  • Calcineurin controls BAD localization by altering its phosphorylation status, leading to mitochondrial-dependent cell death.
  • This mechanism highlights a critical role for calcineurin in neuronal apoptosis.

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