title: Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation.
abstract: The S631C mutation in human ether-à-go-go-related gene (HERG) channels has previously been reported to disrupt C-type inactivation and ion-selectivity when Cys-631 is in the oxidized state. In this study, we report the relation between pharmacology and C-type inactivation for HERGS631C channels. We demonstrate that HERGS631C in its reduced state is fully blocked by 1 microM astemizole, terfenadine and dofetilide, similar to wild-type HERG channels. In contrast, oxidized HERGS631C is insensitive for these blockers. Our results suggest that an interaction with HERG channels in the inactivated state might be a common mechanism to a variety of drugs known to block HERG channels with high affinity.
authors.affiliation: Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Van Evenstraat 4, 3000, Leuven, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Ulens
authors.forename: J
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000818:Animals; D016589:Astemizole / Q000494:pharmacology; D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D015870:Gene Expression; D006801:Humans; D008839:Microelectrodes; D009154:Mutation; D009865:Oocytes / Q000378:metabolism; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology; D016593:Terfenadine / Q000494:pharmacology; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014981:Xenopus
chemical_list: D027682:Cation Transport Proteins; D004268:DNA-Binding Proteins; C072312:ERG protein, human; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; C092509:KCNH6 protein, human; D010627:Phenethylamines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D016593:Terfenadine; D016589:Astemizole; C063533:dofetilide