Proton and zinc effects on HERG currents

Area of Science:

• Ion channel physiology
• Cardiovascular pharmacology
• Molecular biophysics

Background:

• The human ether-a-go-go related gene (HERG) channel is crucial for cardiac repolarization.
• Alterations in HERG channel function are linked to cardiac arrhythmias.
• The influence of protons (pH) and divalent cations like Zn2+ on HERG channel gating is not fully understood.

Purpose of the Study:

• To investigate the effects of extracellular protons and Zn2+ on HERG channel function.
• To determine how these ions modulate HERG channel activation, deactivation, and inactivation.
• To elucidate the specific mechanisms by which protons and Zn2+ interact with HERG channels.

Main Methods:

• HERG channel function was studied in Xenopus oocytes and mammalian L929 cells.
• Electrophysiological techniques, including two-electrode voltage clamp and whole-cell patch clamp, were employed.
• Experiments involved varying extracellular pH and applying Zn2+ to assess effects on channel kinetics and gating.

Main Results:

• Extracellular acidification and Zn2+ significantly accelerated HERG channel tail current deactivation in both oocytes and L929 cells.
• Protons and Zn2+ exhibited distinct binding affinities (Kd) for effects on deactivation kinetics versus current amplitude.
• While moderate acidification did not alter activation gating in oocytes, severe acidification shifted activation voltage dependence.
• In L929 cells, acidification primarily affected deactivation, with no significant impact on activation or inactivation.

Conclusions:

• Protons and Zn2+ directly interact with HERG channels.
• These interactions preferentially regulate the deactivation gating mechanism of HERG channels.
• Understanding these modulatory effects is vital for predicting drug interactions and ion channel behavior in physiological conditions.