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.