Selective Loss of Sphingosine 1-Phosphate Signaling with No Obvious Phenotypic Abnormality in Mice Lacking Its G Protein-coupled Receptor, LP _B3/EDG-3

Sphingosine 1-phosphate (S1P) exerts diverse physiological actions by activating its cognate G protein-coupled receptors. Five S1P receptors have been identified in mammals: LP_B1/EDG-1, LP _B2/H218/AGR16/EDG-5, LP_B3/EDG-3, LP _B4/NRG-1/EDG-8, and LP_C1/EDG-6. One of these receptors, LP_B1, has recently been shown to be essential for mouse embryonic development. Here we disrupted the lP_B3 gene in mice, resulting in the complete absence of lP_B3 gene, transcript, and LP_B3 protein. LP_B3-null mice were viable and fertile and developed normally with no obvious phenotypic abnormality. We prepared mouse embryonic fibroblast (MEF) cells to examine effects of LP_B3 deletion on S1P-induced signal transduction pathways. Wild-type MEF cells expressed lP _B1, lP_B2, and lP_B3 but neither lP_B4 nor lP_C1, and they were highly responsive to S1P in phospholipase C (PLC) activation, adenylyl cyclase inhibition, and Rho activation. Identically prepared LP_B3-null MEF cells showed significant decreases in PLC activation, slight decreases in adenylyl cyclase inhibition, and no change in Rho activation. Retrovirus-mediated rescue of the LP_B3 receptor in LP_B3-null MEF cells restored S1P-dependent PLC activation and adenylyl cyclase inhibition. These results indicate a nonessential role for LP_B3 in normal development of mouse but show nonredundant cellular signaling mediated by a single type of S1P receptor.