Role of PDK1 in Regulation of Gastric Acid Secretion

Abstract

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 (ΔpH/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, ΔpH/min was abolished in the presence of K⁺/H⁺-ATPase inhibitor omeprazole (100 μM). Increase of local K⁺-concentrations to 35 mM (replacing Na⁺/NMDG) significantly increased ΔpH/min in both, pdk1^hm and pdk1^wt mice, and abrogated the differences between genotypes. Similarly, treatment with 5 μM forskolin as well as stimulation of protein kinase C with phorbolester phorbol 12 myristate 13 acetate (100 nM) enhanced ΔpH/min to almost identical values in pdk1^hm and in pdk1^wtmice. Protein kinase A inhibitor H89 (50 nM) decreased ΔpH/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.