Human sodium current voltage-dependence at physiological temperature measured by coupling a patch-clamp experiment to...

Area of Science:

• Electrophysiology
• Cardiology
• Ion Channel Physiology

Background:

• Voltage-gated sodium (Na+) channels are essential for action potential propagation in excitable tissues.
• Accurate measurement of Na+ current is difficult due to high amplitude and rapid kinetics, especially at physiological temperatures.
• Previous studies often perform these measurements at room temperature, potentially affecting results.

Purpose of the Study:

• To measure Na+ current voltage-dependence in stem cell-derived cardiomyocytes at physiological temperature.
• To identify and correct for systematic errors in voltage-clamp measurements.
• To develop an optimized Na+ current model that accurately reflects physiological conditions.

Main Methods:

• Utilized the patch-clamp technique to measure Na+ current in human induced pluripotent stem cell-derived cardiomyocytes.
• Performed measurements at physiological temperature.
• Employed computer simulations and model optimization to account for voltage-clamp artifacts and refine experimental data.

Main Results:

• Identified a systematic error in voltage-clamp measurements caused by membrane potential deviation.
• Optimized patch-clamp model yielded a half-activation of -11.5 mV and half-inactivation of -87 mV.
• The optimized model's Na+ current activation is significantly more depolarized than previously reported but accurately predicts conduction velocity changes with extracellular potassium.

Conclusions:

• Corrected voltage-clamp measurements reveal a substantially more depolarized Na+ current activation than previously estimated.
• The revised Na+ current model enhances understanding of action potential propagation.
• The new model successfully explains action potential propagation under hyperkalemic conditions.