Hysteretic hERG channel gating current recorded at physiological temperature

Area of Science:

• Cardiovascular Physiology
• Ion Channel Biophysics
• Molecular Cardiology

Background:

• Cardiac hERG channels (hERG 1a and hERG 1b) are crucial for cardiac action potential repolarization.
• The hERG 1a subunit possesses a cytoplasmic PAS domain absent in hERG 1b, which is known to regulate voltage sensor domain (VSD) movement.

Purpose of the Study:

• To investigate hERG VSD behavior and its regulation by the hERG 1a PAS domain at near physiological temperatures.
• To characterize the impact of the PAS domain on hERG channel gating dynamics during simulated cardiac action potentials.

Main Methods:

• Electrophysiological recordings of gating charge from homomeric hERG 1a and heteromeric hERG 1a/1b channels.
• Experiments conducted at near physiological temperatures (36 ± 1°C) with pulse durations mimicking the human ventricular action potential.
• Utilized a PAS-targeting antibody to assess the role of the hERG 1a PAS domain in VSD deactivation.

Main Results:

• Observed voltage dependence of deactivation hyperpolarized relative to activation, indicating VSD relaxation (hysteresis) at positive potentials.
• hERG 1a VSD deactivation exhibited a double Boltzmann distribution, while hERG 1a/1b showed a single Boltzmann distribution.
• Disabling the hERG 1a PAS domain converted deactivation from a double to a single Boltzmann distribution, confirming its regulatory role.

Conclusions:

• VSD relaxation (hysteresis) is present in hERG channels at physiological temperatures, potentially delaying pore closure during repolarization.
• The hERG 1a PAS domain significantly contributes to the regulation of VSD movement and gating properties.
• These findings provide novel insights into hERG channel function at physiological temperatures, crucial for understanding cardiac electrophysiology.