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1 Institute of Physiology, Universitätsstrasse 31, 93053 Regensburg, Germany
2 Institute of Physiology, Gmelinstrasse 5, 72076 Tübingen, Germany
3 IPMC, CNRS, 660 Route des Lucioles, 06560 Valbonne Sophia Antipolis, France
4 Institute of Pathology, Albertstrasse 19, 79104 Freiburg, Germany
5 Institute of Physiology, Winterthurerstrasse 190, 8057 Zürich, Switzerland
6 Institute of Biology I, Hauptstrasse 1, 79104 Freiburg, Germany
7 Aventis Pharma GmbH, 65926 Frankfurt, Germany
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 ß subunit of KCNQ1 in the luminal membrane compartment of parietal cells. Expressed in COS cells, hKCNE2/hKCNQ1 channels were activated by acidic pH, PIP2, 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 IC50 of 8 nM. Inhibition of hKCNE1- and hKCNE3-containing channels was weaker with IC50 values of 370 and 440 nM, 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.
(Received 3 September 2004;
accepted after revision 1 October 2004;
first published online 7 October 2004)
Corresponding author R. Warth: Institute of Physiology, Universitätsstrasse 31, 93053 Regensburg, Germany. Email: richard.warth{at}vkl.uni-regensburg.de
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