Inactivation gating determines drug potency: a common mechanism for drug blockade of HERG channels.
OBJECTIVE
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).


CONCLUSIONS
The inactivation gating of HERG channels determines the blocking potency of drugs. This mechanism might be common to drugs of various classes.
Yang
Bao-feng
BF
Department of Pharmacology, Harbin Medical University, Harbin 150086, China. xuchaoqian@0451.com
Xu
Dong-hui
DH
Xu
Chao-qian
CQ
Li
Zhe
Z
Du
Zhi-min
ZM
Wang
Hui-zhen
HZ
Dong
De-li
DL
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D005731:Ganglionic Stimulants / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D009154:Mutation; D009538:Nicotine / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated; D011802:Quinidine / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D016593:Terfenadine / Q000494:pharmacology; D014982:Xenopus laevis
D018926:Anti-Allergic Agents; D000889:Anti-Arrhythmia Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005731:Ganglionic Stimulants; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D009538:Nicotine; D016593:Terfenadine; D011802:Quinidine; C063533:dofetilide