Inhibitory effects of PGE₂ on K⁺ currents and Ca²⁺ oscillations in rat pancreatic acinar cells

Prostaglandin E₂ (PGE₂) inhibits pancreatic enzyme secretion and shows a protective action against pancreatitis. In this study, we tested the effects of PGE₂ on the slowly activating voltage-dependent K⁺ channel current (I_Ks) and cholecystokinin (CCK)-induced oscillations of cytosolic [Ca²⁺] ([Ca²⁺]_i) in rat pancreatic acini (RPA). I_Ks in RPA is reportedly augmented by both Ca²⁺- and cAMP-mediated secretagogues. PGE₂ (10^-7 M) decreased the amplitude of I_Ks, an effect that was more prominent following prior stimulation with secretin. The application of the membrane-permeable cAMP analogue 8-Br-cAMP prevented the effect of PGE₂ on I_Ks. The Ca²⁺-mediated augmentation of I_Ks by ACh was unaffected by pretreatment with PGE₂. Using fura-2 fluorescence ratiometry to assess [Ca²⁺]_i, CCK (≤10^-10 M)-induced Ca²⁺ oscillations were observed in RPAs. The amplitude of the Ca²⁺ oscillations was decreased by PGE₂, irrespective of the presence of 8-Br-cAMP. RT-PCR analysis showed that RPAs express predominantly the EP3 subtype of the PGE₂ receptor and its splice variants. Enzyme-immunoassay showed that the secretin-induced production of cAMP in RPAs was inhibited by treatment with PGE₂. In summary, PGE₂ acts on the EP3 receptors to antagonize the cAMP-generating effect of secretin, resulting in the decrease of I_Ks. In addition, PGE₂ suppresses CCK-induced Ca²⁺ oscillations in a cAMP-independent manner. These effects of PGE₂ may explain the inhibitory action mechanism of PGE₂ in the exocrine pancreas.