Structural determinants for high-affinity block of hERG potassium channels

¹Department of Cell Physiology and Pharmacology, University of Leicester, University Road, Leicester LE1 9HN, UK.

Novartis Foundation Symposium

|July 30, 2005

Summary

Drug-induced long QT syndrome, a cause of sudden death, is often linked to hERG channel block. Drugs trap within the hERG channel

Area of Science:

Background:

Drug-induced long QT syndrome (diLQTS) is a serious adverse effect of certain medications, leading to cardiac arrhythmias and sudden death.
This condition is primarily associated with the blockade of the human Ether-à-go-go-Related Gene (hERG) potassium channels, crucial for cardiac repolarization.
While hERG channel block is the main culprit, inhibition of other repolarizing K+ currents could theoretically cause diLQTS.

Purpose of the Study:

To elucidate the molecular mechanisms underlying the preferential blockade of hERG channels by structurally diverse compounds.
To investigate the role of the hERG channel's inner cavity and specific residues in drug binding and trapping.
To understand why hERG channels are uniquely susceptible to blockade compared to other voltage-gated K+ channels.

Main Methods:

Analysis of state-dependent inhibition and slow recovery kinetics of hERG channel currents.
Drug trapping studies to assess drug interactions within the channel.
Scanning alanine mutagenesis of key residues (Tyr652, Phe656, Ser624, Thr623) in the hERG channel's S6 and pore helix domains.
Investigating the binding affinity of various drug compounds (cisapride, terfenadine, propafenone, methanesulfonanilides).

Main Results:

Many drug compounds bind within the hERG channel's inner cavity and become trapped upon channel closure.
The inner cavity of hERG channels appears larger than that of other voltage-gated K+ channels, facilitating drug trapping.
Mutagenesis studies identified Tyr652 and Phe656 as critical aromatic residues for the interaction of most blockers.
Ser624 and Thr623 residues are important for high-affinity binding of certain compounds but not others.

Conclusions:

The unique structure of the hERG channel, particularly its larger inner cavity and specific residues like Tyr652 and Phe656, explains its susceptibility to blockade by diverse drugs.
Drug trapping within the hERG channel, facilitated by channel gating, is a key mechanism for drug-induced long QT syndrome.
Understanding these interactions is crucial for predicting and preventing drug-induced cardiac side effects.

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