The Link between Inactivation and High-Affinity Block of hERG1 Channels

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Ion Channel Physiology

Background:

• Blockade of human ether-à-go-go-related gene 1 (hERG1) K(+) channels by drugs can lead to cardiac arrhythmias.
• It has been widely assumed that drugs preferentially block hERG1 channels in their inactivated state.

Purpose of the Study:

• To investigate the relationship between inactivation gating and the potency of hERG1 channel block by drugs.
• To determine if mutations disrupting inactivation directly impact drug binding affinity.

Main Methods:

• Utilized concatenated hERG1 tetramers with varying numbers of inactivation-disrupting point mutations (S620T or S631A).
• Assessed the effect of these mutations on channel inactivation gating and drug sensitivity using specific drug compounds (cisapride, dofetilide, MK-499).
• Introduced a secondary mutation (Y652W) to investigate rescue effects on drug sensitivity.

Main Results:

• A single S620T mutation abolished inactivation, while S631A showed a graded effect on inactivation.
• Drug potency for S620T mutants correlated with the number of mutant subunits but was independent of inactivation disruption.
• Drug potency for S631A mutants showed varied relationships with inactivation, with cisapride unaffected and dofetilide showing a graded response.
• A Y652W mutation partially restored drug sensitivity in S620T mutants.

Conclusions:

• The findings suggest that mutations S620T and S631A can allosterically disrupt drug binding to hERG1 channels.
• This disruption occurs independently of the mutations' effects on channel inactivation gating.
• The study challenges the assumption of preferential block in the inactivated state and highlights an allosteric mechanism in drug-channel interactions.