Elevation of propofol sensitivity of cardiac IKs channel by KCNE1 polymorphism D85N.
Elevation of propofol sensitivity of cardiac IKs channel by KCNE1 polymorphism D85N.
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KCNE1 多态性 D85N 提高心脏 IK 通道的异丙酚敏感性。
DOI：
10.1111/bph.15460
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
M. Omatsu-Kanbe and H. Matsuura
中科院分区：
文献类型：
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作者：
A. Kojima;X. Mi;Y. Fukushima;W. G. Ding;M. Omatsu-Kanbe and H. Matsuura
背景与目的人心脏缓慢激活的延迟整流钾通道（IKs）由成孔的KCNQ 1 α亚基和辅助的KCNE 1 β亚基组成，调节心室复极。在临床使用浓度下，丙泊酚适度抑制完整（野生型）IKschannels，因此不太可能明显延长麻醉期间ECG的QT间期。然而，关于丙泊酚对与QT延长相关的基因变异体相关的IKschannel的抑制作用的信息很少。导致D85 N的KCNE 1单核苷酸多态性与药物诱导的QT间期延长相关，因此被认为是临床上重要的遗传变异。本研究检测KCNE 1-D85 N是否影响IKs对丙泊酚抑制的敏感性。实验方法在HEK 293细胞和/或小鼠心肌细胞衍生的HL-1细胞中进行全细胞膜片钳和免疫染色实验，转染野生型KCNQ 1，野生型或变体KCNE 1 cDNA。Key ResultsPropofol抑制HEK 293细胞和HL-1细胞中的KCNQ 1/KCNE 1-D85 N电流比KCNQ 1/KCNE 1电流更有效。在HEK 293细胞中进行的免疫染色实验显示，异丙酚（10 μM）预处理对KCNQ 1/KCNE 1和KCNQ 1/KCNE 1-D85 N通道的KCNQ 1和KCNE 1蛋白表达没有明显影响。本研究检测了KCNE 1-D85 N多态性在丙泊酚诱导的QT间期延长的遗传易感性中的重要功能作用，并进一步表明在携带编码离子通道的基因变异的患者中，麻醉剂对离子电流的抑制作用可能被夸大。
Background and PurposeThe slowly activating delayed rectifier K+channel (IKs), composed of pore‐forming KCNQ1 α‐subunits and ancillary KCNE1 β‐subunits, regulates ventricular repolarization in human heart. Propofol, at clinically used concentrations, modestly inhibits the intact (wild‐type)IKschannels and is therefore unlikely to appreciably prolong QT interval in ECG during anaesthesia. However, little information is available concerning the inhibitory effect of propofol onIKschannel associated with its gene variants implicated in QT prolongation. The KCNE1 single nucleotide polymorphism leading to D85N is associated with drug‐induced QT prolongation and therefore regarded as a clinically important genetic variant. This study examined whether KCNE1‐D85N affects the sensitivity ofIKsto inhibition by propofol.Experimental ApproachWhole‐cell patch‐clamp and immunostaining experiments were conducted in HEK293 cells and/or mouse cardiomyocyte‐derived HL‐1 cells, transfected with wild‐type KCNQ1, wild‐type or variant KCNE1 cDNAs.Key ResultsPropofol inhibited KCNQ1/KCNE1‐D85N current more potently than KCNQ1/KCNE1 current in HEK293 cells and HL‐1 cells. Immunostaining experiments in HEK293 cells revealed that pretreatment with propofol (10 μM) did not appreciably affect cell membrane expression of KCNQ1 and KCNE1 proteins in KCNQ1/KCNE1 and KCNQ1/KCNE1‐D85N channels.Conclusion and ImplicationsThe KCNE1 polymorphism D85N significantly elevates the sensitivity ofIKsto inhibition by propofol. This study detects a functionally important role of KCNE1‐D85N polymorphism in conferring genetic susceptibility to propofol‐induced QT prolongation and further suggests the possibility that the inhibitory action of anaesthetics on ionic currents becomes exaggerated in patients carrying variants in genes encoding ion channels.