Gating charge movement precedes ionic current activation in hERG channels

Area of Science:

• Biophysics
• Molecular Biology
• Cardiovascular Physiology

Background:

• hERG channels are crucial for cardiac repolarization.
• Previous studies identified distinct gating current components in hERG channels.
• Understanding hERG channel kinetics is vital for drug safety and arrhythmia research.

Purpose of the Study:

• To compare hERG channel gating charge kinetics in TSA cells and oocytes.
• To directly compare the activation of gating charge and ionic currents.
• To identify the rate-limiting step in hERG channel opening.

Main Methods:

• Electrophysiological recordings of gating currents from hERG channels expressed in mammalian TSA cells.
• Cut Open Vaseline Gap (COVG) clamp recordings from oocytes.
• Voltage-clamp analysis of charge movement and ionic currents at 0 and +60 mV.

Main Results:

• Two distinct components of charge movement were observed, with a slower component dominating.
• Gating charge movement saturated at positive potentials.
• Gating charge movement was significantly faster than ionic current activation.

Conclusions:

• The rate-limiting step for hERG channel opening occurs downstream from the movement of the bulk of the gating charge.
• This finding has implications for understanding the mechanisms of cardiac arrhythmias.
• Further research is needed to elucidate the molecular basis of this downstream transition.