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 similar to 20 % 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 (Delta pH/min) following an ammonium pulse, which reflects K+/H+-ATPase activity, was however, significantly faster in pdk1hm than in pdk1wt mice. In both genotypes, Delta pH/min was abolished in the presence of K+/H+-ATPase inhibitor omeprazole (100 mu M). Increase of local K+-concentrations to 35 mM (replacing Na+/NMDG) significantly increased Delta pH/min in both, pdk1(hm) and pdk1(wt) mice, and abrogated the differences between genotypes. Similarly, treatment with 5 mu M forskolin as well as stimulation of protein kinase C with phorbolester phorbol 12 myristate 13 acetate (100 nM) enhanced pH/min to almost identical values in pdk1(hm) and in pdk1(wt) mice. Protein kinase A inhibitor H89 (50 nM) decreased pH/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. Copyright (C) 2008 S. Karger AG, Basel