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KCNE Beta Subunits Determine pH Sensitivity of KCNQ1 Potassium ChannelsHeitzmann D.* · Koren V.* · Wagner M.# · Sterner C.# · Reichold M.# · Tegtmeier I.# · Volk T.# · Warth R.#
Institute of Physiology, University of Regensburg,#Institute of Cellular and Molecular Physiology, University of Erlangen-Nürnberg,*These authors contributed equally Corresponding Author
Prof. Dr. Richard Warth
Institute of Physiology
Universitaetstrasse 31, 93053 Regensburg (Germany)
Tel. +49-941-943-2894, Fax: +49-941-943-2896
Background/Aims: Heteromeric KCNEx/KCNQ1 (=KvLQT1, Kv7.1) K+ channels are important for repolarization of cardiac myocytes, endolymph secretion in the inner ear, gastric acid secretion, and transport across epithelia. They are modulated by pH in a complex way: homomeric KCNQ1 is inhibited by external acidification (low pHe); KCNE2/KCNQ1 is activated; and for KCNE1/KCNQ1, variable effects have been reported. Methods: The role of KCNE subunits for the effect of pHe on KCNQ1 was analyzed in transfected COS cells and cardiac myocytes by the patch-clamp technique. Results: In outside-out patches of transfected cells, hKCNE2/hKCNQ1 current was increased by acidification down to pH 4.5. Chimeras with the acid-insensitive hKCNE3 revealed that the extracellular N-terminus and at least part of the transmembrane domain of hKCNE2 are needed for activation by low pHe. hKCNE1/hKCNQ1 heteromeric channels exhibited marked changes of biophysical properties at low pHe: The slowly activating hKCNE1/hKCNQ1 channels were converted into constitutively open, non-deactivating channels. Experiments on guinea pig and mouse cardiac myocytes pointed to an important role of KCNQ1 during acidosis implicating a significant contribution to cardiac repolarization under acidic conditions. Conclusion: External pH can modify current amplitude and biophysical properties of KCNQ1. KCNE subunits work as molecular switches by modulating the pH sensitivity of human KCNQ1.
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