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Modulation of HERG affinity for E-4031 by [K+]o and C-type inactivation
1Department of Medicine, Duke University Medical Center, Durham, NC 27708-0281, USA.
FEBS Letters
|December 12, 1997
Summary
HERG channel rectification involves C-type inactivation. Mutations removing this inactivation significantly reduced E-4031 drug binding, suggesting pore closure is key for drug affinity.
Area of Science:
- Molecular Biology
- Pharmacology
- Ion Channel Physiology
Background:
- HERG (Human Ether-à-go-go-Related Gene) channels are crucial for cardiac repolarization.
- C-type inactivation, a process involving the closure of the external pore mouth, regulates HERG channel function.
- Methanesulfonanilide drugs, like E-4031, interact with HERG channels and are affected by inactivation.
Purpose of the Study:
- To investigate the role of C-type inactivation in the binding of the drug E-4031 to HERG channels.
- To determine if extracellular potassium ([K+]o) affects E-4031 binding through C-type inactivation.
- To differentiate the effects of mutations that remove inactivation from the effects of [K+]o on drug affinity.
Main Methods:
- Utilized site-directed mutagenesis to eliminate C-type inactivation in HERG channels.
- Assessed the binding affinity of the drug E-4031 to both wild-type and mutant HERG channels.
- Examined the influence of varying extracellular potassium concentrations ([K+]o) on drug binding.
Main Results:
- Mutations abolishing C-type inactivation drastically reduced E-4031 binding affinity (over 10-fold).
- Elevated [K+]o decreased E-4031 affinity in wild-type channels, partly via interference with C-type inactivation.
- Elevated [K+]o reduced E-4031 affinity in both wild-type and inactivation-mutant channels by similar amounts.
Conclusions:
- C-type inactivation is essential for high-affinity binding of E-4031 to HERG channels.
- Elevated [K+]o alters E-4031 binding affinity independently of its direct effect on C-type inactivation.
- The mechanism by which [K+]o affects drug binding differs from that of mutations removing C-type inactivation.
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