sq-23377 and 8-(4-((2-aminoethyl)aminocarbonylmethyloxy)phenyl)-1-3-dipropylxanthine

ATP stimulates phosphatidylcholine secretion in type II cells, an effect that is mediated by both adenosine A2 receptors coupled to adenylate cyclase and P2 receptors coupled to phosphoinositide-specific phospholipase C. Activation of these effector enzymes leads to formation of cAMP, diacylglycerols and inositol trisphosphate (IP3). cAMP in turn activates cAMP-dependent protein kinase, diacylglycerols activate protein kinase C and IP3 promotes Ca2+ mobilization. To further investigate the signal-transduction mechanisms mediating the ATP effect, we examined its action in combination with that of other surfactant secretagogues: 5'(N-ethylcarboxyamido)adenosine (NECA), a A2 agonist that activates adenylate cyclase; TPA (12-O-tetradecanoylphorbol-13-acetate), a direct activator of protein kinase C; and ionomycin, an ionophore that increases intracellular Ca2+. The effects of NECA, TPA and ionomycin were additive and thus consistent with independent signaling mechanisms. However, the effects of all combinations of three or four secretagogues that contained ATP were 10-20% less than additive. This suggested that ATP and other secretagogues act via common mechanisms. Calmodulin antagonists decreased the effects of ionomycin and ATP by approx. 60% and 30%, respectively, but did not decrease the effects of NECA, terbutaline or TPA. Complete inhibition of the effect of ATP was achieved with a combination of a calmodulin antagonist, an A2 antagonist and a protein kinase C inhibitor. These and previous data suggest that the stimulatory effect of ATP on phosphatidylcholine secretion in type II cells is mediated by three signal-transduction mechanisms: activation of cAMP-dependent protein kinase; activation of protein kinase C; and a calmodulin-dependent mechanism.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Adenosine; Adenosine Triphosphate; Adenosine-5'-(N-ethylcarboxamide); Animals; Cells, Cultured; Drug Interactions; Ionomycin; Isoquinolines; L-Lactate Dehydrogenase; Lung; Male; Phosphatidylcholines; Piperazines; Rats; Rats, Sprague-Dawley; Signal Transduction; Sulfonamides; Terbutaline; Tetradecanoylphorbol Acetate; Xanthines