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Cell Physiol Biochem. 2009;23(1-3):133-42. doi: 10.1159/000204102. Epub 2009 Feb 18.

APC sensitive gastric acid secretion.

Author information

1
Department of Physiology, University of Tubingen, Tubingen, Germany.

Abstract

Adenomatous polyposis coli (APC) is a tumor suppressor gene inactivated in familial adenomatous polyposis and sporadic colorectal cancer. Mice carrying a loss-of-function mutation in the apc gene (apc(Min/+)) spontaneously develop gastrointestinal tumors. APC fosters degradation of beta-catenin, which in turn upregulates the serum- and glucocorticoid-inducible kinase SGK1. SGK1 stimulates KCNQ1, which is required for luminal K+ recycling and thus for gastric acid secretion. BCECF-fluorescence was utilized to determine gastric acid secretion in isolated gastric glands from apc(Min/+) mice and their wild type littermates (apc(+/+)). Western blotting was employed to analyse beta-catenin and SGK1 expression and immunohistochemistry to determine KCNQ1 protein abundance. beta-catenin and SGK1 expression were enhanced in apc(Min/+) mice. Cytosolic pH was similar in apc(Min/+) mice and apc(+/+) mice. Na+-independent pH recovery following an ammonium pulse (DeltapH/min), which reflects H+/K+ ATPase activity, was, however, significantly faster in apc(Min/+) mice than in apc(+/+)mice. In both genotypes DeltapH/min was abolished in the presence of H+/K+ ATPase inhibitor omeprazole (100 microM). Treatment of apc(Min/+) and apc(+/+)mice with 5 microM forskolin 15 minutes prior to the experiment or increase in local K+-concentrations to 35 mM (replacing Na+/NMDG) significantly increased DeltapH/min and abrogated the differences between genotypes. The increase of DeltapH/min in apc(Min/+)mice required SGK1, as it was abolished by additional knockout of SGK1 (apc(Min/+)/sgk1(-/-)). In conclusion, basal gastric acid secretion is significantly enhanced in apc(Min/+)mice, pointing to a role of APC in the regulation of gastric acid secretion. The effect of APC requires H+/K+ ATPase activity and is at least partially due to SGK1-dependent upregulation of KCNQ1.

PMID:
19255508
DOI:
10.1159/000204102
[Indexed for MEDLINE]
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