Platelet activating factor-induced apoptosis is inhibited by ectopic expression of the platelet activating factor G-protein coupled receptor
| Autor: | Cynthia, Brewer, Fanny, Bonin, Paula, Bullock, Marie-Christine, Nault, Jennifer, Morin, Sophie, Imbeault, T Y, Shen, D J, Franks, Steffany A L, Bennett |
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| Rok vydání: | 2002 |
| Předmět: |
Dose-Response Relationship
Drug Cell Survival Apoptosis Receptors Cell Surface Pheochromocytoma Platelet Membrane Glycoproteins Transfection PC12 Cells Cell Line Rats Receptors G-Protein-Coupled Necrosis Cytoprotection GTP-Binding Proteins In Situ Nick-End Labeling Animals Humans RNA Messenger Platelet Activating Factor Micelles Platelet Aggregation Inhibitors Signal Transduction |
| Zdroj: | Journal of neurochemistry. 82(6) |
| ISSN: | 0022-3042 |
| Popis: | The pro-inflammatory lipid mediator platelet activating factor (PAF: 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) accumulates in ischemia, epilepsy, and human immunodeficiency virus-1-associated dementia and is implicated in neuronal loss. The present study was undertaken to establish a role for its G-protein coupled receptor in regulating neurotoxicity. PC12 cells do not express PAF receptor mRNA as demonstrated by northern analysis and RT-PCR. In the absence of the G-protein coupled receptor, PAF (0.1-1 micro m) triggered chromatin condensation, DNA strand breaks, oligonucleosomal fragmentation, and nuclear disintegration characteristic of apoptosis. Lyso-PAF (0.001-1 micro m), the immediate metabolite of PAF, did not elicit apoptotic death. Concentrations of PAF or lyso-PAF that exceeded critical micelle concentration had physicochemical effects on plasma membrane resulting in necrosis. Apoptosis but not necrosis was inhibited by the PAF antagonist BN52021 (1-100 micro m) but not CV3988 (0.2-20 micro m). Ectopic PAF receptor expression protected PC12 transfectants from ligand-induced apoptosis. PAF receptor-mediated protection was inhibited by CV3988 (1 micro m). These data provide empirical evidence that: (i) PAF can initiate apoptosis independently of its G-protein coupled receptor; (ii) PAF signaling initiated by its G-protein coupled receptor is cytoprotective to PC12 cells; (iii) the pro- and anti-apoptotic effects of PAF on PC12 cells can be pharmacologically distinguished using two different PAF antagonists. |
| Databáze: | OpenAIRE |
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