Outward and inward background currents across the cell membrane balance， determining resting membrane potential. Inward rectifier K channel subfamily 2 (Kir2) channels primarily maintain the resting membrane potential of cardiomyocytes. Human cardiomyocytes exhibit two levels of resting membrane potential at subphysiological extracellular K concentrations or pathological hypokalaemia， however， the underlying mechanism is unclear. In the present study， we show that human cardiomyocytes derived from induced pluripotent stem cells with enhanced expression of isoform 1 of Kir2 (Kir2.1) channels and mouse HL-1 cardiomyocytes with ectopic expression of two pore-domain K channel isoform 1 (K2P1) recapitulate t... More
Outward and inward background currents across the cell membrane balance， determining resting membrane potential. Inward rectifier K channel subfamily 2 (Kir2) channels primarily maintain the resting membrane potential of cardiomyocytes. Human cardiomyocytes exhibit two levels of resting membrane potential at subphysiological extracellular K concentrations or pathological hypokalaemia， however， the underlying mechanism is unclear. In the present study， we show that human cardiomyocytes derived from induced pluripotent stem cells with enhanced expression of isoform 1 of Kir2 (Kir2.1) channels and mouse HL-1 cardiomyocytes with ectopic expression of two pore-domain K channel isoform 1 (K2P1) recapitulate two levels of resting membrane potential， indicating the contributions of Kir2.1 and K2P1 channels to the phenomenon. In Chinese hamster ovary cells that express the channels， Kir2.1 currents non-linearly counterbalance hypokalaemia-induced K2P1 leak cation currents， reconstituting two levels of resting membrane potential. These findings support the hypothesis that Kir2 currents non-linearly counterbalance inward background cation currents， such as K2P1 currents， accounting for two levels of resting membrane potential in human cardiomyocytes and demonstrating a novel mechanism that regulates excitability.
