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Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis

B L Schwab1, D Guerini, C Didszun

  • 1Molecular Toxicology, Faculty of Biology, University of Konstanz, Germany.

Cell Death and Differentiation
|July 11, 2002
PubMed

Insights

Caspases cleave and inactivate the plasma membrane calcium pump (PMCA) during apoptosis. This leads to calcium overload and secondary necrosis, which caspase inhibitors can reduce in brain ischemia.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Neuronal death following ischemic injury or excitotoxin exposure can occur via apoptosis or necrosis.
  • Caspases are key mediators of apoptosis but not directly required for necrosis.
  • The plasma membrane calcium pump (PMCA) regulates intracellular calcium levels.

Purpose of the Study:

  • To investigate the role of caspases in regulating PMCA function during apoptosis.
  • To determine if PMCA cleavage by caspases contributes to secondary necrosis.
  • To explore the therapeutic potential of targeting this pathway in ischemic brain injury.

Main Methods:

  • Utilized neuronal and non-neuronal cell models undergoing apoptosis.
  • Assessed PMCA cleavage and activity using biochemical assays.
  • Employed non-cleavable PMCA mutants to study functional consequences.
  • Evaluated the effect of caspase inhibitors on cell death in an in vivo model of brain ischemia.

Main Results:

  • Demonstrated that caspases cleave and inactivate PMCA in apoptotic cells.
  • Showed that PMCA cleavage impairs intracellular calcium handling, leading to calcium overload.
  • Found that non-cleavable PMCA mutants prevented calcium dysregulation, slowed apoptosis, and delayed secondary necrosis.
  • Confirmed that caspase inhibitors reduced necrosis in a model of brain ischemia.

Conclusions:

  • Caspase-mediated cleavage and inactivation of PMCA contribute to secondary necrosis following apoptotic cell death.
  • Targeting caspases or preserving PMCA function may offer neuroprotective strategies against ischemic brain injury.
  • This study reveals a novel mechanism linking apoptosis, calcium dysregulation, and necrosis.

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