Lysophosphatidic acid regulation of cyclic AMP accumulation in cultured human airway smooth muscle cells.
The effects of the simple bioactive lipid mediator lysophosphatidic acid (LPA) on cAMP accumulation were investigated in cultured human airway smooth muscle cells (ASMC). Pretreatment of cells with LPA induced an increase in subsequent stimulation of cAMP accumulation by forskolin and by isoproterenol. When included during the assay of cAMP accumulation rather than as a pretreatment, LPA inhibited forskolin stimulation but enhanced isoproterenol stimulation. Both effects of LPA on forskolin stimulation were completely blocked by pertussis toxin treatment, whereas the effects on isoproterenol stimulation appeared relatively insensitive to pertussis toxin. The protein kinase C activator phorbol-12-myristate-13-acetate (PMA) sensitized forskolin stimulation to a similar extent as did LPA, and the combination of LPA plus PMA caused markedly more sensitization than either agent alone. In contrast, PMA inhibited isoproterenol stimulation and markedly decreased the sensitization induced by LPA. Serum also induced sensitization, and sensitization by LPA plus serum was no greater than that with LPA alone. LPA-induced sensitization appeared to be independent of protein kinase C activation because it was unchanged in cells treated to down-regulate protein kinase C. LPA also stimulated polyphosphoinositide hydrolysis, and this stimulation was partially inhibited by pertussis toxin treatment. These results suggest that LPA activates receptors coupled to both the pertussis toxin-sensitive G protein Gi and the pertussis toxin-insensitive G protein Gq. The complex effects of LPA, PMA, and pertussis toxin on cAMP accumulation in these cells are consistent with the expression of the type 2 isozyme of adenylyl cyclase in these cells.
D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D006801:Humans; D006868:Hydrolysis; D008246:Lysophospholipids / Q000494:pharmacology / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012680:Sensitivity and Specificity; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014132:Trachea / Q000166:cytology / Q000378:metabolism* / Q000502:physiology
D008246:Lysophospholipids; D010716:Phosphatidylinositols; D000242:Cyclic AMP; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate