The ω-atracotoxins: Selective blockers of insect M-LVA and HVA calcium channels

Chong, Y; Hayes, JL; Sollod, B; Wen, S; Wilson, DT; Hains, PG; Hodgson, WC; Broady, KW; King, GF; Nicholson, GM

The ω-atracotoxins: Selective blockers of insect M-LVA and HVA calcium channels

Chong, Y Hayes, JL Sollod, B Wen, S Wilson, DT Hains, PG Hodgson, WC Broady, KW King, GF Nicholson, GM

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Publication Type:: Journal Article
Citation:: Biochemical Pharmacology, 2007, 74 (4), pp. 623 - 638
Issue Date:: 2007-08-15

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Field	Value	Language
dc.contributor.author	Chong, Y	en_US
dc.contributor.author	Hayes, JL	en_US
dc.contributor.author	Sollod, B	en_US
dc.contributor.author	Wen, S	en_US
dc.contributor.author	Wilson, DT	en_US
dc.contributor.author	Hains, PG	en_US
dc.contributor.author	Hodgson, WC	en_US
dc.contributor.author	Broady, KW	en_US
dc.contributor.author	King, GF	en_US
dc.contributor.author	Nicholson, GM https://orcid.org/0000-0002-4277-4296	en_US
dc.date.available	2007-05-22	en_US
dc.date.issued	2007-08-15	en_US
dc.identifier.citation	Biochemical Pharmacology, 2007, 74 (4), pp. 623 - 638	en_US
dc.identifier.issn	0006-2952	en_US
dc.identifier.uri	http://hdl.handle.net/10453/4733
dc.description.abstract	The ω-atracotoxins (ω-ACTX) are a family of arthropod-selective peptide neurotoxins from Australian funnel-web spider venoms (Hexathelidae: Atracinae) that are candidates for development as biopesticides. We isolated a 37-residue insect-selective neurotoxin, ω-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the ω-ACTX-1 family. The peptide induced potent excitatory symptoms, followed by flaccid paralysis leading to death, in acute toxicity tests in house crickets. Using isolated smooth and skeletal nerve-muscle preparations, the toxin was shown to lack overt vertebrate toxicity at concentrations up to 1 μM. To further characterize the target of the ω-ACTXs, voltage-clamp analysis using the whole-cell patch-clamp technique was undertaken using cockroach dorsal unpaired median neurons. It is shown here for the first time that ω-ACTX-Ar1a, and its homolog ω-ACTX-Hv1a from Hadronyche versuta, reversibly block both mid-low- (M-LVA) and high-voltage-activated (HVA) insect calcium channel (Cav) currents. This block occurred in the absence of alterations in the voltage-dependence of Cav channel activation, and was voltage-independent, suggesting that ω-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 μM ω-ACTX-Ar1a failed to significantly affect global Kv channel currents. However, 1 μM ω-ACTX-Ar1a caused a modest 18% block of insect Nav channel currents, similar to the minor block of Nav channels reported for other insect Cav channel blockers such as ω-agatoxin IVA. These findings validate both M-LVA and HVA Cav channels as potential targets for insecticides. © 2007.	en_US
dc.relation.ispartof	Biochemical Pharmacology	en_US
dc.relation.isbasedon	10.1016/j.bcp.2007.05.017	en_US
dc.subject.classification	Pharmacology & Pharmacy	en_US
dc.subject.mesh	Muscle, Skeletal	en_US
dc.subject.mesh	Vas Deferens	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Chickens	en_US
dc.subject.mesh	Rats	en_US
dc.subject.mesh	Rats, Sprague-Dawley	en_US
dc.subject.mesh	Spiders	en_US
dc.subject.mesh	Periplaneta	en_US
dc.subject.mesh	Gryllidae	en_US
dc.subject.mesh	Calcium Channels	en_US
dc.subject.mesh	Calcium Channel Blockers	en_US
dc.subject.mesh	Spider Venoms	en_US
dc.subject.mesh	Neurotoxins	en_US
dc.subject.mesh	Sequence Analysis, DNA	en_US
dc.subject.mesh	Toxicity Tests	en_US
dc.subject.mesh	Lethal Dose 50	en_US
dc.subject.mesh	Electrophysiology	en_US
dc.subject.mesh	Species Specificity	en_US
dc.subject.mesh	Amino Acid Sequence	en_US
dc.subject.mesh	Sequence Homology, Amino Acid	en_US
dc.subject.mesh	Dose-Response Relationship, Drug	en_US
dc.subject.mesh	Molecular Weight	en_US
dc.subject.mesh	Molecular Sequence Data	en_US
dc.subject.mesh	Female	en_US
dc.subject.mesh	Male	en_US
dc.title	The ω-atracotoxins: Selective blockers of insect M-LVA and HVA calcium channels	en_US
dc.type	Journal Article
utslib.citation.volume	4	en_US
utslib.citation.volume	74	en_US
utslib.for	111506 Toxicology (incl. Clinical Toxicology)	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	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/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	closed_access
pubs.issue	4	en_US
pubs.publication-status	Published	en_US
pubs.volume	74	en_US

Abstract:

The ω-atracotoxins (ω-ACTX) are a family of arthropod-selective peptide neurotoxins from Australian funnel-web spider venoms (Hexathelidae: Atracinae) that are candidates for development as biopesticides. We isolated a 37-residue insect-selective neurotoxin, ω-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the ω-ACTX-1 family. The peptide induced potent excitatory symptoms, followed by flaccid paralysis leading to death, in acute toxicity tests in house crickets. Using isolated smooth and skeletal nerve-muscle preparations, the toxin was shown to lack overt vertebrate toxicity at concentrations up to 1 μM. To further characterize the target of the ω-ACTXs, voltage-clamp analysis using the whole-cell patch-clamp technique was undertaken using cockroach dorsal unpaired median neurons. It is shown here for the first time that ω-ACTX-Ar1a, and its homolog ω-ACTX-Hv1a from Hadronyche versuta, reversibly block both mid-low- (M-LVA) and high-voltage-activated (HVA) insect calcium channel (Cav) currents. This block occurred in the absence of alterations in the voltage-dependence of Cav channel activation, and was voltage-independent, suggesting that ω-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 μM ω-ACTX-Ar1a failed to significantly affect global Kv channel currents. However, 1 μM ω-ACTX-Ar1a caused a modest 18% block of insect Nav channel currents, similar to the minor block of Nav channels reported for other insect Cav channel blockers such as ω-agatoxin IVA. These findings validate both M-LVA and HVA Cav channels as potential targets for insecticides. © 2007.

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http://hdl.handle.net/10453/4733