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hERG Channel Blockade and Antagonistic Interactions of Three Steroidal Alkaloids from Fritillaria Species
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hERG Channel Blockade and Antagonistic Interactions of Three Steroidal Alkaloids from Fritillaria Species
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Journal Article
hERG Channel Blockade and Antagonistic Interactions of Three Steroidal Alkaloids from Fritillaria Species
2025
Overview
The bulb of Fritillaria species called “Bei Mu” is a well-known traditional Chinese medicine. We have reported some potential off-target effects of “Bei Mu” due to peimine’s blockade of hERG (human Ether-a-go-go-Related Gene) channels. This research investigated the modulatory effects of three major alkaloid analogs of “Bei Mu” and their cooperative effects on hERG channels using manual whole-cell patch-clamp techniques. Results showed that peiminine and sipeimine blocked hERG currents with IC50s of 36.8 ± 2.5 μM and 47.6 ± 9.8 μM, which were close to that of peimine (26.1 ± 3.5 μM). Peiminine-induced blockade increased with increasing depolarizing strengths, durations, and frequencies, which suggested a preferential binding to open or inactivated states. The reduced blockade by the less inactivating S631A mutation supported peiminine‘s inactivation preference. Molecular docking and dynamics simulations confirmed the hERG-blocking activities of the three alkaloids and provided further insight into potential mechanisms. We also discovered antagonistic effects of the three alkaloids at nearly all concentrations tested, which might help reduce potential cardiotoxicities. To our knowledge, this is the first study to investigate combination effects of chemicals from one herb on hERG channels. In conclusion, peiminine and sipeimine can block hERG channels in a way similar to peimine, but antagonistic effects exist among them.
Publisher
MDPI AG
Subject
/ Bei Mu
/ ERG1 Potassium Channel - antagonists & inhibitors
/ ERG1 Potassium Channel - chemistry
/ ERG1 Potassium Channel - genetics
/ ERG1 Potassium Channel - metabolism
/ Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
/ Ether-A-Go-Go Potassium Channels - chemistry
/ Ether-A-Go-Go Potassium Channels - metabolism
/ Herbs
/ hERG
/ Humans
/ Molecular Docking Simulation
/ Molecular Dynamics Simulation
/ Potassium Channel Blockers - chemistry
