Optimal experimental designs for characterising ion channel gating by filling the phase-voltage space of model dynamics

Abstract

AbstractVoltage-clamp waveforms are imposed in the patch-clamp electrophysiology technique to provoke ion currents, the particular waveform that is used is known as the ‘voltage-clamp protocol’. Designing protocols to probe and quantify how gating for a particular ion channel occurs has typically been done manually and results in a suite of long protocols. It is desirable to gain the same, or even more, information in a shorter time, and also to automate the process of designing these protocols. In this paper we introduce a new optimal experimental design objective for ion channel characterisation, which involves considering a 3-dimensional phase space for the channel states combined with the voltage, using room-temperature hERG/Kv11.1 currents as an example. A range of designs are proposed, the best of which visits 82% of the discretised phase-voltage space in a 9 second protocol. This new protocol design strategy results in a simulated current visiting a wide range of channel gating states, at a wide variety of voltages, and we therefore expect these designs to be very useful in characterising ion currents, parameterising models, as well as being a challenging test of assumptions made about ion channel gating.