Structure and function of δ-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel

Nicholson, Graham M.; Little, Michelle; Birinyi-Strachan, Liesl C.

doi:10.1016/j.toxicon.2004.02.006

Cited by 79 publications

(52 citation statements)

References 82 publications

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“…Furthermore, a Na V channel targeting family of 56-61 residue insecticidal polypeptides has been isolated from the primitive weaving spider Diguentia canities. Their exact interaction site with the sodium channel still remains unknown although binding studies have shown that it is unlikely that they bind to site 3 (Nicholson et al, 2004). Further electrophysiological studies are awaiting in order to elucidate the binding site of these interesting insecticidal spider neurotoxins (Nicholson, 2007).…”

Section: Spider Venomsmentioning

confidence: 99%

The Sophisticated Peptide Chemistry of Venomous Animals as a Source of Novel Insecticides Acting on Voltage-Gated Sodium Channels

Peigneur¹,

Tytgat²

2012

Insecticides - Advances in Integrated Pest Management

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Section: Spider Venomsmentioning

confidence: 99%

The Sophisticated Peptide Chemistry of Venomous Animals as a Source of Novel Insecticides Acting on Voltage-Gated Sodium Channels

Peigneur¹,

Tytgat²

2012

Insecticides - Advances in Integrated Pest Management

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“…A variety of peptides, known as atracotoxins (ACTXs), have been isolated from the venom of funnelweb spiders. However, the lethal toxins, responsible for the major primatespecific symptoms of envenomation, the δ-ACTXs have been shown to target the Nav channel (for a complete review see (Nicholson et al, 2004)). A single primate-specific variant of the δ-ACTX family is the major component of most Australian funnelweb spider venoms including δ-ACTX-Hv1a from Hadronyche versuta (Sheumack et al, 1985), δACTXAr1a from Atrax robustus (Brown et al, 1988) and δ-ACTXHs20.1a from Hadronyche sp.…”

Section: δ-Atracotoxinsmentioning

confidence: 99%

“…A single primate-specific variant of the δ-ACTX family is the major component of most Australian funnelweb spider venoms including δ-ACTX-Hv1a from Hadronyche versuta (Sheumack et al, 1985), δACTXAr1a from Atrax robustus (Brown et al, 1988) and δ-ACTXHs20.1a from Hadronyche sp. 20 (Nicholson et al, 2004) (Fig. 2B), but some species produce multiple δACTX-1 homologues (Szeto et al, 2000).…”

Section: δ-Atracotoxinsmentioning

confidence: 99%

“…Positive cooperativity (+) indicates enhancement of binding of the toxin and/or stimulation of Na + influx while negative cooperativity (-) refers to a decrease in toxin binding (Gordon et al, 1998). Table is adapted from (Cestèle and Catterall, 2000;Zlotkin et al, 2000;Nicholson et al, 2004). The extracellular domains of the β1 and β2 subunits are shown and represented as immunoglobulinlike folds similar to myelin protein P0 (Shapiro et al, 1996).…”

Section: Nicholson and Little ! 15mentioning

confidence: 99%

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SPider Neurotoxins Targeting Voltage-Gated Sodium Channels

Nicholson¹,

Little²

2005

Toxin Revs.

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The voltage-gated sodium (Nav) channel is a target for a number of drugs, insecticides and neurotoxins. These bind to at least seven identified neurotoxin binding sites and either block conductance or modulate sodium channel gating and / or kinetics. A number of polypeptide toxins from the venoms of araneomorph and mygalomorph spiders have been isolated and characterized that interact with several of these sites. Certain huwentoxins and hainantoxins appear to target site 1 to block Nav channel conductance. The δ-atracotoxins and Magi 4 slow Nav channel inactivation via an interaction with neurotoxin site 3. The δ-palutoxins, and most likely µ-agatoxins and curtatoxins, target site 4. However their action is complex with the µ-agatoxins causing a hyperpolarizing shift the voltage-dependence of activation, an action analogous to scorpion β-toxins, but with both δ-palutoxins and µ-agatoxins slowing Nav channel inactivation, a site 3 like action. Many spider toxins target undefined sites, while others are likely to cross-react with other ion channels due to conservedstructures within domains of voltage-gated ion channels. It is already clear, however, that many spider toxins represent highly potent and specific molecular tools to define novel links between sites modulating channel activation and inactivation. Other spider toxins show phyla-specificity and are being considered as lead compounds for the development of biopesticides. Others display tissue specificity via interactions with specific Nav channel subtypes and should provide useful tools to delineate the molecular determinants to target ligands to these channel subtypes. These studies are being greatly assisted by the determination of the pharmacophore of these toxins, but without precise identification of their binding site and mode of action their potential in the above areas remains underdeveloped.!

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“…This 68-residue protein, ACTX-Hvf17, was isolated from the venom of the Blue Mountains funnel-web spider H. versuta. Interestingly, it does not function like classical funnel-web spider atracotoxins to modulate mammalian or insect voltage-gated ion channel function (for reviews see [35,43]) since it lacks insecticidal activity and fails to affect vas deferens smooth muscle or skeletal muscle contractility.…”

Section: Introductionmentioning

confidence: 99%

Discovery of an MIT-like atracotoxin family: Spider venom peptides that share sequence homology but not pharmacological properties with AVIT family proteins

et al. 2005

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Abbreviations: ACh, acetylcholine; ACTX, atracotoxin; BCA, bicinchoninic acid; Bv8, 8kDa protein from the skin secretions of toads (Bombina variegata); CHO, Chinese hamster ovary; DDH, disulfidedirected -hairpin; EST, expressed sequence tag; FLIPR, fluorometric imaging plate reader; HEK, human embryonic kidney; ICK, inhibitory cystine-knot; MIT1, mamba intestinal toxin 1 from the venom of the black mamba snake Dendroaspis p. polylepis; PK, prokineticin (also known as endocrine-gland vascular endothelial growth factor or EG-VEGF); PKR, prokineticin receptor; RACE, rapid amplification of cDNA ends; TCEP, Tris(2-carboxyethyl)phosphine; TFA, trifluoroacetic acid. Atracinae), that appear to undergo N-and/or C-terminal post-translational modifications and conform to an ancestral protein fold. These peptides all show significant amino acid sequence homology to atracotoxin-Hvf17 (ACTX-Hvf17), a non-toxic peptide isolated from the venom of H. versuta, and a variety of AVIT family proteins including mamba intestinal toxin 1 (MIT1) and its mammalian and piscine orthologs prokineticin 1 (PK1) and prokineticin 2 (PK2). These AVIT family proteins target prokineticin receptors involved in the sensitization of nociceptors and gastrointestinal smooth muscle activation. Given their sequence homology to MIT1, we have named these spider venom peptides the MIT-like atracotoxin (ACTX) family. Using isolated rat stomach fundus or guinea-pig ileum organ bath preparations we have shown that the prototypical ACTX-Hvf17, at concentrations up to 1 GM, did not stimulate smooth muscle contractility, nor did it inhibit contractions induced by human PK1 (hPK1). KeywordsThe peptide also lacked activity on other isolated smooth muscle preparations including rat aorta.Furthermore, a FLIPR Ca 2+ flux assay using HEK293 cells expressing prokineticin receptors showed that ACTX-Hvf17 fails to activate or block hPK1 or hPK2 receptors. Therefore, while the MIT-like ACTX family appears to adopt the ancestral disulfide-directed -hairpin protein fold of MIT1, a motif believed to be shared by other AVIT family peptides, variations in the amino acid sequence and surface charge result in a loss of activity on prokineticin receptors.

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Structure and function of δ-atracotoxins: lethal neurotoxins targeting the voltage-gated sodium channel

Cited by 79 publications

References 82 publications

The Sophisticated Peptide Chemistry of Venomous Animals as a Source of Novel Insecticides Acting on Voltage-Gated Sodium Channels

The Sophisticated Peptide Chemistry of Venomous Animals as a Source of Novel Insecticides Acting on Voltage-Gated Sodium Channels

SPider Neurotoxins Targeting Voltage-Gated Sodium Channels

Discovery of an MIT-like atracotoxin family: Spider venom peptides that share sequence homology but not pharmacological properties with AVIT family proteins

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