We identified and cloned the mouse orthologue of human GPR6 as a new member of the lysophospholipid-receptor family. Sphingosine-1-phosphate (S1P) activated GPR6, transiently expressed in frog oocytes or in Chinese hamster ovary (CHO) cells, with high specificity and nanomolar affinity. The GPR6 gene was found to be located on chromosome 10B1 and a single exon coded for the entire open-reading frame. Signal transduction of SIP was inhibited by pertussis toxin, suggesting a coupling of GPR6 to an inhibitory G protein. In CHO cells transfected with GPR6, the sphingosine-kinase pathway mediated Ca2+ mobilization from internal stores. Apoptotic cell death was induced by serum deprivation or H2O2 treatment and was prevented by S I P in GPR6-, but not in vector-transfected CHO cells. The antiapoptotic effect of SIP required activation of sphingosine kinase and was accompanied by an increase in MAP-kinase phosphorylation. (C) 2003 Elsevier Inc. All rights reserved.