Voltage sensor movement in the hERG K+ channel

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Ion Channel Biophysics

Background:

• The human Ether-à-go-go-Related Gene (hERG) channel is crucial for cardiac electrical activity.
• Its unique gating kinetics, characterized by slow activation and fast inactivation, are vital for normal heart function.

Purpose of the Study:

• To investigate the voltage sensor movement underlying the slow activation and fast inactivation of hERG channels.
• To elucidate the roles of specific residues and domains in hERG channel gating.

Main Methods:

• Measurement of gating currents from wild-type and mutant hERG channels.
• Utilized Ala-scanning mutagenesis in the S4 segment and S4-S5 linker.
• Analysis of charge movement and voltage dependence of channel gating.

Main Results:

• Identified distinct fast and slow gating current components with a 100-fold kinetic difference.
• The slow component dominates charge movement during channel opening, explaining slow hERG activation.
• Inactivation-deficient mutants showed minimal impact on overall gating charge, indicating a limited role in inactivation transitions.
• S4-S5 linker mutations affected channel opening but not charge displacement, suggesting a role in coupling S4 movement to the gate.
• Inactivation-sensitive residues were located on a helical face of S4 adjacent to activation-sensitive residues.

Conclusions:

• The S4 segment functions as the voltage sensor for both hERG activation and inactivation.
• S4 voltage sensor movement is transmitted to the activation gate through the S4-S5 linker.
• Distinct mechanisms govern hERG activation and inactivation, involving specific residue interactions within the S4 segment.