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

doi:10.1006/mcne.2001.0962

Molecular and Cellular Neuroscience

Volume 17, Issue 4, April 2001, Pages 717-731

https://doi.org/10.1006/mcne.2001.0962 Get rights and content

Abstract

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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¹: Present address: H. Lundbeck A/S, Valhy, Denmark.

²: Present address: MRC Toxicolgy Unit, University of Leicester, Leicester, UK.

³: To whom correspondence and reprint requests should be addressed.

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

Abstract

Cell

Cell

J. Biol. Chem.

Cell

Neurobiol. Dis.

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Cell

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Cell

J. Biol. Chem.

Immunity

Cell

J. Biol. Chem.

Activation of the CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis

J. Neurosci.

FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: Evidence for the existence of an immunological brain barrier

Glia

Apoptotic suppression by baculovirus P35 involves cleavage by and inhibition of a virus-induced CED-3/ICE-like protease

J. Virol.

An apoptosis-inhibiting gene from a nuclear polyhedrosis virus encoding a polypeptide with Cys/His sequence motifs

J. Virol.

Inhibition of ICE family proteases by baculovirus antiapoptotic protein p35

Science

Fas/Apo [apoptosis]-1 and associated proteins in the differentiating cerebral cortex: Induction of caspase-dependent cell death and activation of NF-kappaB

J. Neurosci.

Prevention of apoptosis by a baculovirus gene during infection of insect cells

Science

Control of programmed cell death by the baculovirus genes p35 and iap

Mol. Cell. Biol.

An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif

J. Virol.

A DEVD-inhibited caspase other than CPP32 is involved in the commitment of cerebellar granule neurons to apoptosis induced by K+ deprivation

J. Neurochem.

Caspase-3 is required for apoptosis-associated DNA fragmentation but not for cell death in neurons deprived of potassium

J. Neurosci. Res.

Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases

EMBO J.

IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases

EMBO J.

X-linked IAP is a direct inhibitor of cell-death proteases

Nature

ITA, a vertebrate homologue of IAP that is expressed in T lymphocytes

DNA Cell Biol.

Ribozyme-mediated inhibition of caspase-3 protects cerebellar granule cells from apoptosis induced by serum-potassium deprivation

J. Neurosci.

The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells

J. Neurosci.

Crystal structure of baculovirus P35: Role of a novel reactive site loop in apoptotic caspase inhibition

EMBO J.

Prevention of vertebrate neuronal death by the crmA gene

Science

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