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

Voltage-gated sodium channels are crucial to action potential propagation in excitable tissues. Voltage-clamp measurements of sodium current are very challenging and are usually performed at room temperature due to the high amplitude and fast activation of the current. In this study, we measured sodium currents voltage dependence in stem-cell-derived cardiomyocytes at physiological temperature. Although apparent activation and inactivation curves measured as the sodium current amplitude dependence on voltage step is within the range reported in previous studies, we demonstrate a systematic error in our measurements that is due to deviation of membrane potential from the command potential of the amplifier. We show how this artifact can be accounted for by the computer simulation of the patch-clamp experiment. This patch-clamp model optimization technique yields a surprising result: -11.5 mV half-activation and -87 mV half-inactivation of the sodium current. Although the half-activation is strikingly different from what was previously believed to be typical for the cardiac sodium current, we show that this estimate explains conduction velocity dependence on extracellular potassium in hyperkalemic conditions. Key pointsO_LIVoltage gated sodium currents play a crucial role in excitable tissues including neurons, cardiac and skeletal muscles. C_LIO_LIMeasurement of sodium current is challenging because of its high amplitude and rapid kinetics, especially at physiological temperature. C_LIO_LIWe have used the patch-clamp technique to measure human sodium current voltage-dependence in human induced pluripotent stem cell-derived cardiomyocytes. C_LIO_LIThe patch-clamp data was processed by optimization of the model accounting for voltage-clamp experiment artifacts, revealing a large difference between apparent parameters of sodium current and the results of the optimization. C_LIO_LIWe conclude that actual sodium current activation is extremely depolarized in comparison to previous studies. C_LIO_LIThe new sodium current model provides a better understanding of action potential propagation, we demonstrate that it explains propagation in hyperkalemic conditions. C_LI