EPIDERMAL GROWTH-FACTOR INHIBITS CARBACHOL-STIMULATED CANINE PARIETAL-CELL FUNCTION VIA PROTEIN-KINASE-C

Background and Aims: Epidermal growth factor (EGF) inhibits secretagog ue-stimulated gastric acid secretion via an EGF receptor located on pa rietal cells, The aim of this study was to examine whether this growth factor inhibited carbachol-stimulated acid secretion through a protei n kinase C-dependent mechanism, Methods: The effect of EGF on carbacho l-stimulated aminopyrine uptake, inositol trisphosphate formation, and intracellular Ca2+ ([Ca2+](i)) in purified cultured parietal cells wa s studied, The ability of protein kinase A and C inhibitors to alter t he inhibitory action of EGF was assessed. EGF-mediated translocation a nd activation of protein kinase C in parietal cells were determined, R esults: EGF dose dependently inhibited carbachol-stimulated aminopyrin e uptake in a pertussis toxin-insensitive, genistein (tyrosine kinase inhibitor)-sensitive manner, with a maximal inhibitory effect (37.5% /- 6.8%) achieved at 10(-7) mol/L. EGF did not significantly inhibit c arbachol-stimulated inositol trisphosphate formation and did not alter the initial transient increase or sustained plateau in [Ca2+](i) stim ulated by this secretagogue. The protein kinase C inhibitors H-7 and s taurosporine dose dependently reversed the inhibitory action of EGF, w hereas H-89 (protein kinase A inhibitor) failed to alter the effect of EGF, EGF pretreatment increased the translocation of alpha and beta(1 ) isoforms of protein kinase C and stimulated kinase activity in parie tal cells, EGF did not down-regulate the parietal cell muscarinic rece ptor. Conclusions: The inhibitory action of EGF on carbachol-stimulate d parietal cell activity seems to involve protein kinase C.