Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When cultured cerebellar granule neurons (CGN) are transferred from 25 mM KCl (K25) to 5 mM KCl (K5) caspase-3 and caspase-8, but not caspase-1 or caspase-9,activities are induced and cells die apoptotically. CGN death was triggered by a [Ca(2+)](i) modification when [Ca(2+)](i) was reduced from 300 nM to 50 nM in a K5 medium. The [Ca(2+)](i) changes were followed by an increase in ROS levels. The generation of both cytosolic and mitochondrial reactive oxygen species (ROS) occurred at three different times, 10 min, 30 min and 3--4 hr but only those ROS produced after 3--4 hr are involved in the process of cell death. When CGN cultured in a K5 medium are treated with different antioxidants like scavengers of ROS (mannitol, DMSO) or antioxidant enzymes (superoxide dismutase and catalase) phosphatidylserine translocation, caspase activity, chromatin condensation and cell death is markedly diminished. The protective effect of antioxidants is not mediated through a modification in [Ca(2+)](i). Caspase activation, PS translocation and chromatin condensation were downstream of ROS production. In contrast to H(2)O(2), ROS produced by a xanthine/xanthine oxidase system in CGN cultured in K25 were able to directly induce caspase-3 activation and death that resulted sensitive to z-VAD, a caspase inhibitor. These findings indicate that a reduction in [Ca(2+)](i) triggers CGN death by inducing a generation of ROS after 3--4 hr, which could play a critical role in the initial phases of the apoptotic process including PS translocation, chromatin condensation and the activation of initiator and executor caspases.
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PMID:Role of oxidative stress in the apoptotic cell death of cultured cerebellar granule neurons. 1131 73

Apoptotic death is a physiological process with regulatory mechanisms that are under the control of different molecules such as caspases. These are classified as initiators, such as caspases-8 and -9, and effectors, such as caspases-3 and -7. The participation of caspase-2 in the effector phase of apoptosis has been commonly observed in many cell types; however, it is able to act as an initiator caspase, depending on the apoptotic stimulus. Cerebellar granule cells (CGCs) undergo apoptosis when they are transferred from high potassium (K25) to low potassium (K5); this process seems to be mediated by caspase-3 activation. Staurosporine (STS), a full strength inhibitor of kinase proteins, also induces apoptosis in these cells. To characterize the caspase cascade induced by two stimuli in the same cell type we studied the activation of different caspases in CGCs treated with STS or K5. We found that both K5 and STS induce the activation of caspase-3. This result was confirmed by the proteolytic cleavage of poly (ADP-ribose) polymerase (PARP), an endogenous caspase-3 substrate. Caspase-2 was activated preferentially by STS, which showed a temporal course suggesting that this caspase was induced before caspase-3. The initiator caspase-9 was also activated by both K5 and STS, as well as cytochrome-c release. The results obtained in this study suggest that STS and K5 induced different activation caspase pathways for apoptotic cell death of CGCs.
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PMID:Caspase activation pathways induced by staurosporine and low potassium: role of caspase-2. 1252 27

Cerebellar granule cells (CGC) cultured under 5mM KCl (K5) undergo apoptosis after 5 days in vitro (DIV). CGC death is reduced by chronic treatment with 25 mM KCl (K25) or NMDA. Also, when CGC cultured for 6-8 DIV in K25 are transferred to a K5 medium, cells die apoptotically. Moreover, Bcl-2 and Bcl-xL protect neurons from apoptosis, while Bax and Bcl-xS may act as proapototic proteins. It is suggested that these members of the Bcl-2 family may be involved in the cytochrome-c (cyt-c) release to the cytosol. Cytochrome-c is able to form a complex with other proteins to activate a cascade of proteases. In this work, we found that Bcl-2 levels in K5 cells did not show any change during 2-7 days in vitro (DIV); but cells grown with NMDA and K25 displayed an increase (55% approximately) of Bcl-2 from 4 DIV, as compared to control. Under these conditions, Bax levels showed a tendency to decrease with age under control cells and NMDA/K25 induced a reduction of approximately 10% in Bax levels from 4 DIV. On the other hand, in cells maintained in K25 during 7 DIV and then switched to a K5 medium, the levels of Bax showed a consistent decrease (30% after 8h). Under these conditions, the Bcl-2 levels did not show any significant change after 24h. Cytochrome-c levels were unaffected under K5, NMDA and K25 and only a marginal increase of cytochrome-c in the cytosol was detected at 6h after switching. We also found that caspase-9 was only activated under K25-deprivation meanwhile caspase-3 was involved in both protocols. These results suggest that the Bcl-2 family members, caspases activation and cytochrome-c release are involved in CGC death induced by K5 and their participation in this process could be different depending on neuronal maturation in culture.
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PMID:Mechanisms of cell death by deprivation of depolarizing conditions during cerebellar granule neurons maturation. 1282 Sep 87

Several neurotrophic factors, including brain-derived neurotrophic factor (BDNF), and neurotransmitters, such as glutamate, may influence neuronal apoptotic death. Rat cerebellar granule neurons (CGN) cultured in low potassium (5 or 10 mM KCl) for more than 5 days in vitro (DIV) die apoptotically. These cells survive in the presence of high potassium (25 mM KCl, K25) or N-methyl-D-aspartate (NMDA), an agonist of glutamatergic receptors. CGN transferred from high to low potassium die apoptotically. Here, we characterized the effect of BDNF and NMDA on the apoptotic death induced by low potassium in CGN. Cell death of CGN by culturing in low potassium for 6 DIV was inhibited by BDNF and NMDA. When CGN were cultured in K25 and transferred to a low-potassium medium, 65% of neurons died after 48 hr. Under these conditions, BDNF, NMDA, or BDNF + NMDA increased CGN survival. Both BDNF and NMDA decreased caspase-9 activity and mRNA caspase-3 levels and activity induced by low potassium. CGN survival induced by BDNF is mediated by TrkB activation, whereas that induced by NMDA is mediated by NMDA receptor and TrkB activation. NMDA, but not BDNF, raised [Ca(2+)](i), which was reduced by low-potassium treatment. These results suggest that NMDA receptor stimulation induces CGN survival through the influx of extracellular Ca(2+) that may evoke the release of BDNF and the activation of TrkB. Complementary mechanisms induced by depolarization and changes in Ca(2+) levels would also contribute to the neuroprotection exerted by NMDA and potassium.
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PMID:Role of brain-derived neurotrophic factor in the protective action of N-methyl-D-aspartate in the apoptotic death of cerebellar granule neurons induced by low potassium. 1708 48