Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics

Beattie, Kylie and Hill, Adam P. and Bardenet, Rémi and Cui, Yi and Vandenberg, Jamie I. and Gavaghan, David J. and de Boer, Teun P. and Mirams, Gary R. (2018) Sinusoidal voltage protocols for rapid characterisation of ion channel kinetics. Journal of Physiology, 596 (10). pp. 1813-1828. ISSN 1469-7793

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Abstract

Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterisation of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. We present a new method for rapidly exploring and characterising ion channel kinetics, applying it to the hERG potassium channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. We fit a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells over-expressing hERG1a. The model is then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprised of a collection of physiologically-relevant action potentials. We demonstrate that we can make predictive cell-specific models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell-cell variability in current kinetics. Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches.

Item Type: Article
Keywords: hERG, IKr, mathematical model, electrophysiology, patch clamp, voltage protocol
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Mathematical Sciences
Identification Number: https://doi.org/10.1113/JP275733
Depositing User: Mirams, Gary
Date Deposited: 20 Feb 2018 10:02
Last Modified: 14 Jun 2018 16:23
URI: http://eprints.nottingham.ac.uk/id/eprint/49871

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