Biology subjects

Millet, H.

Publications and source records attributed to Millet, H..

4 recordsLinked to original sources

bioRxiv2026

In vivo optical induction of INaL by photoactivation of AaH-II peptide in beating heart using wireless implantable device

Precise spatiotemporal control of pharmacological compounds in cardiac tissue remains an unmet challenge. Systemic drug administration poorly reproduces the localized and transient nature of cardiac events. Photopharmacology, in which light controls drug activity, offers a compelling solution, but its translation to the beating heart requires wireless light delivery to a moving, soft, and electrically active organ. Here, we demonstrate the first in vivo use of a wireless device to photoactivate a peptide that modulates cardiac excitability. Using a flexible, battery-free implantable optoelectronic device, we achieved light-triggered uncaging of AaH-II*, a natural peptide that enhances the late sodium current. We first validated the caged peptide in vitro and ex vivo, showing that caging suppresses its activity and that UV illumination rapidly restores it. In vivo, wireless photoactivation produced a clear modulation of cardiac electrical activity, as monitored by electrocardiography. This work establishes device-based peptide photomodulation as a strategy for remote, temporally controlled pharmacological intervention in the heart. More broadly, it provides a new platform for probing cardiac excitability and developing region-targeted therapies.

pharmacology and toxicology↗

bioRxiv2025

Late INa activation of cardiac TTX-sensitive sodium channels by AaH-II induces an arrhythmogenic phenotype

AimsLate sodium current (INaL) is a key contributor to cardiac arrhythmias, but its precise origin and arrhythmogenic potential from tetrodotoxin-sensitive (TTX-S) sodium (Nav) channels remain unclear. While the FDA-endorsed toxin ATX-II has been widely used to model INaL-associated arrhythmogenesis, it lacks selectivity, limiting its utility in dissecting the roles of individual Nav channel subtypes. This study investigates the proarrhythmic impact of TTX-S Nav channel activation using AaH-II*, a scorpion venom-derived peptide with selective efficacy for TTX-S channels. Methods and ResultsUsing automated patch-clamp recordings, we characterized AaH-II* selectivity across human Nav isoforms and demonstrated potent, preferential activation of INaL in hNav1.1, 1.2, 1.3, and 1.6 over the TTX-resistant cardiac isoform hNav1.5. Calcium imaging in isolated adult rat cardiomyocytes showed that low nanomolar concentrations of AaH-II* induced spontaneous calcium release events and arrhythmogenic calcium transients, even in the absence of Nav1.5 activation. Ex vivo multielectrode array recordings in Langendorff-perfused rat hearts confirmed dose-dependent ventricular conduction slowing, prolonged repolarization, and increased arrhythmia burden, all mitigated by TTX. In vivo, intravenous AaH-II* administration in rats elicited QTc prolongation, atrioventricular block, and ventricular tachyarrhythmias, which were significantly suppressed by TTX pretreatment. ConclusionWe identify AaH-II* as a powerful and selective tool to study INaL from TTX-S Nav channels in cardiac tissue. Our findings reveal that TTX-S channel-mediated INaL alone is sufficient to induce arrhythmias and that pharmacological inhibition of these channels offers a promising antiarrhythmic strategy. These results advocate for broader consideration of TTX-S Nav channels as targets in arrhythmia research and drug safety screening.

physiology↗

bioRxiv2023

Analysis of the effect of the scorpion toxin AaH-II on action potential generation in the axon initial segment

The toxin AaH-II, from the scorpion Androctonus australis Hector venom, is a 64 amino acid peptide that targets voltage-gated Na+ channels (VGNCs) and slows their inactivation. While at macroscopic cellular level AaH-II prolongs the action potential (AP), a functional analysis of the effect of the toxin in the axon initial segment (AIS), where VGNCs are highly expressed, was never performed so far. Here, we report an original analysis of the effect of AaH-II on the AP generation in the AIS of neocortical layer-5 pyramidal neurons from mouse brain slices. After determining that AaH-II does not discriminate between Nav1.2 and Nav1.6, i.e. between the two VGNC isoforms expressed in this neuron, we established that 7 nM was the smallest toxin concentration producing a minimal detectable deformation of the somatic AP after local delivery of the toxin. Using membrane potential imaging, we found that, at this minimal concentration, AaH-II substantially widened the AP in the AIS. Using ultrafast Na+ imaging, we found that local application of 7 nM AaH-II caused a large increase in the slower component of the Na+ influx in the AIS. Finally, using ultrafast Ca2+ imaging, we observed that 7 nM AaH-II produces a spurious slow Ca2+ influx via Ca2+-permeable VGNCs. Molecules targeting VGNCs, including peptides, are proposed as potential therapeutic tools. Thus, the present analysis in the AIS can be considered a general proof-of-principle on how high-resolution imaging techniques can disclose drug effects that cannot be observed when tested at the macroscopic level.

neuroscience↗

bioRxiv2023

Optical control of cardiac rhythm by in vivo photoactivation of an ERG channel peptide inhibitor

RATIONALECardiac rhythm, conduction and synchronization of electrical activity require the coordinated action of different types of ion channels that differ according to transmural and regional specificities. Classical pharmacology affects these ion channels in a non-regionalized way which explains why treating arrhythmias, that often occur in specific foci, has often limited efficacy in addition to negative side-effects on non-targeted organs. Photopharmacology is an emergent technology that has the potential to counteract all the negative aspects of classical pharmacology by restricting drug activity in a spatio-temporal manner. OBJECTIVEWe tested the potential of photopharmacology in specifically regulating heart activity by using a caged derivative of a natural peptide inhibitor of the ERG channel, BeKm1. The peptide was uncaged and activity monitored in vitro on a cell line expressing the hERG channel, on human cardiomyocytes derived from iPS cells, and ex vivo and in vivo on zebrafish larvae and rat hearts. METHODS AND RESULTSCaged BeKm-1 is inactive and fully active upon uncaging. Uncaging of the peptide on human iPS-derived cardiomyocytes enlarges the action potential duration and triggers arrhythmias. Uncaging also triggers bradycardia and disturbs cardiac conduction within the atria in perfused rat hearts upon illumination. The potency of photopharmacology for cardiac electrical modulation was further validated in zebrafish larvae where illumination of the caged compound induces bradycardia and atrio-ventricular desynchrony. Finally, in anesthetized rats, illumination of the caged peptide in the right atria, containing the sino-atrial node, leads to bradycardia without arrhythmia. CONCLUSIONSThis report demonstrates that photopharmacology, using the caged peptide strategy, can be used for dynamically regulating cardiac electrical activity in vivo and that spatial illumination restriction can dissociate the bradycardic effect from the arrhythmic one. The technology is applicable to all kinds of cardiac ion channels and regions of interest to create arrhythmogenic models or investigate new clinical applications.

pharmacology and toxicology↗