The cardiac K+ channel KCNQ1 is essential for gastric acid secretion

Background & Aims: Gastric H+ secretion via the H+/ K+-adenosine triphospha tase is coupled to the uptake of H+. However, the molecular identity of lum inal K+ channels enabling K+ recycling in parietal cells is unknown, This s tudy was aimed to investigate these luminal Kf channels. Methods: Acid secr etion was measured in vivo and in vitro; HCNQ1 protein localization was ass essed by immunofluorescence, and acid-sensitivity of KCNQ1 by patch-clamp, Results: We identified KCNQ1, which is mutated in cardiac long QT syndrome, as a K+ channel located in tubulovesicles and apical membrane of parietal cells, where it colocalized with H+/K+-adenosine triphosphatase, Blockade o f HCNQ1 current by 293B led to complete inhibition of acid secretion. The p utative KCNQ1 subunits, KCNE2 and KCNE3, were abundant in human stomach; KC NE1, however, was absent. Coexpression of KCNE3/KCNQ1 in COS cells led to a n acid-insensitive current; KCNE2/KCNQ1 was activated by low extracellular pH, Conclusions: We identified KCNQ1 as the missing luminal H+ channel in p arietal cells and characterized its crucial role in acid secretion. Because KCNEB and KCNE2 are expressed in human stomach, one or both are candidates to coassemble with KCNQ1 in parietal cells. Thus, stomach- and subunit-spe cific inhibitors of HCNQ1 might offer new therapeutical perspectives for pe ptic ulcer disease.