The omega-atracotoxins: selective blockers of insect M-LVA and HVA calcium channels

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Journal Article
Biochemical Pharmacology, 2007, 74 (4), pp. 623 - 638
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The w-atracotoxins (w-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, w-ACTX-Ar1a, from the venom of the Sydney funnel-web spider Atrax robustus, with high homology to several previously characterized members of the w-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 mM. To further characterize the target of the w-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 w-ACTX-Ar1a, and its homolog w-ACTX-Hv1a from Hadronyche versuta, reversibly block both midâlow- (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 w-ACTX-1 family toxins are pore blockers rather than gating modifiers. At a concentration of 1 mM w-ACTX-Ar1a failed to significantly affect global Kv channel currents. However, 1 mM w-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 w-agatoxin IVA. These findings validate both M-LVA and HVA Cav channels as potential targets for insecticides
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