Sphingosine 1-phosphate activates nuclear factor-kappa B through Edg receptors. Activation through Edg-3 and Edg-5, but not Edg-1, in human embryonic kidney 293 cells.
Sphingosine 1-phosphate (S1P) exerts a variety of actions as a second messenger or as an agonist that binds to one or more members of the Edg family of G protein-coupled receptors. By using human embryonic kidney 293 cells, we show that S1P activates nuclear factor-kappa B (NF-kappa B) in a receptor-dependent fashion. Edg-3 and Edg-5, which are coupled to G(i), G(q), and G(13), affect activation of NF-kappa B, whereas Edg-1, which is coupled to G(i) alone, does not. We find that the activation of NF-kappa B requires protein kinase C and Ca(2+), probably downstream of G(q), but that the activation of Rho alone by S1P, whether through G(q) or G(13), does not translate into the activation of NF-kappa B. G beta gamma has little effect of its own but potentiates the activation of NF-kappa B achieved through other G proteins. We conclude that the activation of NF-kappa B by S1P is a receptor-mediated process that relies primarily on the activation of a phospholipase C by G(q) and secondarily on effector regulation through other G proteins.
Siehler
S
S
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Wang
Y
Y
Fan
X
X
Windh
R T
RT
Manning
D R
DR
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D018679:Cholinergic Agonists / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008246:Lysophospholipids; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D043587:Receptor, Muscarinic M3; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D011976:Receptors, Muscarinic / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D018679:Cholinergic Agonists; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D017874:Immediate-Early Proteins; D008246:Lysophospholipids; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D043587:Receptor, Muscarinic M3; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D011976:Receptors, Muscarinic; D000072000:NF-KappaB Inhibitor alpha; C060506:sphingosine 1-phosphate; D002217:Carbachol; D011493:Protein Kinase C; D020962:Heterotrimeric GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D013110:Sphingosine; D002118:Calcium