CHARACTERIZATION OF SPHINGOSINE 1-PHOSPHATE-INDUCED ACTIONS AND ITS SIGNALING PATHWAYS IN RAT HEPATOCYTES

Sphingosine 1-phosphate (S-1-P) and lysophosphatidic acid (LPA) stimul ated glycogen phosphorylase, a rate-limiting enzyme responsible for gl ycogenolysis, in association with Ca2+ mobilization and phospholipase C (PLC) activation in rat hepatocytes. S-1-P, but not LPA, also inhibi ted adenosine 3',5'-cyclic monophosphate accumulation reflecting adeny lyl cyclase inhibition. S-1-P-induced PLC activation, Ca2+ mobilizatio n, and phosphorylase activation were markedly enhanced by primary cult ure of the cells for 24 h, whereas the inhibitory adenosine 3',5'-cycl ic monophosphate response was unchanged by increasing culture time. Ac tivation of the PLC-Ca2+ system during primary culture was specific to the lysosphingolipid; PLC and Ca2+ responses to LPA and NaF were unch anged or slightly attenuated by increasing culture time. Pertussis tox in treatment almost completely suppressed the S-1-P-induced inhibition of adenylyl cyclase but hardly influenced the lipid-induced activatio n of PLC and its cascade reactions. We conclude that S-1-P, through an LPA receptor-independent mechanism, stimulates two signaling pathways , i.e., activation of the PLC-Ca2+ system and inhibition of adenylyl c yclase, through distinct S-1-P receptor-transducer systems, resulting in the modulation of glycogenolysis in rat hepatocytes.