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 (Thr¹¹⁸) 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.