Hypokalemia refers to lower-than-normal blood potassium (K+) levels, which often result in cardiac arrhythmias. In lowered extracellular K+ concentrations ([K+]o) under hypokalemia, the resting membrane potential of human cardiomyocytes can paradoxically depolarize inconsistent with the Nernst equation. Such a well-known paradoxical depolarization is the key to understanding thepathological mechanism of hypokalemia-induced cardiac arrhythmias. An inward leak sodium (Na+) current was implied to cause cardiac paradoxical depolarization, but its molecular mechanism is not yet understood. Background K+ channels primarily maintain normal cardiac resting membrane potentials at around −80 mV, close to the K+ equilibrium potential. A fundamental characteristic of K+ channels, the ion selectivity, is generally considered to be static and independent of physiological regulation. None of over 80 mammalian K+ channels shows dynamic ion selectivity in response to physiological or pathological stimuli, but several voltage-gated K+ channels conduct Na+ currents in the absence of intracellular K+, implying that the selectivity filter of K+ channels can be dynamic. Here we show that 1) a cardiac background K+ channel exhibits dynamic ion selectivity, becomes permeable to Na+, and conducts inward leak Na+ currents in hypokalemia or lowered [K+]o; 2) a specific residue within the selectivity filter determines dynamic ion selectivity of the K+ channels; 3) in lowered [K+]o, over-expression of the K+ channels results in acquired paradoxical depolarization in mouse HL-1 cardiomyocytes and inhibits hyperpolarization in rat primary hippocampal neurons, and knock-down of the K+ channels eliminates paradoxical depolarization in human primary cardiomyocytes. These findings demonstrate that ion selectivity of the K+ channels is regulated by a pathological stimulus, elucidate a molecular basis of inward leak Na+ currents that may contribute to hypokalemia-induced cardiac paradoxical depolarization, and indicate a novel mechanism that regulates potentially cardiac excitability.