Established dogma concerning the action of insecticidal peptides (e.g., scorpion toxins), was that they acted on the peripheral nervous system and were excluded from the central nervous system (CNS) by barrier systems. Initial evidence for a toxin effect on the CNS following parenteral administration was for a novel peptide from the invasive Hobo spider, Tegeneria agrestis (https://doi.org/10.1002/(SICI)1520-6327(1998)38:1&lt;19::AID-ARCH3&gt;3.0.CO;2-Q) that was inactive on peripheral sensory and motor nerves of insects, but had a potent excitatory effect on the CNS. Subsequent experiments on omega-atracotoxin-HV1 from an Australian funnel web spider found that 1 hr after injection all locomotion ceased and there was high frequency twitching and extension of the legs, followed at later times by immobility and death (https://www.nature.com/articles/nsb0797-559.pdf). This study also reported that this toxin was a specific blocker of cockroach central calcium channel currents at 1 µM. Further studies of this toxin showed that it was inactive on peripheral nerve, had a potent neuroexcitatory effect followed by central depression that was difficult to reconcile with a blocking action on calcium channels, and also could move through the CNS barrier within a few minutes, in vitro. Recently, a commercialized formulation of GA-omega/kappa-Hxtx-Hv1a was introduced for use in agriculture by Vestaron Corp. (https://www.vestaron.com/spear-lep/) and its mode of action found to be central neuroexcitation via positive allosteric modulation of the nicotinic acetylcholine receptor (nAchR) (http://dx.doi.org/10.1016/j.neuropharm.2017.04.008). This peptide shows hyperexcitation followed by a decrease in firing of the D. melanogaster CNS that is prevented by co-exposure to alpha-bungarotoxin, a classical nAchR noncompetitive antagonist. This effect is mirrored in isobologram analysis showing an antagonism between the two toxins when injected into adult houseflies. Interestingly, U1-agatoxin-Ta1b-QA from Tegeneria agrestis (http://www.ir4project.org/wp-content/uploads/2021/07/Vestaron-DCPeck-IR-4-July-2021.pdf), thought to act at a distinct site, had a similar biphasic action but showed increased nerve discharge when co-exposed with alpha-bungarotoxin, and with roughly additive effects in isobologram studies. The implications of these results will be discussed.

Insectcidal centrally-acting spider toxin polypeptides

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ACS Fall 2022

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