Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neurons.
The platelet-activating factor (PAF) family of glycerophospholipids accumulates in damaged brain tissue following injury. Little is known about the role of individual isoforms in regulating neuronal survival. Here, we compared the neurotoxic and neuroprotective activities of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16-PAF) and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine (C18-PAF) in cerebellar granule neurons. We find that both C16-PAF and C18-PAF cause PAF receptor-independent death but signal through different pathways. C16-PAF activates caspase-7, whereas C18-PAF triggers caspase-independent death in PAF receptor-deficient neurons. We further show that PAF receptor signaling is either pro- or anti-apoptotic, depending upon the identity of the sn-1 fatty acid of the PAF ligand. Activation of the PAF G-protein-coupled receptor (PAFR) by C16-PAF stimulation is anti-apoptotic and inhibits caspase-dependent death. Activation of PAFR by C18-PAF is pro-apoptotic. These results demonstrate the importance of the long-chain sn-1 fatty acid in regulating PAF-induced caspase-dependent apoptosis, caspase-independent neurodegeneration, and neuroprotection in the presence or absence of the PAF receptor.
Ryan
Scott D
SD
Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada.
Harris
Cory S
CS
Carswell
Casey L
CL
Baenziger
John E
JE
Bennett
Steffany A L
SA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002244:Carbon; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008823:Micelles; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity; D010742:Phospholipid Ethers / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D008823:Micelles; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C037145:1-hexadecyl-2-acetyl-glycero-3-phosphocholine; D002244:Carbon; C037913:CV 3988; C026613:1-0-octadecyl 2-0-acetyl sn-glycero-3-phosphorylcholine; D020169:Caspases