Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments

Clerx, Michael; Lei, Chon Lok; Whittaker, Dominic G.; Gavaghan, David J.; de Boer, Teun P.; Mirams, Gary R.

Abstract

Mathematical models of ion channels, which constitute indispensable components of action potential models, are commonly constructed by fitting to whole-cell patch-clamp data. In a previous study, we fitted cell-specific models to hERG1a (Kv11.1) recordings simultaneously measured using an automated high-throughput system, and studied cell-cell variability by inspecting the resulting model parameters. However, the origin of the observed variability was not identified. Here, we study the source of variability by constructing a model that describes not just ion current dynamics, but the entire voltage-clamp experiment. The experimental artefact components of the model include: series resistance, membrane and pipette capacitance, voltage offsets, imperfect compensations made by the amplifier for these phenomena, and leak current. In this model, variability in the observations can be explained by either cell properties, measurement artefacts, or both. Remarkably, by assuming that variability arises exclusively from measurement artefacts, it is possible to explain a larger amount of the observed variability than when assuming cell-specific ion current kinetics. This assumption also leads to a smaller number of model parameters. This result suggests that most of the observed variability in patch-clamp data measured under the same conditions is caused by experimental artefacts, and hence can be compensated for in post-processing by using our model for the patch-clamp experiment. This study has implications for the question of the extent to which cell-cell variability in ion channel kinetics exists, and opens up routes for better correction of artefacts in patch-clamp data. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Citation

Clerx, M., Lei, C. L., Whittaker, D. G., Gavaghan, D. J., de Boer, T. P., & Mirams, G. R. (2020). Accounting for variability in ion current recordings using a mathematical model of artefacts in voltage-clamp experiments. Philosophical Transactions A: Mathematical, Physical and Engineering Sciences, 378(2173), Article 20190348. https://doi.org/10.1098/rsta.2019.0348

• Journal Article Type: Article
• Acceptance Date: Apr 8, 2020
• Online Publication Date: May 25, 2020
• Publication Date: Jun 12, 2020
• Deposit Date: May 27, 2020
• Publicly Available Date: May 27, 2020
• Journal: Philosophical transactions. Series A, Mathematical, physical, and engineering sciences
• Print ISSN: 1364-503X
• Electronic ISSN: 1471-2962
• Publisher: The Royal Society
• Peer Reviewed: Peer Reviewed
• Volume: 378
• Issue: 2173
• Article Number: 20190348
• DOI: https://doi.org/10.1098/rsta.2019.0348
• Public URL: https://nottingham-repository.worktribe.com/output/4518841
• Publisher URL: https://royalsocietypublishing.org/doi/10.1098/rsta.2019.0348
• Additional Information: Accepted: 2020-04-08; Published: 2020-05-25