칼슘의 작용: Sphingosine Kinase Versus Phospholipase C

초록

Calcium mobilization through Fc receptors is thought to be mediated by inositol 1,4,5-trisphophate production (IP3). Studies in RBL-2H3 cells transfected with the m1 muscarinic receptor (RBL-m1), however, revealed that, whereas there was a good correlation between IP3 production and the Ca2+-response in RBL-m1 cells stimulated with the muscarinic agonist carbachol, this was not the case when FceRI is cross-linked with antigen, suggesting an additional mechanism for release of Ca2+. We have subsequently shown that antigen clustering of FceRI activates a sphingosine kinase (SK) and produces sphingosine-1-phosphate (S1P), an alternative second messenger for intracellular calcium mobilization. A selective and competitive inhibitor of SK, DL-threo-dihydrosphingosine (DHS), substantially suppresses the FceRI-mediated calcium signal, but leaves intact syk tyrosine kinase activation and IP3 production. The entire IP3-dependent pathway activated via m1 muscarinic receptors is not affected. Similarly, specific cross-lnking of FcgRIIa in human neutrophils induces calcium mobilization and an increase in S1P production with no significant increase in the production of IP3. This calcium response is completely inhibited by another competitive and selective inhibitor of SK, N,N-dimethylsphingosine (DMS) without affecting fMLP-mediated calcium reponses or IP3 production by either stimulant. The present data suggest that Fc receptors use both the IP3 and SK pathways to mobilize calcium. In addition, cloning of SK provided us a useful tool to characterize the enzyme at the molecular level.Northern blot analysis indicates that SK is ubiquitously distributed through out the human tissues. We speculate that SK is involved not only in mobilizing calcium in immune system but also in other signaling pathways such as regulation of proliferation.