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doi: 10.1242/10.1242/jcs.00621
Research Article |
RI
1 Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY
14853, USA
2 Department of Molecular Medicine, Veterinary Medical Center, Cornell
University, Ithaca, NY 14853, USA
Author for correspondence (e-mail:
bab13{at}cornell.edu)
Accepted 15 April 2003
Specialized plasma membrane domains known as lipid rafts participate in
signal transduction and other cellular processes, and their liquid-ordered
properties appear to be important for their function. We investigated the
possibility of using amphiphiles to disrupt lipid rafts and thereby inhibit
IgE-Fc
RI signaling. We find that short-chain ceramides –
C2-ceramide and C6-ceramide – decrease plasma
membrane lipid order and reduce the extent of fluorescence resonance energy
transfer between lipid-raft-associated molecules on intact cells; by contrast,
biologically inactive C2-dihydroceramide does neither. Structural
perturbations by these ceramides parallel their inhibitory effects on
antigen-stimulated Ca2+ mobilization in RBL mast cells in the
presence and absence of extracellular Ca2+. Similar inhibition of
Ca2+ mobilization is caused by n-butanol, which prevents
phosphatidic acid production by phospholipase D, but not by t-butanol, which
does not prevent phosphatidic acid production. These results and previously
reported effects of short-chain ceramides on phospholipase D activity prompted
us to compare the effects of C2-ceramide,
C2-dihydroceramide and C16-ceramide on phospholipase D1
and phospholipase D2 activities in vitro. We find that the effects of these
ceramides on phospholipase D1 activity strongly correlate with their effects
on antigen-stimulated Ca2+ mobilization and with their disruption
of lipid order. Our results indicate that phospholipase D activity is upstream
of antigen-stimulated Ca2+ mobilization in these cells, and they
demonstrate that ceramides can serve as useful probes for investigating roles
of plasma membrane structure and phospholipase D activity in cellular
signaling.
Key words: Ceramides, Lipid rafts, IgE receptors, Phospholipase D, Mast cells
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