Heteromeric KCNE2/KCNQ1 potassium channels in the luminal membrane of gastric parietal cells

Recently, we and others have shown that luminal K + recycling via KCNQ1 K + channels is required for gastric H + secretion. Inhibition of KCNQ1 by the chromanol 293B strongly diminished H + secretion. The present study aims at clarifying KCNQ1 subunit composition, subcellular localization, regulation and pharmacology in parietal cells. Using in situ hybridization and immunofluorescence techniques, we identified KCNE2 as the β subunit of KCNQ1 in the luminal membrane compartment of parietal cells. Expressed in COS cells, hKCNE2/hKCNQ1 channels were activated by acidic pH, PIP 2 , cAMP and purinergic receptor stimulation. Qualitatively similar results were obtained in mouse parietal cells. Confocal microscopy revealed stimulation‐induced translocation of H + ,K + ‐ATPase from tubulovesicles towards the luminal pole of parietal cells, whereas distribution of KCNQ1 K + channels did not change to the same extent. In COS cells the 293B‐related substance IKs124 blocked hKCNE2/hKCNQ1 with an IC 50 of 8 n m . Inhibition of hKCNE1‐ and hKCNE3‐containing channels was weaker with IC 50 values of 370 and 440 n m , respectively. In conclusion, KCNQ1 coassembles with KCNE2 to form acid‐activated luminal K + channels of parietal cells. KCNQ1/KCNE2 is activated during acid secretion via several pathways but probably not by targeting of the channel to the membrane. IKs124 could serve as a leading compound in the development of subunit‐specific KCNE2/KCNQ1 blockers to treat peptic ulcers.