TWIK-1 channels contribute to hypokalemia induced paradoxical depolarization in cardiac myocytes

Abstract

TWIK-1 potassium channels contributes to background K+ conductance in diverse cell types including human cardiac myocytes. TWIK-1 potassium channels changes ion selectivity and conduct inward Na+ currents at sub-physiological [K+]e. However, the pathological implications of the functional changes of TWIK-1 channels remains largely unknown. In hypokalemia, human cardiomyocytes show paradoxical depolarization which cause cardiac arrhythmia. However, the underlying mechanism is unknown. In the present study, we show that TWIK-1 channels conduct inward leak Na+ currents and contribute to the paradoxical membrane potential depolarization in cardiac myocytes in hypokalemia. First, under hypokalemia conditions, Chinese hamsterovary cells that heterologously express TWIK-1-WT channels show depolarization; in contrast, the cells with expression of TWIK-1-T118I mutant channels show hyperpolarization. Second, both human cardiomyocytes derived from induced pluripotent stem cells with enhanced Kir2.1 expression and mouse HL-1 cardiomyocytes with ectopic expression of TWIK-1 channels show paradoxical depolarization phenomenon. These cardiomyocytes display a nearly linear current-voltage relationship with a reversal potential at about -30 mV at 1 mM [K+]e, indicating a cation conductance. Substitution extra-cellular Na+ with NMDG+ shift the reversal potential to -110 mV and abolish the paradoxical depolarization phenomenon. Besides, inhibition of K2P1 expression eliminates the phenomenon, suggesting contributions of TWIK-1 channels to paradoxical depolarization. These findings reveal the mechanisms underlying hypokalemia induced paradoxical depolarization in human cardiac myocytes, and support that the inward leak Na+ currents carried by TWIK-1 channels induce paradoxical depolarization in cardiac myocytes under hypokalemia conditions.