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Sphingosine 1-Phosphate Stimulates Hydrogen Peroxide Generation through Activation of Phospholipase C-Ca²⁺ System in FRTL-5 Thyroid Cells: Possible Involvement of Guanosine Triphosphate-Binding Proteins in the Lipid Signaling¹

Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan

Address all correspondence and requests for reprints to: Dr. Fumikazu Okajima, Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3–39-15 Showa-machi, Maebashi 371, Japan.

Exogenous sphingosine 1-phosphate (S1P) stimulated hydrogen peroxide (H₂O₂) generation in association with an increase in intracellular Ca²⁺ concentration in FRTL-5 thyroid cells. S1P also induced inositol phosphate production, reflecting activation of phospholipase C (PLC) in the cells. These three S1P-induced events were inhibited partially by pertussis toxin (PTX) and markedly by U73122, a PLC inhibitor, and were conversely potentiated by N⁶-(L-2-phenylisopropyl)adenosine, an A₁-adenosine receptor agonist. In FRTL-5 cell membranes, S1P also activated PLC in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTPS), but not in its absence. Guanosine 5'-O-(2-thiodiphosphate) inhibited the S1P-induced GTPS-dependent activation of the enzyme. To characterize the signaling pathways, especially receptors and G proteins involved in the S1P-induced responses, cross-desensitization experiments were performed. Under the conditions where homologous desensitization occurred in S1P-, lysophosphatidic acid (LPA)-, and bradykinin-induced induction of Ca²⁺ mobilization, no detectable cross-desensitization of S1P and bradykinin was observed. This suggests that the primary action of S1P in its activation of the PLC-Ca²⁺ system was not the activation of G proteins common to S1P and bradykinin, but the activation of a putative S1P receptor. On the other hand, there was a significant cross-desensitization of S1P and LPA; however, a still significant response to S1P (50–80% of the response in the nontreated control cells) was observed depending on the lipid dose employed after a prior LPA challenge. S1P also inhibited cAMP accumulation in a PTX-sensitive manner. We conclude that S1P stimulates H₂O₂ generation through a PLC-Ca²⁺ system and also inhibits adenylyl cyclase in FRTL-5 thyroid cells. The S1P-induced responses may be mediated partly through a putative lipid receptor that is coupled to both PTX-sensitive and insensitive G proteins.

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