Calcium mobilization via sphingosine kinase in signalling by the FcɛRI antigen receptor

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Abstract
CALCIUM mobilization through antigen receptors, including high-affinity IgE receptors (FcsRI), is thought to be mediated by inositol-l,4,5-trisphosphate production (InsP3)1–4. Here we show that antigen clustering of FceRI on the rat mast-cell line (RBL-2H3) activates a sphingosine kinase (SK) and produces sphingo-sine-1-phosphate (SIP), an alternative second messenger for intracellular calcium mobilization. The sphingosine analogue, D-L-threo-dihydrosphingosine (DHS), inhibits the SK enzyme competitively with a dissociation constant,Ki, of 5 to 18 µM. This inhibition substantially suppresses the FceRI-mediated calcium signal, but leaves intact the syk tyrosine kinase activation and the small InsP3 production. The entire InsP3-dependent pathway activated by a transfected G-protein coupled receptor, used here as a positive control, also remained intact. Thus FcsRI principally utilizes a SK pathway to mobilize calcium.