APC sensitive gastric acid secretion.
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.
Rotte
Anand
A
Department of Physiology, University of Tubingen, Tubingen, Germany.
Bhandaru
Madhuri
M
Föller
Michael
M
Biswas
Raja
R
Mack
Andreas F
AF
Friedrich
Björn
B
Rexhepaj
Rexhep
R
Nasir
Omaima
O
Ackermann
Teresa F
TF
Boini
Krishna M
KM
Kunzelmann
Karl
K
Behrens
Jürgen
J
Lang
Florian
F
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D005576:Colforsin / Q000494:pharmacology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051657:KCNQ1 Potassium Channel / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009853:Omeprazole / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
D025601:Adenomatous Polyposis Coli Protein; D005576:Colforsin; D017874:Immediate-Early Proteins; D051657:KCNQ1 Potassium Channel; D009853:Omeprazole; D017346:Protein Serine-Threonine Kinases; D051176:beta Catenin; D000099184:Serum-Glucocorticoid Regulated Kinases; C496910:Kcnq1 protein, mouse