Zusammenfassung
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 pH e); KCNE2/KCNQ1 is activated; and for KCNE1/KCNQ1, variable effects ...
Zusammenfassung
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 pH e); KCNE2/KCNQ1 is activated; and for KCNE1/KCNQ1, variable effects have been reported. Methods: The role of KCNE subunits for the effect of pH(e) 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 pH(e). hKCNE1/ hKCNQ1 heteromeric channels exhibited marked changes of biophysical properties at low pH e: 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. Copyright (c) 2007 S. Karger AG, Basel
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