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

Abstract

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 current's 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.