Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway.
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 S1P 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 Ca(2+) mobilization from internal stores. Apoptotic cell death was induced by serum deprivation or H(2)O(2) treatment and was prevented by S1P in GPR6-, but not in vector-transfected CHO cells. The antiapoptotic effect of S1P required activation of sphingosine kinase and was accompanied by an increase in MAP-kinase phosphorylation.
Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Martinistr. 52, D-22246 Hamburg, Germany.
Atanas
A
Ignatov
Julia
J
Lintzel
Hans-Jürgen
HJ
Kreienkamp
H Chica
HC
Schaller
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D008024:Ligands; D008246:Lysophospholipids; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014982:Xenopus laevis; D000099157:Sphingosine Kinase
D002118:Calcium; D008024:Ligands; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D013110:Sphingosine; D000099157:Sphingosine Kinase; C091672:GPR6 protein, human; C060506:sphingosine 1-phosphate