EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16

AGR16/H218/EDG5 and EDG1 are functional receptors for lysosphingolipids, wh ereas EDG2 and EGD4 are receptors for lysophosphatidic acid (LPA). The pres ent study demonstrates that EDG3, the yet poorly defined member of the EDG family G protein-coupled receptors, shows identical agonist specificity, bu t distinct signaling characteristics, compared to AGR16 and EDG1. Overexpre ssion of EDG3 conferred a specific [P-32]S1P binding, which was displaced b y S1P and sphingosylphosphorylcholine (SPC), but not by LPA or other relate d lipids. In cells overexpressing EDG3, S1P induced inositol phosphate prod uction and [Ca2+](i) increase in a manner only partially sensitive to pertu ssis toxin (PTX), which was similar to the case of AGR16, but quite differe nt from the case of EDG1, in which the S1P-induced responses were totally a bolished by PTX EDG3 also mediated activation of mitogen-activated protein kinase (MAPK) in PTX-sensitive and Ras-dependent manners, as in the cases o f EDG1 and AGR16, although EDG3 and EDG1 were more effectively coupled to a ctivation of MAPK, compared to AGR16. Additionally, EDG3 mediated a decreas e in cellular cyclic AMP content, like EDG1, but contrasting with AGR16 whi ch mediated an increase in cyclic AMP. These and previous results establish that EDG1, AGR16 and EDG3 comprise the lysosphingolipid receptor subfamily , each showing distinct signaling characteristics. (C) 1999 Academic Press.