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bioRxiv · 10.1101/2024.09.12.612741

Multiple mechanisms of action of an extremely painful venom

Borjon, L. J.·de Assis Ferreira, L. C.·Trinidad, J. C.·Sasic, S.·Hohmann, A. G.·Tracey, W. D.
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Abstract

Evolutionary arms races between predator and prey can lead to extremely specific and effective defense mechanisms. Such defenses include venoms that deter predators by targeting nociceptive (pain-sensing) pathways. Through co-evolution, venom toxins can become extremely efficient modulators of their molecular targets. The venom of velvet ants (Hymenoptera: Mutillidae) is notoriously painful. The intensity of a velvet ant sting has been described as "Explosive and long lasting, you sound insane as you scream. Hot oil from the deep fryer spilling over your entire hand." [1] The effectiveness of the velvet ant sting as a deterrent against potential predators has been shown across vertebrate orders, including mammals, amphibians, reptiles, and birds [2-4]. The venoms low toxicity suggests it has a targeted effect on nociceptive sensory mechanisms [5]. This leads to the hypothesis that velvet ant venom targets a conserved nociception mechanism, which we sought to uncover using Drosophila melanogaster as a model system. Drosophila larvae have peripheral sensory neurons that sense potentially damaging (noxious) stimuli such as high temperature, harsh mechanical touch, and noxious chemicals [6-9]. These polymodal nociceptors are called class IV multidendritic dendritic arborizing (cIV da) neurons, and they share many features with vertebrate nociceptors, including conserved sensory receptor channels [10,11]. We found that velvet ant venom strongly activated Drosophila nociceptors through heteromeric Pickpocket/Balboa (Ppk/Bba) ion channels. Furthermore, we found a single venom peptide (Do6a) that activated larval nociceptors at nanomolar concentrations through Ppk/Bba. Drosophila Ppk/Bba is homologous to mammalian Acid Sensing Ion Channels (ASICs) [12]. However, the Do6a peptide did not produce behavioral signs of nociception in mice, which was instead triggered by other non-specific, less potent, peptides within the venom. This suggests that Do6a is an insect-specific venom component that potently activates insect nociceptors. Consistent with this, we showed that the velvet ants defensive sting produced aversive behavior in a predatory praying mantis. Together, our results indicate that velvet ant venom evolved to target nociceptive systems of both vertebrates and invertebrates, but through different molecular mechanisms.

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Borjon, L. J., de Assis Ferreira, L. C., Trinidad, J. C., Sasic, S., Hohmann, A. G., Tracey, W. D.. 2024-09-12. Multiple mechanisms of action of an extremely painful venom. https://doi.org/10.1101/2024.09.12.612741

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