Pathways of transduction engaged by sphingosine 1-phosphate through G protein-coupled receptors

Pathways of transduction employed by receptors for sphingosine 1-phosphate (SIP) are identified by the nature of second messengers and/or downstream targets regulated and, more formally, by direct assays of heterotrimeric G protein activation. The different methods generally agree. S1P, couples to members of the G(i) family, apparently selectively, although reported pertussis toxin (PTX)-insensitive actions make categorical statements regarding exclusivity difficult. S1P2 and S1PS couple to members of the G(i), G(q), and G(12/13) families. S1P(4) couples to G(i) and possibly G(12/13), while S1PS couples to G(i) and G(12/13) but not to G(q), In virtually all circumstances, coupling of SIP receptors to Gi is reflected in PTX-sensitive inhibition of adenylyl cyclase, activation of extracellular-regulated kinases (ERKs), and, depending on the cell, activation of phospholipase C (PLC). Coupling to G(q) is reflected in PTX-insensitive activation of phospholipase C. Coupling to G(12/13) is reflected in activation of Rho and subsequent activation of serum response factor (SRF). Specific linkages have been verified in almost all instances by receptor-promoted [S-35]GTPgammaS/GDP exchange on identified G proteins. (C) 2002 Elsevier Science B.V. All rights reserved.