TWIK-1 two-pore domain potassium channels change ion selectivity and conduct inward leak sodium currents in hypokalemia.

Background potassium (K + ) channels, which are normally selectively permeable to K + , maintain the cardiac resting membrane potential at around −80 mV. In subphysiological extracellular K + concentrations ([K + ] o ), which occur in pathological hypokalemia, the resting membrane potential of human cardiomyocytes can depolarize to around −50 mV, whereas rat and mouse cardiomyocytes become hyperpolarized, consistent with the Nernst equation for K + . This paradoxical depolarization of cardiomyocytes in subphysiological [K + ] o , which may contribute to cardiac arrhythmias, is thought to involve an inward leak sodium (Na + ) current. Here, we show that human cardiac TWIK-1 (also known as K2P1) two-pore domain K + channels change ion selectivity, becoming permeable to external Na + , and conduct inward leak Na + currents in subphysiological [K + ] o . A specific threonine residue (Thr 118 ) within the pore selectivity sequence TxGYG was required for this altered ion selectivity. Mouse cardiomyocyte–derived HL-1 cells exhibited paradoxical depolarization with ectopic expression of TWIK-1 channels, whereas TWIK-1 knockdown in human spherical primary cardiac myocytes eliminated paradoxical depolarization. These findings indicate that ion selectivity of TWIK-1 K + channels changes during pathological hypokalemia, elucidate a molecular basis for inward leak Na + currents that could trigger or contribute to cardiac paradoxical depolarization in lowered [K + ] o , and identify a mechanism for regulating cardiac excitability.