Effect of TWIK-1 channel on hypokalemia-induced abnormal pacemaker activities in human cardiomyocytes and its mechanisms
10.3969/j.issn.1000-4718.2025.05.007
- VernacularTitle:TWIK-1通道在低血钾诱发人心肌细胞异常起搏活动中的作用及其机制
- Author:
Hengxi ZHANG
1
;
Lei XIONG
;
Yue WU
;
Jinhua LV
;
Zheng ZUO
;
Ruolan LI
;
Dechou ZHANG
;
Ping LIU
;
Dongchuan ZUO
Author Information
1. 西南医科大学心血管医学研究所,电生理学教育部重点实验室,四川 泸州 646000
- Publication Type:Journal Article
- Keywords:
TWIK-1 two-pore potassium channels;
hypokalemia;
cardiomyocytes;
abnormal pacemaker ac-tivities
- From:
Chinese Journal of Pathophysiology
2025;41(5):895-901
- CountryChina
- Language:Chinese
-
Abstract:
AIM:This study aims to investigate the impact of TWIK-1 channels on abnormal pacemaker activi-ties induced by hypokalemia and to elucidate the underlying mechanisms.METHODS:The gene sequences encoding hu-man TWIK-1,specific TWIK-1 shRNA and TWIK-1-T118i mutant were synthesized and subsequently subcloned into lenti-viral vectors.To knock down the TWIK-1 gene in human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),the cells were transduced with lentivirus carrying the specific TWIK-1 shRNA sequences.For the overexpression of TWIK-1 or the TWIK-1-T118i mutant in HL-1 mouse cardiomyocytes,the cells received lentiviral transduction containing the respective gene sequences.Patch-clamp techniques were employed to assess the effects of 1 mmol/L extracellular K+on the membrane potentials and whole-cell currents of the cardiomyocytes.RESULTS:Under conditions of 1 mmol/L extra-cellular K+,depolarization of membrane potentials was observed in the hiPSC-CMs and the HL-1 mouse cardiomyocytes ex-pressing human TWIK-1 channel,leading to the induction of abnormal pacemaker activities.This phenomenon could be reversibly abolished by the removal of extracellular Na+or inhibited through TWIK-1 knockdown.In contrast,the mem-brane potentials of HL-1 mouse cardiomyocytes expressing human TWIK-1-T118i mutant hyperpolarized,with no occur-rence of abnormal pacemaker activities.The hiPSC-CMs exhibiting abnormal pacemaker activities at 1 mmol/L extracellu-lar K+demonstrated TWIK-1-like Na+leak currents,which were blocked by quinine,a non-selective blocker of TWIK-1.CONCLUSION:The TWIK-1 channels play a critical role in the development of hypokalemia-induced abnormal pace-maker activities in human cardiomyocytes by facilitating Na+leak currents.
