Elevation of propofol sensitivity of cardiac IKs channel by KCNE1 polymorphism D85N

• Published in: British journal of pharmacology 2021-07, Vol.178 (13), p.2690-2708
• Main Authors: Kojima, Akiko, Mi, Xinya, Fukushima, Yutaka, Ding, Wei‐Guang, Omatsu‐Kanbe, Mariko, Matsuura, Hiroshi
• Format: Article
• Language: English
• Subjects: Anesthesia; Anesthetics; Cardiomyocytes; Cell membranes; EKG; Gene polymorphism; Genetic diversity; I Ks; Ion channels; KCNE1; KCNQ1 protein; Polymorphism; Potassium channels (voltage-gated); Propofol; QT interval; Single-nucleotide polymorphism; Ventricle
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.15460

Background and Purpose The 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) IKs 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 IKs 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 IKs 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 μM) 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 IKs 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.