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Originally published In Press as doi:10.1194/jlr.M800263-JLR200 on June 12, 2008

Papers In Press, published online ahead of print October 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800263-JLR200
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Journal of Lipid Research, Vol. 49, 2250-2258, October 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Heterogeneity in the sn-1 carbon chain of platelet-activating factor glycerophospholipids determines pro- or anti-apoptotic signaling in primary neuronsboxs

Scott D. Ryan*,{dagger}, Cory S. Harris*,{dagger},§, Casey L. Carswell{dagger}, John E. Baenziger{dagger} and Steffany A. L. Bennett1,*,{dagger}

* Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada
{dagger} Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
§ Department of Biology, University of Ottawa, Ottawa, Canada

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of one figure.

This work was supported by an operating grant from the Ontario Mental Health Foundation (OMHF) to S.A.L.B. S.A.L.B. is a Canadian Institutes of Health Research New Investigator and an OMHF Intermediate Investigator. S.D.R. is funded by an OMHF graduate studentship. C.S.H. is funded by a Canadian graduate studentship.

Published, JLR Papers in Press, June 12, 2008.

1 To whom correspondence should be addressed. e-mail: sbennet{at}uottawa.ca

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.

Supplementary key words receptor • neurodegeneration • isoform • inhibitor • analog • antagonist • central nervous system • neurotoxicity • affinity • ligand

Abbreviations: C16-PAF, 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine; C18-PAF, 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine; CGN, cerebellar granule neuron; CMC, critical micellar concentration; EGFP, enhanced green fluorescent protein; EMEM, Eagle's minimum essential medium; PAF, platelet-activating factor; PAFR, platelet-activating factor G-protein-coupled receptor


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