Calcium mobilization via sphingosine kinase in signalling by the Fc epsilon RI antigen receptor.
Calcium mobilization through antigen receptors, including high-affinity IgE receptors (Fc epsilon RI), is thought to be mediated by inositol-1,4,5-trisphosphate production (InsP3). Here we show that antigen clustering of Fc epsilon RI on the rat mast-cell line (RBL-2H3) activates a sphingosine kinase (SK) and produces sphingosine-1-phosphate (S1P), and alternative second messenger for intracellular calcium mobilization. The sphingosine analogue, D-L-threo-dihydrosphingosine (DHS), inhibits the SK enzyme competitively with a dissociation constant, K1, of 5 to 18 microM. This inhibition substantially suppresses the Fc epsilon RI-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 Fc epsilon RI principally utilizes a SK pathway to mobilize calcium.
Choi
O H
OH
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland 20852, USA.
Kim
J H
JH
Kinet
J P
JP
D016475:3T3 Cells; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology; D008246:Lysophospholipids; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000099157:Sphingosine Kinase
D002118:Calcium; D004791:Enzyme Inhibitors; D019833:Genistein; D015544:Inositol 1,4,5-Trisphosphate; D007529:Isoflavones; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; D017455:Receptors, IgE; D011976:Receptors, Muscarinic; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C005682:safingol