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S641 contributes HERG K+ channel inactivation.

Jin-Song Bian¹, Jie Cui, Yonathan Melman

¹Departments of Medicine and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.

Cell Biochemistry and Biophysics

|September 17, 2004

Summary

The HERG channel

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Area of Science:

Molecular biology
Biophysics
Cardiology

Background:

The rapidly activating delayed rectifier potassium current (IKr) exhibits unique voltage-dependent inactivation kinetics.
The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr, sharing homology with non-inactivating ether-a-gogo (EAG) channels.
HERG channels possess serine residues within pore-associated segments, distinct from EAG channels, implicated in inactivation.

Purpose of the Study:

To investigate the role of serine residue S641 in the voltage-dependent inactivation of HERG channels.
To determine the impact of S641 substitutions on HERG channel inactivation, ion selectivity, and drug block.
To elucidate the contribution of a network of serine residues to HERG channel function.

Main Methods:

Site-directed mutagenesis of the HERG channel at serine residue S641.
Electrophysiological recordings to assess channel inactivation kinetics.
Analysis of ion selectivity and sensitivity to E4031 block.

Main Results:

Substitution of S641 with charged or polar residues disrupted C-type inactivation.
Smaller, conservative substitutions at S641 (S641A, S641C) facilitated C-type inactivation.
Mutations at S620, S631, and S641 exhibited dominant effects on inactivation, permeation, and rectification.

Conclusions:

Serine 641 is critical for normal rapid inactivation of HERG channels, similar to S620 and S631.
A network of hydroxyl side chains involving S620, S631, and S641 is essential for HERG channel inactivation, permeation, and rectification.
These findings highlight the structural basis for the unique functional properties of HERG channels.

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