Acta pharmacologica Sinica · 2004
Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels.
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Yang Bao-feng, Xu Dong-hui, Xu Chao-qian, Li Zhe, Du Zhi-min, Wang Hui-zhen, Dong De-li
Аннотация
AIM: To determine the mechanisms of interactions between different drugs and HERG channels.
METHODS: Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine) agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used.
RESULTS: All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K+), relieved HERG blockade by all drugs. Moreover, the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 (S631A).
CONCLUSION: The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.
METHODS: Various antiarrhythmic (dofetilide, quinidine, azimilide, RP58866) and non-antiarrhythmic (terfenadine, nicotine) agents were used on HERG channels expressed in Xenopus oocyte. Whole-cell voltage-clamp techniques were used.
RESULTS: All drugs produced concentration-dependent block of HERG current. The inhibition was markedly facilitated with voltage protocols favoring channel inactivation (eg, less negative holding potentials). Maneuvers that weakened channel inactivation (eg, elevation of external K+), relieved HERG blockade by all drugs. Moreover, the inhibitory potency was reduced by at least 20-300 fold with varying compounds when rapid C-type inactivation was removed by a mutation located between the transmembrane domains 5 and 6 (S631A).
CONCLUSION: The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.
Предметные рубрики MeSH
AnimalsAnti-Allergic AgentsAnti-Arrhythmia AgentsDose-Response Relationship, DrugERG1 Potassium ChannelEther-A-Go-Go Potassium ChannelsFemaleGanglionic StimulantsIon Channel GatingMutationNicotineOocytesPatch-Clamp TechniquesPhenethylaminesPotassium Channel BlockersPotassium ChannelsPotassium Channels, Voltage-GatedQuinidineSulfonamidesTerfenadineXenopus laevis