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First published on December 29, 2004; DOI: 10.1124/mol.104.004317

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Received for publication June 28, 2004.
Revised November 26, 2004.
Accepted for publication December 28, 2004.

Sphingosine-1-Phosphate Receptors Mediate the Lipid-Induced cAMP Accumulation Through Cyclooxygenase-2/Prostaglandin I2 Pathway in Human Coronary Artery Smooth Muscle Cells

ALATANGAOLE DAMIRIN 1, HIDEAKI TOMURA 1*, MAYUMI KOMACHI 1, MASAYUKI TOBO 1, KOICHI SATO 1, CHIHIRO MOGI 1, HIROMI NOCHI 2, KOICHI TAMOTO 2, FUMIKAZU OKAJIMA 1

1 Institute for Molecular and Cellular Regulation 2 Faculty of Pharmaceutical Sciences

* Address correspondence to: E-mail: tomurah{at}showa.gunma-u.ac.jp

Abstract

Sphingosine 1-phosphate (S1P) has been shown to exert a variety of biological responses through extracellular specific receptors or intracellular mechanisms. In the present study, we characterized a signaling pathway of S1P-induced cAMP accumulation in human coronary artery smooth muscle cells (CASMCs). S1P induced biphasic cAMP accumulation composed of an acute and transient response (a peak at 2.5 min) and a late and sustained response (4~6 h). The late phase of cAMP accumulation was parallel to the increment of cyclooxygenase-2 protein expression and was inhibited by NS398, a cyclooxygenase-2-specific inhibitor. Unexpectedly, the cyclooxygenase-2 inhibitor also inhibited acute cAMP accumulation even when cyclooxygenase-2 protein expression was not yet increased. More interestingly, the acute cAMP accumulation was also completely inhibited by pertussis toxin, an inhibitor of Gi/o-proteins. JTE-013, a specific antagonist for S1P2 receptors, inhibited the S1P-induced cAMP accumulation. Furthermore, small interfering RNAs targeted for S1P2 receptors significantly inhibited the S1P-induced cAMP accumulation. The cAMP response was also inhibited by specific inhibitors for phospholipase C, extracellular signal-regulated kinase pathways, and cytosolic phospholipase A2. S1P actually activated these enzyme activities and stimulated prostaglandin I2 (PGI2) synthesis. Finally, exogenously applied arachidonic acid and PGI2 induced cAMP accumulation to the similar extent as S1P. In conclusion, S1P induced cAMP accumulation through S1P receptors including S1P2 receptor and Gi/o-protein-mediated stimulation of intracellular signaling pathways involving cyclooxygenase-2-dependent PGI2 synthesis.


Key words: Prostanoid, Gi family, Phospholipase A2's, cAMP, Sphingolipids, G protein regulation, MAP Kinase, RNA/siRNA


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