HERG K+ channel blockade by the novel antiviral drug sophocarpine.
Human ether-à-go-go-related gene (HERG) encodes the rapid component of the cardiac delayed rectifier K+ current, which has an important role in the repolarization of the cardiac action potential. QT interval prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The effects of the novel antiviral drug sophocarpine (SC) were examined on stably expressed HERG channels in human embryonic kidney (HEK293) cells using a whole-cell patch clamp technique, Western blot analysis and immunofluorescence experiments. SC inhibited HERG channels in a concentration-dependent manner, with an IC50 of 100-300 microM. SC significantly accelerated channel inactivation, recovery from inactivation and onset of inactivation. In addition, it had no effect on channel activation and deactivation. Based on Western blot and immunofluorescence results, SC had no significant effect on the expression of HERG protein. In summary, SC is a potent blocker of HERG K+ channels that functions by changing the channel inactivation kinetics. In addition, SC has no effect on the generation and trafficking of HERG protein.
Zhao
Xue-Ling
XL
Department of Pharmacology, Harbin Medical University, 194 Xuefu Road, Harbin 150081, China.
Qi
Zhi-Ping
ZP
Fang
Cheng
C
Chen
Ming-Hong
MH
Lv
Yan-Jie
YJ
Li
Bao-Xin
BX
Yang
Bao-Feng
BF
D000470:Alkaloids / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D004591:Electrophoresis, Polyacrylamide Gel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000502:physiology; D006801:Humans; D007700:Kinetics; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D000093842:Matrines
D000470:Alkaloids; D000998:Antiviral Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D026902:Potassium Channel Blockers; C000606913:KCNH2 protein, human; C035933:sophocarpine; D000093842:Matrines