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

Windley, MJ; Vetter, I; Lewis, RJ; Nicholson, GM

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

Windley, MJ Vetter, I Lewis, RJ Nicholson, GM

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Publication Type:: Journal Article
Citation:: Neuropharmacology, 2017, 127 pp. 224 - 242
Issue Date:: 2017-12-01

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Field	Value	Language
dc.contributor.author	Windley, MJ	en_US
dc.contributor.author	Vetter, I	en_US
dc.contributor.author	Lewis, RJ	en_US
dc.contributor.author	Nicholson, GM https://orcid.org/0000-0002-4277-4296	en_US
dc.date.available	2020-05-25T19:03:28Z
dc.date.issued	2017-12-01	en_US
dc.identifier.citation	Neuropharmacology, 2017, 127 pp. 224 - 242	en_US
dc.identifier.issn	0028-3908	en_US
dc.identifier.uri	http://hdl.handle.net/10453/91702
dc.description.abstract	© 2017 Elsevier Ltd 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. This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’	en_US
dc.relation.ispartof	Neuropharmacology	en_US
dc.relation.isbasedon	10.1016/j.neuropharm.2017.04.008	en_US
dc.subject.classification	Neurology & Neurosurgery	en_US
dc.subject.mesh	Neurons	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Gryllidae	en_US
dc.subject.mesh	Neuroblastoma	en_US
dc.subject.mesh	Indoles	en_US
dc.subject.mesh	Receptors, Nicotinic	en_US
dc.subject.mesh	Potassium Channel Blockers	en_US
dc.subject.mesh	Spider Venoms	en_US
dc.subject.mesh	Neurotoxins	en_US
dc.subject.mesh	Patch-Clamp Techniques	en_US
dc.subject.mesh	Analysis of Variance	en_US
dc.subject.mesh	Electric Stimulation	en_US
dc.subject.mesh	Allosteric Regulation	en_US
dc.subject.mesh	Allosteric Site	en_US
dc.subject.mesh	Membrane Potentials	en_US
dc.subject.mesh	Dose-Response Relationship, Drug	en_US
dc.subject.mesh	Voltage-Dependent Anion Channels	en_US
dc.title	Lethal effects of an insecticidal spider venom peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors	en_US
dc.type	Journal Article
utslib.citation.volume	127	en_US
utslib.for	1109 Neurosciences	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	en_US
utslib.for	1701 Psychology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access
pubs.publication-status	Published	en_US
pubs.volume	127	en_US

Abstract:

© 2017 Elsevier Ltd 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. This article is part of the Special Issue entitled ‘Venom-derived Peptides as Pharmacological Tools.’

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http://hdl.handle.net/10453/91702