Effects of open-channel blocking peptides in NaV1.5 ΔKPQ

Riedersberger M, Woltereck M, Wagner PJ, Focke K, Höller S, Lampert A, Alzheimer C, Düsterhöft S, Huth T (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Biophysical Journal Biophysical Society

DOI: 10.1016/j.bpj.2025.05.030

Abstract

Resurgent sodium currents (INaRs) result from an unorthodox gating behavior of voltage-activated sodium channels (NaV), allowing transient re-openings during repolarization from an apparently inactivated state. In both native cells not normally exhibiting INaR and in heterologous expression systems, intracellular delivery of small positively charged peptides through the recording pipette elicits robust INaRs, suggesting that INaRs arise from a peptide-mediated open-channel block that is relieved upon repolarization. Here we examined the hNaV1.5 ΔKPQ mutant, which causes a long QT syndrome in the heart, to probe the open-channel block hypothesis of INaR in a channel with altered inactivation properties due to the deletion near the canonical inactivation gate. We investigated INaRs with peptides derived from the hNaV β4 subunit, FGF13-1a and FGF14-1a, using the HEK293T expression system. Surprisingly, the peptides not only gave rise to pronounced INaRs with unusually fast kinetics but also altered the late sodium current of the channel mutant. To elucidate the molecular basis of these effects, we employed AlphaFold modeling of hNaV1.5, incorporating the ΔKPQ mutation and the β4 peptide. This model supports the open-channel block mechanism of INaR and its mutual exclusivity with fast inactivation. It also demonstrates a lack of interaction between the IFM linker and the C-terminal domain in hNaV1.5 ΔKPQ, offering a plausible explanation for why the peptides are capable of affecting both INaR and persistent currents (INaPs). Finally, the peptides generated a considerable increase in repolarization-associated Na+ currents with the ΔKPQ mutant, highlighting the presumed impact of pathologically enhanced INaR on cardiac electrophysiology.

Involved external institutions

Universitätsklinikum Aachen (UKA) DE Germany (DE)

How to cite

APA:

Riedersberger, M., Woltereck, M., Wagner, P.J., Focke, K., Höller, S., Lampert, A.,... Huth, T. (2025). Effects of open-channel blocking peptides in NaV1.5 ΔKPQ. Biophysical Journal. https://doi.org/10.1016/j.bpj.2025.05.030

MLA:

Riedersberger, Maria, et al. "Effects of open-channel blocking peptides in NaV1.5 ΔKPQ." Biophysical Journal (2025).

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