Effect of phorbol ester and calcium ionophore on chloride secretion in canine tracheal epithelium.
The control of Cl- secretion was examined by two of the terminal events in the phosphoinositide regulatory pathway: activation of protein kinase C and an increase in cell Ca2+. The phorbol ester phorbol 12-myristate 13-acetate (PMA), which activates protein kinase C, stimulated Cl- secretion in both native and cultured monolayers of tracheal epithelium. Approximately 1.5 nM of mucosal PMA was required for half-maximal stimulation. Stimulation was not dependent on prostaglandin production nor was it accompanied by an increase in cellular levels of cAMP. Although the maximal rate of PMA-induced Cl- secretion was less than that induced by cAMP, there was a synergistic effect between PMA and forskolin, an agent that activates adenylate cyclase. The response to PMA was at least partly transient and PMA may also attenuate Cl- secretion under some circumstances. Thus the response to PMA, and presumably protein kinase C activation, may be complex. An increase in cell Ca2+ produced by addition of the Ca2+ ionophore A23187 also stimulated Cl- secretion. However, the effect was at least partly indirect. A23187 enhanced prostaglandin E2 production and the prostaglandin synthesis inhibitor, indomethacin, blocked A23187-induced secretion in native epithelia and attenuated the effect of A23187 in cultured monolayers. These results indicate the presence of a non-cAMP-dependent regulatory pathway capable of controlling Cl- secretion in tracheal epithelium. Activation of protein kinase C may stimulate secretion directly or modulate the response to cAMP. An increase in cell Ca2+ may stimulate secretion at least partly by stimulating endogenous prostaglandin production.
Welsh
M J
MJ
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242.
D000001:Calcimycin / Q000494:pharmacology*; D002712:Chlorides / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D015232:Dinoprostone; D004357:Drug Synergism; D004553:Electric Conductivity; D004848:Epithelium / Q000378:metabolism; D007213:Indomethacin / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis; D011493:Protein Kinase C / Q000502:physiology*; D012636:Secretory Rate / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014132:Trachea / Q000378:metabolism*
D002712:Chlorides; D011458:Prostaglandins E; D000001:Calcimycin; D000242:Cyclic AMP; D011493:Protein Kinase C; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin