Selective activation of tetrodotoxin-sensitive sodium channels by AaH-II drives arrhythmogenic late Na+ current in the heart
Abstract
Increased late sodium current (INaL) is a central mechanism underlying both inherited and acquired cardiac arrhythmias. Although Nav1.5 is the dominant cardiac sodium channel, multiple tetrodotoxin-sensitive (TTX-S) Nav isoforms are also expressed in cardiomyocytes, particularly within transverse tubules, where they influence excitation-contraction coupling. Whether these channels contribute directly to pathological INaL and arrhythmogenesis remains unresolved, in part because available pharmacological tools lack isoform selectivity. Herein, our objective was to determine the contribution of TTX-S Nav channels to pathological cardiac INaL and arrhythmia and to establish selective pharmacological tools to dissect their role. Using automated patch-clamp and human Nav isoform profiling, we show that the reference INaL inducer ATX-II predominantly activates TTX-resistant Nav1.5 Nav channels. However, ATX-II lacks Nav isoform selectivity when inappropriately used, questioning the conclusions reached by numerous cardiac INaL studies. In contrast, AaH-II, a peptide from Androctonus australis hector scorpion venom, more selectively and potently enhances INaL through TTX-S Nav isoforms. In human iPS-derived cardiomyocytes, TTX-S INaL leads to action potential prolongation. In adult ventricular cardiomyocytes, AaH-II induces abnormal Ca2+ handling and spontaneous Ca2+ release events. In isolated hearts and in vivo, selective TTX-S INaL activation produces conduction abnormalities, QT prolongation, and ventricular proarrhythmic events, which are prevented by nanomolar tetrodotoxin concentrations that spare Nav1.5. These findings demonstrate that TTX-S sodium channels are sufficient to generate arrhythmogenic late Na+ current in the heart, independently of Nav1.5. AaH-II provides a powerful new tool to selectively probe TTX-S INaL and reveals these channels as previously underappreciated contributors to cardiac electrical instability. Targeting TTX-S Nav channels may therefore represent a novel and potentially safer strategy for antiarrhythmic therapy.
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BibTeX
@article{millet2026selective,
title = {{Selective activation of tetrodotoxin-sensitive sodium channels by AaH-II drives arrhythmogenic late Na+ current in the heart}},
author = {Hugo Millet and Maureen Choteau-Bodor and Thomas Stervinou and Floriane Bibault and Sarah Godin and Pauline Belhumeur and Matthias Dereli and Agnès Hivonnait and Morteza Erfanian and Agnès Tessier and Aurore Girardeau and Guillaume Lamirault and Flavien Charpentier and Mikael Croyal and Nathalie Gaborit and Jérôme Montnach and Michel de Waard},
journal = {EP-Europace},
year = {2026},
month = sep,
doi = {10.1093/europace/euag249},
url = {https://hal.science/hal-05761085v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective activation of tetrodotoxin-sensitive sodium channels by AaH-II drives arrhythmogenic late Na+ current in the heart
AU - Hugo Millet
AU - Maureen Choteau-Bodor
AU - Thomas Stervinou
AU - Floriane Bibault
AU - Sarah Godin
AU - Pauline Belhumeur
AU - Matthias Dereli
AU - Agnès Hivonnait
AU - Morteza Erfanian
AU - Agnès Tessier
AU - Aurore Girardeau
AU - Guillaume Lamirault
AU - Flavien Charpentier
AU - Mikael Croyal
AU - Nathalie Gaborit
AU - Jérôme Montnach
AU - Michel de Waard
PY - 2026
DA - 2026/09/23
JO - EP-Europace
DO - 10.1093/europace/euag249
UR - https://hal.science/hal-05761085v1
AB - Increased late sodium current (INaL) is a central mechanism underlying both inherited and acquired cardiac arrhythmias. Although Nav1.5 is the dominant cardiac sodium channel, multiple tetrodotoxin-sensitive (TTX-S) Nav isoforms are also expressed in cardiomyocytes, particularly within transverse tubules, where they influence excitation-contraction coupling. Whether these channels contribute directly to pathological INaL and arrhythmogenesis remains unresolved, in part because available pharmacological tools lack isoform selectivity. Herein, our objective was to determine the contribution of TTX-S Nav channels to pathological cardiac INaL and arrhythmia and to establish selective pharmacological tools to dissect their role. Using automated patch-clamp and human Nav isoform profiling, we show that the reference INaL inducer ATX-II predominantly activates TTX-resistant Nav1.5 Nav channels. However, ATX-II lacks Nav isoform selectivity when inappropriately used, questioning the conclusions reached by numerous cardiac INaL studies. In contrast, AaH-II, a peptide from Androctonus australis hector scorpion venom, more selectively and potently enhances INaL through TTX-S Nav isoforms. In human iPS-derived cardiomyocytes, TTX-S INaL leads to action potential prolongation. In adult ventricular cardiomyocytes, AaH-II induces abnormal Ca2+ handling and spontaneous Ca2+ release events. In isolated hearts and in vivo, selective TTX-S INaL activation produces conduction abnormalities, QT prolongation, and ventricular proarrhythmic events, which are prevented by nanomolar tetrodotoxin concentrations that spare Nav1.5. These findings demonstrate that TTX-S sodium channels are sufficient to generate arrhythmogenic late Na+ current in the heart, independently of Nav1.5. AaH-II provides a powerful new tool to selectively probe TTX-S INaL and reveals these channels as previously underappreciated contributors to cardiac electrical instability. Targeting TTX-S Nav channels may therefore represent a novel and potentially safer strategy for antiarrhythmic therapy.
SN - 1099-5129
SN - 1532-2092
ER -