Protein Kinase Cδ Is a Key Downstream Mediator of Manganese-Induced Apoptosis in Dopaminergic Neuronal Cells
| العنوان: | Protein Kinase Cδ Is a Key Downstream Mediator of Manganese-Induced Apoptosis in Dopaminergic Neuronal Cells |
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| المؤلفون: | Calivarathan Latchoumycandane, Yongjie Yang, Masashi Kitazawa, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 313:46-55 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | Small interfering RNA, Cell signaling, Programmed cell death, Dopamine, Apoptosis, DNA Fragmentation, Biology, environment and public health, Cell Line, chemistry.chemical_compound, Mesencephalon, Animals, Kinase activity, Protein kinase A, Protein Kinase C, Neurons, Pharmacology, Manganese, Dose-Response Relationship, Drug, Cytochromes c, Molecular biology, Rats, Cell biology, Protein Kinase C-delta, enzymes and coenzymes (carbohydrates), chemistry, Caspases, Mutation, Molecular Medicine, DNA fragmentation, RNA Interference, biological phenomena, cell phenomena, and immunity, Rottlerin |
| الوصف: | Manganese (Mn) exposure causes manganism, a neurological disorder similar to Parkinson's disease. However, the cellular mechanism by which Mn induces dopaminergic neuronal cell death remains unclear. In the present study, we sought to investigate the key downstream apoptotic cell signaling events that contribute to Mn-induced cell death in mesencephalic dopaminergic neuronal (N27) cells. Mn exposure induced a dose-dependent increase in neuronal cell death in N27 cells. The cell death was accompanied by sequential activation of mitochondrial-dependent proapoptotic events, including cytochrome c release, caspase-3 activation, and DNA fragmentation, but not caspase-8 activation, indicating that the mitochondrial-dependent apoptotic cascade primarily triggers Mn-induced apoptosis. Notably, Mn treatment proteolytically activated protein kinase Cdelta (PKCdelta), a member of a novel class of protein kinase C. The caspase-3 specific inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-fluoromethylketone (Z-DEVD-FMK) significantly blocked PKCdelta cleavage and its kinase activity, indicating that caspase-3 mediates the proteolytic activation. Cotreatment with the PKCdelta inhibitor rottlerin or the caspase-3 inhibitor Z-DEVD-FMK almost completely blocked Mn-induced DNA fragmentation. Additionally, N27 cells expressing a catalytically inactive PKCdelta(K376R) protein (PKCdelta dominant negative mutant) or a caspase cleavage resistant PKCdelta(D327A) protein (PKCdelta cleavage resistant mutant) were found to be resistant to Mn-induced apoptosis. To further establish the proapoptotic role of PKCdelta, RNA interference-mediated gene knockdown was performed. Small interfering RNA suppression of PKCdelta expression protected N27 cells from Mn-induced apoptotic cell death. Collectively, these results suggest that caspase-3-dependent proteolytic activation of PKCdelta plays a key role in Mn-induced apoptotic cell death. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a7049fb98167fba3fba4a1afd840f325Test https://doi.org/10.1124/jpet.104.078469Test |
| رقم الانضمام: | edsair.doi.dedup.....a7049fb98167fba3fba4a1afd840f325 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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