Resolving Artifacts in Voltage-Clamp Experiments with Computational Modeling: An Application to Fast Sodium Current Recordings.

TitleResolving Artifacts in Voltage-Clamp Experiments with Computational Modeling: An Application to Fast Sodium Current Recordings.
Publication TypeJournal Article
Year of Publication2025
AuthorsLei, CLok, Clark, AP, Clerx, M, Wei, S, Bloothooft, M, de Boer, TP, Christini, DJ, Krogh-Madsen, T, Mirams, GR
JournalAdv Sci (Weinh)
Volume12
Issue30
Paginatione00691
Date Published2025 Aug
ISSN2198-3844
KeywordsAction Potentials, Electrophysiological Phenomena, HEK293 Cells, Humans, Ion Channels, Models, Biological, Patch-Clamp Techniques, Sodium
Abstract

Cellular electrophysiology underpins fields from basic science in neurology, cardiology, and oncology to safety critical applications for drug safety testing, risk assessment of rare mutations, and models based on cellular electrophysiology data even guide clinical interventions. Patch-clamp voltage clamp is the gold standard for measuring ionic current dynamics that explain cellular electrophysiology, but recordings can be influenced by artifacts introduced by the measurement process. A computational approach is developed, validated through electrical model cell experiments, to explain and predict intricate artifacts in voltage-clamp experiments. Applied to various cardiac fast sodium current measurements, the model resolved artifacts in the experiments by coupling observed current with simulated membrane voltage, explaining some typically observed shifts and delays in recorded currents. It is shown that averaging data for current-voltage relationships can introduce biases comparable to effect sizes reported for disease-causing mutations. The computational pipeline provides improved assessment and interpretation of voltage-clamp experiments, correcting, and enhancing understanding of ion channel behavior.

DOI10.1002/advs.202500691
Alternate JournalAdv Sci (Weinh)
PubMed ID40476539
PubMed Central IDPMC12376535
Grant ListSRG2024-00014-FHS / / University of Macau /
0155/2023/RIA3 / / Science and Technology Development Fund of Macau SAR /
0048/2022/A / / Science and Technology Development Fund of Macau SAR /
U01HL136297 / HL / NHLBI NIH HHS / United States
F31HL154655 / HL / NHLBI NIH HHS / United States
212203/Z/18/Z / WT_ / Wellcome Trust / United Kingdom
U01HL136297 / HL / NHLBI NIH HHS / United States
F31HL154655 / HL / NHLBI NIH HHS / United States
114022502 / ZONMW_ / ZonMw / Netherlands