Nature 380, 634 - 636 (18 April 1996); doi:10.1038/380634a0

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

Oksoon Hong Choi, Jae-Heup Kim & Jean-Pierre Kinet^*

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA
^* Laboratory of Allergy and Immunology, Beth Israel Hospital, and Department of Pathology, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA

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,K _i, of 5 to 18 M. 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.

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