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Journal of Lipid Research, Vol. 46, 1833-1839, September 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a G_i-coupled receptor response

Edward D. Johnstone^*,, Gary Chan^*,**, Colin P. Sibley, Sandra T. Davidge^,**, Bonnie Lowen^* and Larry J. Guilbert^1,*,**

^* Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada
^** Perinatal Research Centre, University of Alberta, Edmonton, Alberta, Canada
Academic Unit of Child Health, University of Manchester, Manchester, United Kingdom

Published, JLR Papers in Press, July 1, 2005. DOI 10.1194/jlr.M500095-JLR200

¹ To whom correspondence should be addressed. e-mail: larry.guilbert{at}ualberta.ca

The failure of placental trophoblasts to differentiate properly is thought to play an important role in the cause of pregnancy disorders such as preeclampsia. We looked at the effects of the bioactive lipid sphingosine-1-phosphate (S1P) on the differentiation of primary human cytotrophoblasts (CTs) into syncytiotrophoblasts (STs) in culture. We found that S1P inhibited CT differentiation measured by human chorionic gonadotropin (hCG) secretion and the expression of placental alkaline phosphatase but had no effect on their fusion into multinucleated syncytialized cells. G-protein-linked S1P receptors 1, 2, and 3 were found in CTs by reverse transcriptase-polymerase chain reaction, and receptor 1 was found by Western blot analysis. Disruption of G_i signaling with pertussis toxin reversed the inhibitory effects of S1P. S1P reduced intracellular cAMP, and the addition of 8-bromo-cAMP reversed S1P inhibition of hCG secretion.

Therefore, we suggest that S1P inhibits the differentiation of CTs into STs through G_i-coupled S1P receptor interaction(s), leading to the inhibition of adenylate cyclase and reduced production of intracellular cAMP. This is the first reported effect of S1P on placental trophoblast function.

Supplementary key words sphingosine-1-phosphate receptors • adenosine 3',5'-cyclic monophosphate • chorionic gonadotropin • fusion • epidermal growth factor • G_i proteins

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