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Title of Journal: J Gastroenterol

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Abbravation: Journal of Gastroenterology

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Springer Japan

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DOI

10.1007/978-1-4614-1662-3_3

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1435-5922

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Regulation of basal gastric acid secretion by the

Authors: Anand Rotte Venkanna Pasham Melanie Eichenmüller Wenting Yang Syed M Qadri Madhuri Bhandaru Florian Lang
Publish Date: 2010/06/16
Volume: 45, Issue: 10, Pages: 1022-1032
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Abstract

According to previous observations basal gastric acid secretion is downregulated by phosphoinositol3PI3kinase phosphoinositidedependent kinase PDK1 and protein kinase B PKBβ/Akt2 signaling PKB/Akt phosphorylates glycogen synthase kinase GSK3 The present study explored whether PKB/Aktdependent GSK3phosphorylation modifies gastric acid secretionUtilizing 2′7′biscarboxyethyl56′carboxyfluorescein BCECFfluorescence basal gastric acid secretion was determined from Na+independent pH recovery ∆pH/min following an ammonium pulse which reflects H+/K+ATPase activity Experiments were performed in gastric glands from genetargeted mice gsk3 KI with PKB/serum and glucocorticoidinducible kinase SGKinsensitive GSKαβ in which the serines within the PKB/SGK phosphorylation site were replaced by alanine GSK3α21A/21A GSK3β9A/9AThe cytosolic pH in isolated gastric glands was similar in gsk3 KI and their wildtype littermates gsk3 WT However ∆pH/min was significantly larger in gsk3 KI than in gsk3 WT mice and ∆pH/min was virtually abolished by the H+/K+ATPase inhibitor omeprazole 100 μM in gastric glands from both gsk3 KI and gsk3 WT Plasma gastrin levels were lower in gsk3 KI than in gsk3 WT Both an increase of extracellular K+ concentration to 35 mM replacing Na+/Nmethyldglucamine NMDG and treatment with forskolin 5 μM significantly increased ∆pH/min to virtually the same value in both genotypes The protein kinase A PKA inhibitor H89 150 nM and the H2receptor antagonist ranitidine 100 μM decreased ∆pH/min in gsk3 KI but not gsk3 WT and again abrogated the differences between the genotypes The protein abundance of phosphorylated but not of total PKA was significantly larger in gsk3 KI than in gsk3 WT Basal gastric acid secretion is enhanced by the disruption of PKB/SGKdependent phosphorylation and the inhibition of GSK3 Thus the inhibition of GSK3 participates in the signaling of PI3kinasedependent downregulation of basal gastric acid secretion

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