LUMINAL K+ RECYCLING VIA KCNE2/KCNQ1 K+ CHANNELS IS REQUIRED FOR GASTRIC ACID SECRETION.

D. Heitzmann (1), A. Schmitt-Gräff (2), F. Grahammer (1), J. Barhanin (3), R. Warth (1).
Institute of Physiology, Zürich, Switzerland (1); Institute of Pathology, Freiburg, Germany (2); CNRS Sophia Antipolis, France (3).

H+ secretion of gastric parietal cells via the H+/K+ ATPase is coupled to the uptake of K+. Recently we have shown that KCNQ1, which is mutated in cardiac long QT-syndrome, is the pore forming alpha-subunit of a gastric luminal K+ channel enabling K+ recycling. Immunofluorescence in human tissue revealed a colocalization of KCNQ1 and H+/K+ ATPase in tuboluvesicles of gastric parietal cells. Inhibition of KCNQ1 K+ channels by the chromanol 293B or KCNQ1 gene disruption in mice abolish H+ secretion completely. The small regulatory proteins KCNE1, 2 and 3 are known to coassemble with KCNQ1 leading to distinct functional properties of the heteromultimeric channel. This study was aimed to investigate subunit composition and regulation of heterologously expressed and native KCNQ1 K+ channels. In rodent stomach, KCNE1-3 are expressed. In situ hybridization and immunostaining of parietal cells showed only a strong KCNE2-specific labeling. To examine the functional properties of the putative channel complex, COS cells were cotransfected with KCNE2 and KCNQ1. Compared to cells transfected with KCNQ1 alone, KCNE2 cotransfected cells exhibit less K+ current under control conditions. In addition, KCNQ1-typic slow activation kinetics and voltage dependence of the current was changed to an instantaneous and voltage-independent current. Interestingly, KCNE2/KCNQ1 current was activated by acidic extracellular pH and by stimulation of cAMP and IP3/Ca2+ pathways. 293B inhibited KCNE2/KCNQ1 current in transfected cells and whole cell current of freshly isolated mouse parietal cells. In in vivo experiments of stomach lumen perfused rats stimulation of gastric acid secretion by pentagastrin, histamine and CCH was completely abolished by 293B. In conclusion, KCNE2 is the most likely beta subunit to coassemble with KCNQ1 in the luminal membrane compartment. The channel is activated by cAMP and IP3/Ca2+ which represent physiological stimuli of acid production. In contrast to many other K+ channels, KCNE2/KCNQ1 is activated by acidic extracellular pH. Stomach and subunit specific inhibition of KCNE2/KCNQ1 by 293B derivates could offer new perspectives for the treatment of peptic ulcer disease.