Muscarinic, alpha 1-adrenergic and peptidergic agonists stimulate phosphoinositide hydrolysis and regulate mucin secretion in rat submandibular gland cells.
Three classes of agonists associated with Ca2+-mobilization--alpha 1-adrenergic (methoxamine), muscarinic (carbachol) and peptidergic (substance P, SP)--significantly stimulated the secretion of mucin from enzymatically-dispersed rat submandibular gland acinar cells. The same three secretagogues also caused the hydrolysis of membrane inositol phospholipids, resulting in elevated cellular levels of inositol phosphates, particularly inositol 1,4,5-trisphosphate (IP3). Exogenous IP3 elicited the dose-dependent release of mucin in dispersed cells suggesting that agonist-generated endogenous IP3 may provoke a secretory response. IP3 and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in combination, stimulated an additive secretion of mucin in the model. The potential use of these two agents as specific probes of the IP3- and diacylglycerol-associated legs of the polyphosphoinositide (PPI) breakdown pathway is indicated. Although all three agonists shared a common action in stimulating PPI hydrolysis, their effects on the beta-adrenergic mucosecretory response were inconsistent. A brief preincubation of cells with carbachol or SP significantly reduced the subsequent isoproterenol (IPR)-provoked secretion of mucin, whereas methoxamine plus IPR stimulated an additive response. The mechanisms underlying these opposite effects are not known. Failure of IP3 or TPA to modify IPR responses suggests that modulation of the beta response may operate at a locus before the generation of diacylglycerol and IP3, possibly at the level of signal transduction. The study indicates a role for Ca2+-mobilizing agonists in controlling submandibular mucin secretion and provides evidence that receptor-linked phosphoinositide hydrolysis is an early stage in their stimulus-secretion coupling mechanism.
D000818:Animals; D002217:Carbachol / Q000494:pharmacology*; D002478:Cells, Cultured; D006868:Hydrolysis; D015544:Inositol 1,4,5-Trisphosphate; D007295:Inositol Phosphates / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D008729:Methoxamine / Q000494:pharmacology*; D009077:Mucins / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013363:Submandibular Gland / Q000187:drug effects / Q000502:physiology*; D013373:Substance P / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007295:Inositol Phosphates; D009077:Mucins; D010716:Phosphatidylinositols; D013373:Substance P; D015544:Inositol 1,4,5-Trisphosphate; D002217:Carbachol; D008729:Methoxamine; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate