The cardiac potassium channel KCNQ1, responsible for action potential repolarisation and mutated in long-QT-syndrome, co-assembles with members of the KCNE family to form native channels. Recently we and others showed that KCNQ1/KCNE2 are essential for gastric acid secretion and that this channel complex is activated by acidic extracellular pH. In KCNQ1 homomultimers the slowely activating component was more pronounced and the current amplitude was decreased by acidic pH. KCNE3 containing channels were completely insensitive to pH changes. Studies on chimeric proteins revealed that the N-terminus and the transmembrane domain of KCNE2 are necessary for pH activation of KCNQ1/KCNE2. In patch clamp experiments on transfected COS cells KCNQ1/KCNE1 currents were also activated by acidic pH and showed a transformation of the biophysical characteristics with a progressive loss of voltage dependence and deactivation. In freshly isolated guinea pig cardiomyocytes HMR 1556 revealed the importance of KCNQ1 dependent currents under acidic conditions. In conclusion, dependent on the respective KCNE subunit extracellular pH modulates basic biophysical characteristics in parts dramatically as most obvious in KCNQ1/KCNE1 heteromultimers. This mechanism might affect the susceptibility for arrhythmias after cardiac ischemia accompanied by local acidosis.