Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes

Abstract

Strong inward rectifier K⁺ (Kir2) channels primarily maintain normal resting membrane potential of cardiomyocytes. In sub-physiological extracellular K⁺ concentrations or pathological hypokalaemia, human cardiomyocytes show both hyperpolarized and depolarized resting membrane potentials; these depolarized potentials cause cardiac arrhythmia; however, the underlying mechanism is unknown. Here we show that Kir2.1 currents non-linearly counterbalance hypokalaemia-induced K2P1 leak cation currents, reconstituting two levels of resting membrane potential in cardiomyocytes. Under hypokalaemic conditions, both human cardiomyocytes derived from induced pluripotent stem cells with enhanced Kir2.1 expression and mouse HL-1 cardiomyocytes with ectopic expression of K2P1 channels recapitulate two levels of resting membrane potential. These cardiomyocytes display N-shaped current-voltage relationships that cross the voltage axis three times, and the first and third zero-current potentials match the two levels of resting membrane potential. Inhibition of K2P1 expression eliminates the phenomenon, indicating contributions of Kir2.1 and K2P1 channels to two levels of resting membrane potential. Second, in Chinese hamster ovary cells that heterologously express the channels, Kir2.1 currents non-linearly counterbalance hypokalaemia-induced K2P1 leak cation currents, yielding the N-shaped current-voltage relationships, causing resting membrane potential spontaneously jump from hyperpolarization at the first zero-current potential to depolarization at the third zero-current potential, again recapitulating two levels of resting membrane potential. These findings reveal ionic mechanisms of two levels of resting membrane potential, demonstrate a previously unknown mechanism of regulation of excitability, and support the hypothesis that Kir2 currents non-linearly balance inward background cation currents, accounting for two levels of resting membrane potential of human cardiomyocytes.

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