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| The EMBO Journal
(1998) 17, 2830–2837, doi:10.1093/emboj/17.10.2830 |
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| Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors |
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| Dagmar Meyer zu Heringdorf1, Holger Lass1, Regina Alemany1, Kai T. Laser1, Eva Neumann1, Chunyi Zhang1, Martina Schmidt1, Ursula Rauen2, Karl H. Jakobs1 and Chris J. van Koppen1 |
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1 Institut für Pharmakologie, Universität GH Essen, Hufelandstrasse 55, D-45122 Essen, Germany 2 Institut für Physiologische Chemie, Universität GH Essen, Hufelandstrasse 55, D-45122 Essen, Germany Received 19 January 1998; Revised 17 March 1998; Accepted 17 March 1998. |
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| Abstract |
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Formation of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC) with subsequent release of Ca2+ from intracellular stores, is one of the major Ca2+ signalling pathways triggered by G-protein-coupled receptors (GPCRs). However, in a large number of cellular systems, Ca2+ mobilization by GPCRs apparently occurs independently of the PLC–IP3 pathway, mediated by an as yet unknown mechanism. The present study investigated whether sphingosine kinase activation, leading to production of sphingosine-1-phosphate (SPP), is involved in GPCR-mediated Ca2+ signalling as proposed for platelet-derived growth factor and Fc RI antigen receptors. Inhibition of sphingosine kinase by DL-threo-dihydrosphingosine and N,N-dimethylsphingosine markedly inhibited [Ca2+]i increases elicited by m2 and m3 muscarinic acetylcholine receptors (mAChRs) expressed in HEK-293 cells without affecting mAChR-induced PLC stimulation. Activation of mAChRs rapidly and transiently stimulated production of SPP in HEK-293 cells. Finally, intracellular injection of SPP induced a rapid and transient Ca2+ mobilization in HEK-293 cells which was not antagonized by heparin. We conclude that mAChRs utilize the sphingosine kinase–SPP pathway in addition to PLC–IP3 to mediate Ca2+ mobilization. As Ca2+ signalling by various, but not all, GPCRs in different cell types was likewise attenuated by the sphingosine kinase inhibitors, we suggest a general role for sphingosine kinase, besides PLC, in mediation of GPCR-induced Ca2+ signalling. |
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| Keywords: calcium mobilization, G-proteins, muscarinic acetylcholine receptor, sphingosine kinase, sphingosine-1-phosphate |
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