TWIK-1 双孔钾通道在低细胞外钾条件下对心肌细胞的影响。

The Effect of TWIK-1 Two Pore Potassium Channels on Cardiomyocytes in Low Extracellular Potassium Conditions.

机构信息

National Traditional Chinese Medicine Clinical Research Base and Department of Cardiovascular Medicine of the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China.

Institute of Integrated Chinese and Western Medicine, Southwest Medical University, 646000 Luzhou, Sichuan, China.

出版信息

Front Biosci (Landmark Ed). 2023 Mar 15;28(3):51. doi: 10.31083/j.fbl2803051.

DOI:10.31083/j.fbl2803051

PMID:37005754

Abstract

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.

摘要

背景

在细胞外钾浓度（[K+]e）较低的情况下，人类心肌细胞可去极化至-40 mV。这与低钾血症引起的致命性心律失常密切相关。然而，其潜在机制尚不清楚。TWIK-1 通道是背景 K+通道，在人类心肌细胞中高度表达。我们之前报道过，TWIK-1 通道在低 [K+]e 条件下改变离子选择性并传导漏钠电流。此外，离子选择性过滤器内的特定苏氨酸残基（Thr118）负责这种改变的离子选择性。

方法

采用膜片钳技术研究 TWIK-1 通道对低 [K+]e 条件下心肌细胞膜电位的影响。

结果

在 2.7 mM [K+]e 和 1 mM [K+]e 下，中国仓鼠卵巢（CHO）细胞和 HL-1 细胞中异位表达的人 TWIK-1 通道均显示内向漏钠电流，并使膜电位重新去极化。相比之下，对 K+保持高选择性的人 TWIK-1-T118I 突变通道表达的细胞表现出膜电位超极化。此外，人诱导多能干细胞衍生的心肌细胞在 1 mM [K+]e 下表现出膜电位去极化，而 TWIK-1 表达的敲低消除了这种现象。