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