Role of PDK1 in regulation of gastric acid secretion.
Pharmacological inhibition of phosphoinositide 3-kinase (PI3K) has previously been shown to enhance basal gastric acid secretion. Signaling of PI-3-kinase includes activation of the phosphoinositide dependent kinase PDK1. We thus hypothesized that PDK1 may influence gastric acid secretion. In the present study gastric acid secretion in mice expressing ñ20 % of PDK1 (pdk1(hm)) was compared to gastric acid secretion in their wild type littermates (pdk1(wt)). According to BCECF-fluorescence cytosolic pH in isolated gastric glands was similar in pdk1(hm) and in pdk1(wt) mice. Na(+)-independent pH recovery (DeltapH/min) following an ammonium pulse, which reflects K(+)/H(+)-ATPase activity, was however, significantly faster in pdk1(hm) than in pdk1(wt) mice. In both genotypes, DeltapH/min was abolished in the presence of K(+)/H(+)-ATPase inhibitor omeprazole (100 microM). Increase of local K(+)-concentrations to 35 mM (replacing Na(+)/NMDG) significantly increased DeltapH/min in both, pdk1(hm) and pdk1(wt) mice, and abrogated the differences between genotypes. Similarly, treatment with 5 microM forskolin as well as stimulation of protein kinase C with phorbolester phorbol 12 myristate 13 acetate (100 nM) enhanced DeltapH/min to almost identical values in pdk1(hm) and in pdk1(wt)mice. Protein kinase A inhibitor H89 (50 nM) decreased DeltapH/min in pdk1(hm) to values similar to those in pdk1(wt). In conclusion, deficient activity of PDK1 leads to a marked increase of gastric acid secretion. The present observations thus disclose a novel element in the regulation of gastric H(+) secretion.
Rotte
Anand
A
Department of Physiology, University of Tübingen, Tübingen, Germany.
Bhandaru
Madhuri
M
Ackermann
Teresa F
TF
Boini
Krishna M
KM
Lang
Florian
F
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005744:Gastric Acid / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000378:metabolism; D011188:Potassium / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007546:Isoquinolines; D000644:Quaternary Ammonium Compounds; D013449:Sulfonamides; D005576:Colforsin; D002217:Carbachol; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D009853:Omeprazole; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium