Functionally diverse purinergic P2Y-receptors mediate prostanoid synthesis in cultured rat astrocytes: the role of ATP-induced phosphatidyl-inositol breakdown.
Cultured rat astrocytes possess purinergic P2Y-receptors. Stimulation of these receptors with ATP (10(-3) M) results in increased phosphatidylinositol biphosphate (PIP2)-breakdown and prostanoid formation. We have investigated the relevance of the PIP2-pathway in prostanoid synthesis. The intracellular Ca(2+)-mobilizing agent thapsigargin (TG) (10(-6) M) and the diacylglycerol (DAG)-mimetic tetradecaoylphorbol acetate (TPA) (10(-8)-10(-6) M) both stimulate prostaglandin D2 production. ATP-induced prostanoid formation can be mimicked by combined addition of TG and TPA, suggesting the importance of the second messengers IP3 and DAG, generated during P2Y-receptor mediated PIP2-breakdown. Inhibition of ATP-induced PIP2-hydrolysis by TPA (IC50 about 5 x 10(-8) M) or by 10(-4) M neomycine, however, does not affect astroglial prostanoid synthesis, showing that P2Y-receptor mediated prostanoid formation may occur also in the absence of PIP2-hydrolysis. These findings suggest that additional postreceptor mechanisms exist in the signal transduction chain of ATP-induced astroglial prostanoid synthesis. A possible involvement of phospholipase A2 and/or of Ca(2+)-channels, directly coupled to P2Y-receptors is proposed.
Seregi
A
A
Department of Pharamcology, University of Freiburg, FRG.
Doll
S
S
Schobert
A
A
Hertting
G
G
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D009355:Neomycin / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000096:biosynthesis; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology*; D013729:Terpenes / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin
D019269:Phosphatidylinositol 4,5-Diphosphate; D010716:Phosphatidylinositols; D011453:Prostaglandins; D011983:Receptors, Purinergic; D013729:Terpenes; D019284:Thapsigargin; D000255:Adenosine Triphosphate; D009355:Neomycin; D013755:Tetradecanoylphorbol Acetate; D015230:Prostaglandin D2