Febrile temperature facilitates hERG/IKr degradation through an altered K(+) dependence.
Dysfunction of the rapidly activating delayed rectifier K(+) channel (IKr) encoded by the human ether-à-go-go-related gene (hERG) is the primary cause of acquired long QT syndrome (LQTS). Fever has been reported to trigger LQTS in various conditions.



We aim to clarify the effect and underlying mechanisms of febrile temperature on hERG expressed in HEK cells, IKr in neonatal rat ventricular myocytes, and the QT interval in rabbits.



Western blot analysis was used to determine the expression of hERG channel protein in stably transfected HEK 293 cells. Immunocytochemistry was used to visualize the localization of hERG channels. The whole-cell patch clamp technique was used to record hERG K(+) current (IhERG) in hERG expressing HEK 293 cells, as well as IKr, transient outward K(+) current (Ito), and L-type Ca(2+) current (ICa) in neonatal rat ventricular myocytes. Electrocardiographic recordings were performed in an in vivo rabbit model.



Compared with culture at 37°C, culture at 40°C reduced the mature hERG expression and IhERG in an extracellular K(+) concentration-dependent manner. Point mutations that remove the K(+) dependence of hERG-S624T and F627Y-also abolished the febrile temperature-induced hERG reduction. In neonatal rat ventricular myocytes, febrile temperature prolonged the action potential duration and selectively reduced IKr in a manner similar to low K(+) culture. In an in vivo rabbit model, fever and hypokalemia synergistically prolonged the QT interval.



Febrile temperature facilitates the development of LQTS by expediting hERG degradation through altered K(+) dependence.
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Yan
Y
Zhao
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China.
Tingzhong
T
Wang
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Jun
J
Guo
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Tonghua
T
Yang
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Wentao
W
Li
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Jennifer
J
Koichopolos
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Shawn M
SM
Lamothe
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
Yudi
Y
Kang
Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China.
Aiqun
A
Ma
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada,. Electronic address: shetuan.zhang@queensu.ca.
Shetuan
S
Zhang
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005334:Fever / Q000150:complications*; D057809:HEK293 Cells; D006801:Humans; D007008:Hypokalemia / Q000150:complications / Q000378:metabolism; D008133:Long QT Syndrome / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D051381:Rats
D051638:Ether-A-Go-Go Potassium Channels; D011188:Potassium
Arrhythmias; Fever; Hypokalemia; Long QT syndrome; hERG