PT  - JOURNAL ARTICLE
AU  - Alatangaole Damirin
AU  - Hideaki Tomura
AU  - Mayumi Komachi
AU  - Masayuki Tobo
AU  - Koichi Sato
AU  - Chihiro Mogi
AU  - Hiromi Nochi
AU  - Koichi Tamoto
AU  - Fumikazu Okajima
TI  - Sphingosine 1-Phosphate Receptors Mediate the Lipid-Induced cAMP Accumulation through Cyclooxygenase-2/Prostaglandin I<sub>2</sub> Pathway in Human Coronary Artery Smooth Muscle Cells
AID  - 10.1124/mol.104.004317
DP  - 2005 Apr 01
TA  - Molecular Pharmacology
PG  - 1177--1185
VI  - 67
IP  - 4
4099  - http://molpharm.aspetjournals.org/content/67/4/1177.short
4100  - http://molpharm.aspetjournals.org/content/67/4/1177.full
SO  - Mol Pharmacol2005 Apr 01; 67
AB  - 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 a short-term 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 N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS398), a cyclooxygenase-2-specific inhibitor. We were surprised to find that the cyclooxygenase-2 inhibitor also inhibited short-term cAMP accumulation even when cyclooxygenase-2 protein expression was not yet increased. More interestingly, the short-term 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 a 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.