Pharmacological inhibition of phosphoinositol 3 kinase (PI3K) and partial deficiency of phosphoinositide dependent kinase PDK1 have previously been shown to enhance basal gastric acid secretion. PI3K/PDK1 dependent signaling involves activation of protein kinase B/Akt, which may thus be similarly involved in the regulation of gastric acid secretion. To test that hypothesis, gastric acid secretion was determined in isolated glands from gene targeted mice lacking functional Akt2 (akt2-/-) or from their wild type littermates (akt2+/+). According to BCECF-fluorescence cytosolic pH in isolated gastric glands was similar in akt2-/- and akt2+/+ mice. Na+-independent pH recovery (ΔpH/min) following an ammonium pulse, a measure of H+/K+ ATPase activity, was, however, significantly faster in akt2-/- than in akt2+/+ mice. In both genotypes, ΔpH/min was virtually abolished by H+/K+ ATPase inhibitor omeprazole (100 µM). Increase of extracellular K+ concentrations to 35 mM (replacing Na+) increased ΔpH/min to a significantly larger extent in akt2+/+ than in akt2-/- mice and dissipated the differences between the genotypes. Similarly, treatment with 5 µM forskolin enhanced ΔpH/min significantly only in akt2+/+ mice and abolished the differences between the genotypes. Conversely, protein kinase A inhibitor H89 (50 nM) decreased ΔpH/min to similarly low values in both genotypes. In conclusion, Akt2 suppresses gastric acid secretion and contributes to or even accounts for the inhibition of gastric acid secretion by PI3K.

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