Key result
Knockdown of TWIK-1 channels in human iPSC-derived cardiomyocytes significantly reduced the proportion of cells exhibiting membrane depolarization at 1 mM extracellular potassium from 31% to less than 10% (p=0.0001).
Why the study?
Human cardiomyocytes depolarize at low extracellular potassium conditions, contributing to hypokalemia-induced fatal cardiac arrhythmia, but the underlying mechanism remains poorly understood.
Does TWIK-1 channel expression cause membrane potential depolarization in cardiomyocytes under low extracellular potassium conditions?
Does TWIK-1 channel expression cause membrane potential depolarization in cardiomyocytes under low extracellular potassium conditions?
Absolute Event Rate: 10% vs 31%
p-value: p=0.0001
TWIK-1 channels conduct leak Na+ currents that contribute to the paradoxical depolarization of human cardiomyocytes under hypokalemic conditions, providing a potential mechanistic basis for hypokalemia-induced arrhythmias.
Hypothesis-generating for TWIK-1 targeting in hypokalemia-induced arrhythmias; leaves open in vivo and clinical validation.
BACKGROOUND: At low extracellular potassium ([K+]e) conditions, human cardiomyocytes can depolarize to -40 mV. This is closely related to hypokalemia-induced fatal cardiac arrhythmia. The underlying mechanism, however, is still not well understood. TWIK-1 channels are background K+ channels that are highly expressed in human cardiomyocytes. We previously reported that TWIK-1 channels changed ion selectivity and conducted leak Na+ currents at low [K+]e. Moreover, a specific threonine residue (Thr118) within the ion selectivity filter was responsible for this altered ion selectivity. METHODS: Patch clamp were used to investigate the effects of TWIK-1 channels on the membrane potentials of cardiomyocytes in response to low [K+]e. RESULTS: At 2.7 mM [K+]e and 1 mM [K+]e, both Chinese hamster ovary (CHO) cells and HL-1 cells ectopically expressed human TWIK-1 channels displayed inward leak Na+ currents and reconstitute depolarization of membrane potential. In contrast, cells ectopically expressed human TWIK-1-T118I mutant channels that remain high selectivity to K+ exhibited hyperpolarization of membrane potential. Furthermore, human iPSC-derived cardiomyocytes showed depolarization of membrane potential in response to 1 mM [K+]e, while the knockdown of TWIK-1 expression eliminated this phenomenon. CONCLUSIONS: These results demonstrate that leak Na+ currents conducted by TWIK-1 channels contribute to the depolarization of membrane potential induced by low [K+]e in human cardiomyocytes.
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Liu et al. (2023) studied Hypokalemia-induced membrane potential depolarization. TWIK-1 channel knockdown (shRNA) vs. Scrambled shRNA (control) was evaluated on Proportion of cells showing depolarization of membrane potential in 1 mM [K+]e (p=0.0001). Knockdown of TWIK-1 channels in human iPSC-derived cardiomyocytes significantly reduced the proportion of cells exhibiting membrane depolarization at 1 mM extracellular potassium from 31% to less than 10% (p=0.0001).
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