Muscarinic, α1 and peptidergic agonists stimulate phosphoinositide hydrolysis and regulate mucin secretion in rat submandibular gland cells

Abstract

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.

The effects of acute and chronic lithium treatment on rat submandibular salivation

“…Signal transduction mechanism underlying stimulation of muscarinic cholinergic receptors in salivary glands involves G‐proteins activation resulting in hydrolysis of phosphatidylinositol biphosphate by phospholipase C and thereby production of phosphatidylinositol 1,4,5‐triphosphate (IP 3 ) which leads to a rise in the intracellular calcium concentration and consequently to fluid secretion (Fleming et al , 1987; Nauntofte, 1992). It has been demonstrated that lithium interferes with phosphatidylinositol turnover in rat brain slices and parotid fragments, by inhibiting inositolmonophosphatase and consequently decreasing level of IP 3 in uncompetitive and time‐dependent manner (Berridge et al , 1982).…”

“…We have also found that chronic administration of lithium reduces phenylephrine‐induced secretory response in uncompetitive manner, as in the case of carbachol. Phenylephrine, as a selective α 1 agonist, produces salivation because of activation of α 1 adrenoceptor associated with phosphoinositide signalling (Fleming et al , 1987). The inhibitory effect of lithium on phenylephrine‐induced secretion supports the suggestion that its antisialogouge effect could be a consequence of its interference with phosphatidylinositol turnover.…”

Immunohistochemical and morphometric investigations of the influence of botulinum toxin on the submandibular gland of the rat

“…The salivary glands of the head derive their innervation from both the adrenergic and cholinergic branches of the autonomic nervous system [8], with cholinergic stimulation being more important for the secretion of water and electrolytes [11,17,21] but less important for that of protein (e.g., amylase) and mucous substances [3,7]. During cholinergic stimulation of a salivary gland there occurs a rise in intracellular Ca 2+ concentration [15].…”