Cascade of Caspase Activation in Potassium-Deprived Cerebellar Granule Neurons : Targets for Treatment with Peptide and Protein Inhibitors of Apoptosis

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2001
Autor:innen
Gerhardt, Ellen
Kügler, Sebastian
Beier, Christoph
Berliocchi, Laura
Volbracht, Christiane
Weller, Michael
Bähr, Mathias
Schulz, Jörg B.
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Cerebellar granule neurons (CGN) cultured in the presence of serum and depolarizing potassium concentrations undergo apoptosis when switched to serum-free medium containing physiological potassium concentrations. Here we show that processing of the key protease, caspase-3, depends on the activation of caspase-9, but not of caspase-8. Selective peptide inhibitors of caspase-9 block processing of caspase-3 and caspase-8 and inhibit apoptosis, whereas a selective inhibitor of caspase-8 blocks neither processing of caspase-3 nor cell death. The data obtained with peptide inhibitors were confirmed by adenovirally mediated ectopic expression of the cytokine response modifier A (crmA), the baculovirus protein p35, and the X chromosome-linked inhibitor of apoptosis (XIAP). Further, caspase-8-activating death receptors do not mediate apoptosis in CGN and potassium withdrawal-induced apoptosis evolves unaltered in gld or lpr mice, which harbor mutations in the CD95/CD95 ligand system. Thus, neuronal apoptosis triggered by potassium deprivation is death receptor-independent but involves the mitochondrial pathway of caspase activation.

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ISO 690GERHARDT, Ellen, Sebastian KÜGLER, Marcel LEIST, Christoph BEIER, Laura BERLIOCCHI, Christiane VOLBRACHT, Michael WELLER, Mathias BÄHR, Pierluigi NICOTERA, Jörg B. SCHULZ, 2001. Cascade of Caspase Activation in Potassium-Deprived Cerebellar Granule Neurons : Targets for Treatment with Peptide and Protein Inhibitors of Apoptosis. In: Molecular and Cellular Neuroscience. Elsevier. 2001, 17(4), pp. 717-731. ISSN 1044-7431. eISSN 1095-9327. Available under: doi: 10.1006/mcne.2001.0962
BibTex
@article{Gerhardt2001-04Casca-51267,
  year={2001},
  doi={10.1006/mcne.2001.0962},
  title={Cascade of Caspase Activation in Potassium-Deprived Cerebellar Granule Neurons : Targets for Treatment with Peptide and Protein Inhibitors of Apoptosis},
  number={4},
  volume={17},
  issn={1044-7431},
  journal={Molecular and Cellular Neuroscience},
  pages={717--731},
  author={Gerhardt, Ellen and Kügler, Sebastian and Leist, Marcel and Beier, Christoph and Berliocchi, Laura and Volbracht, Christiane and Weller, Michael and Bähr, Mathias and Nicotera, Pierluigi and Schulz, Jörg B.}
}
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