Journal Article

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

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

2023

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: Antibiotics / Cisapride - metabolism / Cisapride - pharmacology / Electrocardiography / ERG1 Potassium Channel / Erythromycin / Erythromycin - pharmacology / Ether-A-Go-Go Potassium Channels / Heart / hERG / Physiological aspects / Physiology / Potassium Channel Blockers - pharmacology / steady-state activation / steady-state inactivation / Temperature