TY - JOUR
T1 - Elevation of propofol sensitivity of cardiac IKs channel by KCNE1 polymorphism D85N
AU - Kojima, Akiko
AU - Mi, Xinya
AU - Fukushima, Yutaka
AU - Ding, Wei Guang
AU - Omatsu-Kanbe, Mariko
AU - Matsuura, Hiroshi
N1 - Funding Information:
The authors are grateful to Professor Jacques Barhanin (Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Valbonne, France) for kindly providing the KCNQ1 plasmid, Professor Minoru Horie (Shiga University of Medical Science, Otsu, Japan) and Dr. Takeru Makiyama (Kyoto University, Kyoto, Japan) for the generous gift of the KCNE1-D85N plasmid, and Professor Michael Sanguinetti (University of Utah, Salt Lake City, UT, USA) for the generous gift of the HERG plasmid. The authors are also grateful to Professor William C. Claycomb (Louisiana State University Health Sciences Center, New Orleans, LA, USA) for the generous gift of mouse cardiomyocyte-derived HL-1 cells. The authors are also grateful to Professor Keiji Imoto (National Institute for Physiological Sciences, Okazaki, Japan) and Professor Hideki Itoh (Hiroshima University Hospital, Hiroshima, Japan) for invaluable comments on computational simulation experiments using the O'Hara-Rudy dynamic model.
Publisher Copyright:
© 2021 The British Pharmacological Society
PY - 2021/7
Y1 - 2021/7
N2 - 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.
AB - 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.
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U2 - 10.1111/bph.15460
DO - 10.1111/bph.15460
M3 - Article
C2 - 33763865
AN - SCOPUS:85104844412
VL - 178
SP - 2690
EP - 2708
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
SN - 0007-1188
IS - 13
ER -