Gastric acid secretion is accomplished by the apical K+ /H+ ATPase. The K+ thus taken up by the parietal cell is recycled through apical K+ channels. Gastric acid secretion is stimulated by glucocorticoids, an effect involving the serum and glucocorticoid inducible kinase SGK1. The kinase stimulates the voltage gated K+ channel KCNQ1, which plays a critical role in gastric acid secretion. The present study explored whether the contribution of SGK1 to the effects of glucocorticoids on gastric acid secretion involves K+ channels. BCECF fluorescence was utilized for determination of H+ secretion ([Delta]pH) in isolated gastric glands from gene targeted mice lacking functional SGK1 (sgk1-/- ) and their wild type littermates (sgk1+/+ ). [Delta]pH was similar in sgk1-/- and sgk1+/+ mice prior to dexamethasone (DEX) treatment. DEX (10 mg/g bw) increased [Delta]pH more than 4 fold in sgk1+/+ mice and 2-3 fold in sgk1-/- mice. Pretreatment of the mice with K+ channel blocker HOE 293B (5 mg/g bw) or local application of K+ /H+ ATPase inhibitor omeprazole (50 mM) completely abrogated the increase of [Delta]pH following DEX in both genotypes. Increase of extracellular K+ concentration to 35 mM enhanced [Delta]pH to similar values in both genotypes, which could not be further increased by DEX. In conclusion, stimulation of gastric acid secretion by glucocorticoids is in part dependent on the presence of SGK1 and fully dependent on H+ /K+ ATPase and KCNQ1 channel activity.