Lethal effects of an insecticidal spider venom peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors

Windley, Monique J., Vetter, Irina, Lewis, Richard J. and Nicholson, Graham M. (2017) Lethal effects of an insecticidal spider venom peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors. Neuropharmacology, . doi:10.1016/j.neuropharm.2017.04.008


Author Windley, Monique J.
Vetter, Irina
Lewis, Richard J.
Nicholson, Graham M.
Title Lethal effects of an insecticidal spider venom peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 1873-7064
0028-3908
Publication date 2017-04-08
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2017.04.008
Open Access Status Not yet assessed
Total pages 19
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon Press
Language eng
Formatted abstract
κ-Hexatoxins (κ-HXTXs) are a family of excitotoxic insect-selective neurotoxins from Australian funnel-web spiders that are lethal to a wide range of insects, but display no toxicity towards vertebrates. The prototypic κ-HXTX-Hv1c selectively blocks native and expressed cockroach large-conductance calcium-activated potassium (BKCa or KCa1.1) channels, but not their mammalian orthologs. Despite this potent and selective action on insect KCa1.1 channels, we found that the classical KCa1.1 blockers paxilline, charybdotoxin and iberiotoxin, which all block insect KCa1.1 channels, are not lethal in crickets. We therefore used whole-cell patch-clamp analysis of cockroach dorsal unpaired median (DUM) neurons to study the effects of κ-HXTX-Hv1c on sodium-activated (KNa), delayed-rectifier (KDR) and 'A-type' transient (KA) K+ channels. 1 μM κ-HXTX-Hv1c failed to significantly inhibit cockroach KNa and KDR channels, but did cause a 30 ± 7% saturating inhibition of KA channel currents, possibly via a Kv4 (Shal-like) action. However, this modest action at such a high concentration of κ-HXTX-Hv1c would indicate a different lethal target. Accordingly, we assessed the actions of κ-HXTX-Hv1c on neurotransmitter-gated ion channels in cockroach DUM neurons. We found that κ-HXTX-Hv1c failed to produce any major effects on GABAA or glutamate-Cl receptors but dramatically slowed nicotine-evoked ACh receptor (nAChR) current decay and reversed nAChR desensitization. These actions occurred without any alterations to nAChR current amplitude or the nicotine concentration-response curve, and are consistent with a positive allosteric modulation of nAChRs. κ-HXTX-Hv1c therefore represents the first venom peptide that selectively modulates insect nAChRs with a mode of action similar to the excitotoxic insecticide spinosyn A.
Keyword Bioinsecticide
Insect-selective
NAChR PAM
Peptide toxins
Spider toxins
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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