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Calcineurin-mediated Bad translocation regulates cyanide-induced neuronal apoptosis.
- Source :
-
The Biochemical journal [Biochem J] 2004 May 01; Vol. 379 (Pt 3), pp. 805-13. - Publication Year :
- 2004
-
Abstract
- In cyanide-induced apoptosis, an increase in cytosolic free Ca2+ and generation of reactive oxygen species are initiation stimuli for apoptotic cell death. Previous studies have shown that cyanide-stimulated translocation of Bax (Bcl-associated X protein) to mitochondria is linked with release of cytochrome c and subsequent activation of a caspase cascade [Shou, Li, Prabhakaran, Borowitz and Isom (2003) Toxicol. Sci. 75, 99-107]. In the present study, the relationship of the cyanide-induced increase in cytosolic free Ca2+ to activation of Bad ( Bcl-2/Bcl-X(L)- antagonist, causing cell death) was determined in cortical cells. Bad is a Ca2+-sensitive pro-apoptotic Bcl-2 protein, which on activation translocates from cytosol to mitochondria to initiate cytochrome c release. In cultured primary cortical cells, cyanide produced a concentration- and time-dependent translocation of Bad from cytosol to mitochondria. Translocation occurred early in the apoptotic response, since mitochondrial Bad was detected within 1 h of cyanide treatment. Mitochondrial levels of the protein continued to increase up to 12 h post-cyanide exposure. Concurrent with Bad translocation, a Ca2+-sensitive increase in cellular calcineurin activity was observed. Increased cytosolic Ca2+ and calcineurin activation stimulated Bad translocation since BAPTA [bis-(o-aminophenoxy)ethane-N, N, N', N'-tetra-acetic acid], an intracellular Ca2+ chelator, and cyclosporin A, a calcineurin inhibitor, significantly reduced translocation. BAPTA also blocked release of cytochrome c from mitochondria as well as apoptosis. Furthermore, treatment of cells with the calcineurin inhibitors cyclosporin A or FK506 blocked the apoptotic response, linking calcineurin activation and the subsequent translocation of Bad to cell death. These observations show that by inducing a rapid increase in cytosolic free Ca2+, cyanide can partially initiate the apoptotic cascade through a calcineurin-mediated translocation of Bad to mitochondria.
- Subjects :
- Animals
Calcineurin Inhibitors
Calcium antagonists & inhibitors
Calcium metabolism
Calcium Signaling drug effects
Cells, Cultured
Chelating Agents metabolism
Chelating Agents pharmacology
Cyanides antagonists & inhibitors
Cytochromes c metabolism
Cytosol drug effects
Cytosol metabolism
Mitochondria drug effects
Mitochondria metabolism
Mitogen-Activated Protein Kinases metabolism
NF-kappa B metabolism
Neurons cytology
Neurons metabolism
Protein Transport drug effects
Rats
Rats, Sprague-Dawley
bcl-Associated Death Protein
p38 Mitogen-Activated Protein Kinases
Apoptosis drug effects
Calcineurin metabolism
Carrier Proteins metabolism
Cyanides pharmacology
Neurons drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 379
- Issue :
- Pt 3
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 14741051
- Full Text :
- https://doi.org/10.1042/BJ20031107