The Strength of hERG Inhibition by Erythromycin at Different Temperatures Might Be Due to Its Interacting Features with the Channels

Dongrong Cheng; Xiaofeng Wei; Yanting Zhang; Qian Zhang; Jianwei Xu; Jiaxin Yang; Junjie Yu; Antony Stalin; Huan Liu; Jintao Wang; Dian Zhong; Lanying Pan; Wei Zhao; Yuan Chen

doi:10.3390/molecules28135176

The Strength of hERG Inhibition by Erythromycin at Different Temperatures Might Be Due to Its Interacting Features with the Channels

Molecules. 2023 Jul 3;28(13):5176. doi: 10.3390/molecules28135176.

Authors

Dongrong Cheng^{1

2}, Xiaofeng Wei^{1

2}, Yanting Zhang^{1

2}, Qian Zhang^{1

2}, Jianwei Xu^{1

2}, Jiaxin Yang^{1

2}, Junjie Yu^{1

2}, Antony Stalin³, Huan Liu^{1

2}, Jintao Wang^{1

2}, Dian Zhong^{1

2}, Lanying Pan⁴, Wei Zhao^{1

2}, Yuan Chen^{1

2}

Affiliations

¹ Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 666 Wusu Street, Hangzhou 311300, China.
² The State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 666 Wusu St, Hangzhou 311300, China.
³ Institute of Fundamental and Frontier Sciences, University of Electronic Science and Technology of China, Chengdu 610064, China.
⁴ Shuren International Medical College, Zhejiang Shuren University, Hangzhou 310009, China.

Abstract

Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds.

Keywords: erythromycin; hERG; steady-state activation; steady-state inactivation; temperature.

MeSH terms

Cisapride / metabolism
Cisapride / pharmacology
ERG1 Potassium Channel
Erythromycin* / pharmacology
Ether-A-Go-Go Potassium Channels*
Heart
Potassium Channel Blockers / pharmacology
Temperature

Substances

Ether-A-Go-Go Potassium Channels
Erythromycin
Cisapride
ERG1 Potassium Channel
Potassium Channel Blockers

Grants and funding

This research was funded by Scientific Research & Development Fund of Zhejiang A & F University grant number [2013FR032] to Yuan chen, [2016FR027] to Langying Pan, and also funded by Zhejiang provincial Natural Science Foundation grant number [LBY22H270002] to Wei zhao, [LY20C040001] to Langying Pan.