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Redox state dependency of HERGS631C channel pharmacology: relation to C-type inactivation
1Laboratory of Toxicology, Faculty of Pharmaceutical Sciences, Van Evenstraat 4, 3000, Leuven, Belgium.
Insights
The S631C mutation in human ether-à-go-go-related gene (HERG) channels affects drug interactions. Oxidized HERGS631C channels are insensitive to common blockers, unlike their reduced state.
Area of Science:
- Pharmacology
- Molecular Biology
- Ion Channel Physiology
Background:
- The S631C mutation in human ether-à-go-go-related gene (HERG) channels impacts C-type inactivation and ion selectivity.
- The oxidized state of Cys-631 is implicated in these functional disruptions.
Purpose of the Study:
- To investigate the relationship between drug interactions and C-type inactivation in HERGS631C channels.
- To determine how the redox state of Cys-631 influences the channel's response to known HERG blockers.
Main Methods:
- Electrophysiological recordings of HERGS631C channels.
- Application of astemizole, terfenadine, and dofetilide to assess channel block.
- Comparison of channel behavior in reduced versus oxidized states.
Main Results:
- HERGS631C channels in the reduced state are fully blocked by 1 microM astemizole, terfenadine, and dofetilide, similar to wild-type HERG.
- Oxidized HERGS631C channels exhibit insensitivity to these same drug blockers.
- The redox state of Cys-631 significantly modulates drug sensitivity.
Conclusions:
- The inactivated state of HERG channels may be a common target for various high-affinity blocking drugs.
- The S631C mutation alters drug interaction profiles depending on the redox state of the channel.
- Understanding redox-dependent drug interactions is crucial for HERG channel pharmacology.
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.