Chinese Herb Medicine Division, Zhejiang Agriculture and Forestry University, 666 Wusu Street, Hangzhou 311300, China.
The State Key Laboratory of Subtropical Silviculture, Zhejiang Agriculture and Forestry University, 666 Wusu St, Hangzhou 311300, China.
Molecules. 2023 Jul 3;28(13):5176. doi: 10.3390/molecules28135176.
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.
红霉素是少数几种能显著增加 hERG（醚-ago-go 相关基因）抑制作用的化合物之一，从室温（RT）到生理温度（PT）。了解红霉素如何抑制 hERG 有助于我们决定哪些化合物需要进一步研究。本文采用全细胞膜片钳技术，在不同温度下研究了红霉素对 hERG 通道的影响。红霉素对心肌 hERG 通道呈浓度依赖性抑制作用，且能使通道的稳态激活和稳态失活向左侧移位，并在两种温度下显著加速失活的起始，但温度本身会使 hERG 通道动力学发生深刻变化。我们的数据还表明，通道 S6 结合模式在 PT 时发生改变。相反，已知的 hERG 阻滞剂 cisapride 的抑制作用不受温度影响，其关键结合位点在温度升高至 PT 后并未改变。我们的数据表明，红霉素是独特的，hERG 抑制的转变可能不适用于其他化合物。
