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Lethal effects of an insecticidal spider venom peptide involve positive allosteric modulation of insect nicotinic acetylcholine receptors
- Source :
- Neuropharmacology. 127
- Publication Year :
- 2017
-
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.’
- Subjects :
- 0301 basic medicine
Indoles
Patch-Clamp Techniques
Charybdotoxin
Neurotoxins
Spider Venoms
Pharmacology
Receptors, Nicotinic
Membrane Potentials
Gryllidae
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Neuroblastoma
Allosteric Regulation
biology.animal
Cell Line, Tumor
Potassium Channel Blockers
Animals
Humans
Voltage-Dependent Anion Channels
Ion channel
Acetylcholine receptor
Neurons
Cockroach
Analysis of Variance
Neurology & Neurosurgery
biology
Dose-Response Relationship, Drug
GABAA receptor
Anatomy
Iberiotoxin
Spider toxin
Electric Stimulation
030104 developmental biology
Nicotinic agonist
chemistry
Allosteric Site
Subjects
Details
- ISSN :
- 18737064
- Volume :
- 127
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....c9b1da6d6b7bd7158a4458395a2a380d