Febrile temperature facilitates hERG/I_Kr degradation through an altered K⁺ dependence

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• 作者：Yan Zhao ; MSc^* ; Tingzhong Wang ; PhD^&dagger ; ; Jun Guo ; BM^* ; Tonghua Yang ; BM^* ; Wentao Li ; BSc^* ; Jennifer Koichopolos ; BSc^* ; Shawn M. Lamothe ; MSc^* ; Yudi Kang ; MSc^* ; Aiqun Ma ; MD^&dagger ; ; Shetuan Zhang ; PhD^* ; ^{shetuan.zhang@queensu.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Arrhythmias ; Fever ; hERG ; Hypokalemia ; Long QT syndrome
• 刊名：Heart Rhythm
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：13
• 期：10
• 页码：2004-2011
• 全文大小：2795 K

文摘

Dysfunction of the rapidly activating delayed rectifier K⁺ channel (I_Kr) 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.

Objective

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

Methods

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 (I_hERG) in hERG expressing HEK 293 cells, as well as I_Kr, transient outward K⁺ current (I_to), and L-type Ca²⁺ current (I_Ca) in neonatal rat ventricular myocytes. Electrocardiographic recordings were performed in an in vivo rabbit model.

Results

Compared with culture at 37°C, culture at 40°C reduced the mature hERG expression and I_hERG 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 I_Kr in a manner similar to low K⁺ culture. In an in vivo rabbit model, fever and hypokalemia synergistically prolonged the QT interval.

Conclusion

Febrile temperature facilitates the development of LQTS by expediting hERG degradation through altered K⁺ dependence.