Elevation Of Propofol Sensitivity Of Cardiac I-Ks Channel By Kcne1 Polymorphism D85n
BRITISH JOURNAL OF PHARMACOLOGY(2021)
摘要
Background and Purpose The slowly activating delayed rectifier K+ channel (I-Ks), composed of pore-forming KCNQ1 alpha-subunits and ancillary KCNE1 beta-subunits, regulates ventricular repolarization in human heart. Propofol, at clinically used concentrations, modestly inhibits the intact (wild-type) I-Ks channels and is therefore unlikely to appreciably prolong QT interval in ECG during anaesthesia. However, little information is available concerning the inhibitory effect of propofol on I-Ks channel 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 of I-Ks to inhibition by propofol.Experimental Approach Whole-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 Results Propofol 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 mu M) did not appreciably affect cell membrane expression of KCNQ1 and KCNE1 proteins in KCNQ1/KCNE1 and KCNQ1/KCNE1-D85N channels.Conclusion and Implications The KCNE1 polymorphism D85N significantly elevates the sensitivity of I-Ks to 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.
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关键词
I (Ks), KCNE1, propofol, QT interval, single nucleotide polymorphism
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