Characterization of sphingosine 1-phosphate-induced actions and its signaling pathways in rat hepatocytes.
Sphingosine 1-phosphate (S-1-P) and lysophosphatidic acid (LPA) stimulated glycogen phosphorylase, a rate-limiting enzyme responsible for glycogenolysis, in association with Ca2+ mobilization and phospholipase C (PLC) activation in rat hepatocytes. S-1-P, but not LPA, also inhibited adenosine 3',5'-cyclic monophosphate accumulation reflecting adenylyl cyclase inhibition. S-1-P-induced PLC activation, Ca2+ mobilization, and phosphorylase activation were markedly enhanced by primary culture of the cells for 24 h, whereas the inhibitory adenosine 3',5'-cyclic monophosphate response was unchanged by increasing culture time. Activation of the PLC-Ca2+ system during primary culture was specific to the lysosphingolipid; PLC and Ca2+ responses to LPA and NaF were unchanged or slightly attenuated by increasing culture time. Pertussis toxin treatment almost completely suppressed the S-1-P-induced inhibition of adenylyl cyclase but hardly influenced the lipid-induced activation 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 cyclase, through distinct S-1-P receptor-transducer systems, resulting in the modulation of glycogenolysis in rat hepatocytes.
Im
D S
DS
Laboratory of Signal Transduction, Gunma University, Maebashi, Japan.
Fujioka
T
T
Katada
T
T
Kondo
Y
Y
Ui
M
M
Okajima
F
F
D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D007295:Inositol Phosphates / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D006005:Phosphorylases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D012969:Sodium Fluoride / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D007295:Inositol Phosphates; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D012969:Sodium Fluoride; D000242:Cyclic AMP; D006005:Phosphorylases; D010738:Type C Phospholipases; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium