Skip to main content
SpringerLink
Log in

Mechanistic insights on spider neurotoxins

  • Chapter
Molecular, Clinical and Environmental Toxicology

Part of the book series: Experientia Supplementum ((EXS,volume 100))

Abstract

In physiology research, animal neurotoxins historically have served as valuable tools for identification, purification, and functional characterization of voltage-dependent ion channels. In particular, toxins from scorpions, sea anemones and cone snails were at the forefront of work aimed at illuminating the three-dimensional architecture of sodium channels. To date, at least six different receptor binding sites have been identified and — most of them — structurally assigned in terms of protein sequence and spatial disposition. Recent work on Australian funnel-web spiders identified certain peptidic ingredients as being responsible for the neurotoxicity of the crude venom. These peptides, termed δ-atracotoxins (δ-ACTX), consist of 42 amino acids and bind to voltage-gated sodium channels in the same way as classical scorpion α-toxins. According to the ‘voltage-sensor trapping model’ proposed in the literature, δ-ACTX isoforms interact with the voltage sensor S4 transmembrane segment of α-subunit domain IV, thereby preventing its normal outward movement and concurrent conformational changes required for inactivation of the channel. As consequence prolonged action potentials at autonomic or somatic synapses induce massive transmitter release, resulting in clinical correlates of neuroexcitation (e.g., muscle fasciculation, spasms, paresthesia, tachycardia, diaphoresis, etc.). On the other hand, the major neurotoxin isolated from black widow spiders, α-latrotoxin (α-LTX), represents a 132 kDa protein consisting of a unique N-terminal sequence and a C-terminal part harboring multiple ankyrin-like repeats. Upon binding to one of its specific presynaptic receptors, α-LTX has been shown to tetramerize under physiological conditions to form Ca2+-permeable pores in presynaptic membranes. The molecular model worked out during recent years separates two distinguishable receptormediated effects. According to current knowledge, binding of the N terminus of α-LTX at one of its specific receptors either triggers intracellular signaling cascades, resulting in phospholipase C-mediated mobilization of presynaptic Ca2+ stores, or leads to the formation of tetrameric pore complexes, allowing extracellular Ca2+ to enter the presynaptic terminal. α-LTX-triggered exocytosis and fulminant transmitter release at autonomic synapses may then provoke a clinical syndrome referred to as ‘latrodectism’, characterized by local and incapacitating pain, diaphoresis, muscle fasciculation, tremor, anxiety, and so forth. The present review aims at providing a short introduction into some of the exciting molecular effects induced by neurotoxins isolated from black widow and funnel-web spiders.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Currie BJ (2008) Snakes, jellyfish and spiders. Adv Exp Med Biol 609: 43–53

    PubMed  Google Scholar 

  2. Isbister GK, White J (2004) Clinical consequences of spider bites: Recent advances in our understanding. Toxicon 43: 477–492

    CAS  PubMed  Google Scholar 

  3. Isbister GK, Gray MR, Balit CR, Raven RJ, Stokes BJ, Porges K, Tankel AS, Turner E, White J, Fisher MM (2005) Funnel-web spider bite: A systematic review of recorded clinical cases. Med J Aust 182: 407–412

    PubMed  Google Scholar 

  4. Coddington JA, Levi HW (1991) Systematics and evolution of spiders (Araneae). Annu Rev Ecol Syst 22: 565–592

    Google Scholar 

  5. Platnick NI (2006) The World Spider Catalog, Version 10.0 (online available at: http://research. amnh.org/entomology/spiders/catalog/COUNTS.html, accessed at July 29, 2009)

    Google Scholar 

  6. Fernandes Pedrosa Mde F, Junqueira de Azevedo Ide L, Conçalves de Andrade RM, van den Berg CW, Ramos CR, Ho PL, Tambourgi DV (2002) Molecular cloning and expression of a functional dermonecrotic and haemolytic factor from Loxosceles laeta venom. Biochem Biophys Res Commun 298: 638–645

    PubMed  Google Scholar 

  7. Gomez MV, Kalapothakis E, Guatimosim C, Prado MA (2002) Phoneutria nigriventer venom: A cocktail of toxins that affect ion channels. Cell Mol Neurobiol 22: 579–588

    CAS  PubMed  Google Scholar 

  8. Rash LD, Hodgson WC (2002) Pharmacology and biochemistry of spider venoms. Toxicon 40: 225–254

    CAS  PubMed  Google Scholar 

  9. Garb JE, Gonzalez A, Gillespie RG (2004) The black widow spider genus Latrodectus (Araneae: Theridiidae): Phylogeny, biography, and invasion history. Mol Phylogenet Evol 31: 1127–1142

    PubMed  Google Scholar 

  10. Warrell DA, Shaheen J, Hillyard PD, Jones D (1991) Neurotoxic envenoming by an immigrant spider (Steatoda nobilis) in southern England. Toxicon 29: 1263–1265

    CAS  PubMed  Google Scholar 

  11. Grishin EV (1998) Black widow spider toxins: The present and the future. Toxicon 36: 1693–1701

    CAS  PubMed  Google Scholar 

  12. Nicholson GM, Graudins A (2002) Spiders of medical importance in the Asia-Pacific: Atracotoxin, latrotoxin and related spider neurotoxins. Clin Exp Pharmacol Physiol 29: 785–794

    CAS  PubMed  Google Scholar 

  13. Maretic Z (1983) Latrodectism. Variations in clinical manifestations provoked by Latrodectus species of spiders. Toxicon 21: 457–466

    CAS  PubMed  Google Scholar 

  14. Vetter RS, Isbister GK (2008) Medical aspects of spider bites. Annu Rev Entomol 53: 409–429

    CAS  PubMed  Google Scholar 

  15. Isbister GK, Gray MR (2003) Latrodectism: A prospective cohort study of bites by formally identified redback spiders. Med J Aust 179: 88–91

    PubMed  Google Scholar 

  16. Trethewy CE, Bolisetty S, Wheaton G (2003) Red-back spider envenomation in children in Central Australia. Emerg Med 15: 170–175

    Google Scholar 

  17. Grasso A (1976) Preparation and properties of a neurotoxin purified from the venom of black widow spider (Latrodectus mactans tredecimguttatus). Biochim Biophys Acta 439: 406–412

    CAS  PubMed  Google Scholar 

  18. Frontali N, Ceccarelli B, Gorio A, Mauro A, Siekevitz P, Tzeng MC, Hurlbut WP (1976) Purification from black widow spider venom of a protein factor causing the depletion of synaptic vesicles at neuromuscular junctions. J Cell Biol 68: 462–479

    CAS  PubMed  Google Scholar 

  19. Ushkarev IA, Grishin EV (1986) Neurotoxin of the black widow spider and its interaction with receptors from the rat brain. Bioorg Khim 12: 71–80

    CAS  PubMed  Google Scholar 

  20. Krasnoperov VG, Shamotienko OG, Grishin EV (1990) Isolation and properties of insect-specific neurotoxins from venoms of the spider Latrodectus mactans tredecimguttatus. Bioorg Khim 16: 1138–1140

    CAS  PubMed  Google Scholar 

  21. Krasnoperov VG, Shamotienko OG, Grishin EV (1990) A crustacean-specific neurotoxin from the venom of the black widow spider Latrodectus mactans tredecimguttatus. Bioorg Khim 16: 1567–1569

    CAS  PubMed  Google Scholar 

  22. Kiyatkin NI, Dulubova IE, Chekhovskaya IA, Grishin EV (1990) Cloning and structure of cDNA encoding α-latrotoxin from black widow spider venom. FEBS Lett 270: 127–131

    CAS  PubMed  Google Scholar 

  23. Ushkaryov YA, Volynski KE, Ashton AC (2004) The multiple actions of black widow spider toxins and their selective use in neurosecretion studies. Toxicon 43: 527–542

    CAS  PubMed  Google Scholar 

  24. Stieneke-Gröber A, Vey M, Angliker H, Shaw E, Thomas G, Roberts C, Klenk HD, Garten W (1992) Influenza virus hemagglutinin with multibasic cleavage site is activated by furin, a subtilisin-like end oprotease. EMBO J 11: 2407–2414

    PubMed  Google Scholar 

  25. Volynski KE, Nosyreva ED, Ushkaryov YA, Grishin EV (1999) Functional expression of α-latrotoxin in baculovirus system. FEBS Lett 442: 25–28

    CAS  PubMed  Google Scholar 

  26. Cavalieri M, Corvaja N, Grasso A (1990) Immunocytological localization by monoclonal antibodies of α-latrotoxin in the venom gland of the spider Latrodectus tredecimguttatus. Toxicon 28: 341–346

    CAS  PubMed  Google Scholar 

  27. Duan ZG, Yan XJ, He XZ, Zhou H, Chen P, Cao R, Xiong JX, Hu WJ, Wang XC, Liang SP (2006) Extraction and protein component analysis of venom from the dissected venom glands of Latrodectus tredecimguttatus. Comp Biochem Physiol B Biochem Mol Biol 145: 350–357

    CAS  PubMed  Google Scholar 

  28. Sedgwick SG, Smerdon SJ (1999) The ankyrin repeat: A diversity of interactions on a common structural framework. Trends Biochem Sci 24: 311–316

    CAS  PubMed  Google Scholar 

  29. Li J, Mahajan A, Tsai MD (2006) Ankyrin repeat: A unique motif mediating protein-protein interactions. Biochemistry 45: 15168–15178

    CAS  PubMed  Google Scholar 

  30. Orlova EV, Rahman MA, Gowen B, Volynski KE, Ashton AC, Manser C, van Heel M, Ushkaryov YA (2000) Structure of α-latrotoxin oligomers reveals that divalent cation-dependent tetramers form membrane pores. Nat Struct Biol 7: 48–53

    CAS  PubMed  Google Scholar 

  31. Volkova TM, Pluzhnikov KA, Woll PG, Grishin EV (1995) Low molecular weight components from black widow spider venom. Toxicon 33: 483–489

    CAS  PubMed  Google Scholar 

  32. Pescatori M, Bradbury A, Bouet F, Gargano N, Mastrogiacomo A, Grasso A (1995) The cloning of cDNA encoding a protein (latrodectin) which co-purifies with the α-latrotoxin from the black widow spider Latrodectus tredecimguttatus (Theridiidae). Eur J Biochem 230: 322–328

    CAS  PubMed  Google Scholar 

  33. Ichtchenko K, Khvotechev M, Kiyatkin N, Simpson L, Sugita S, Südhof TC (1998) α-Latrotoxin action probed with recombinant toxin: Receptors recruit α-larotoxin but do not transduce an exocytotic signal. EMBO J 17: 6188–6199

    CAS  PubMed  Google Scholar 

  34. Kiyatkin NI, Kulikovskaya IM, Grishin EV, Beadle DJ, King LA (1995) Functional characterization of black widow spider neurotoxins synthesised in insect cells. Eur J Biochem 230: 854–859

    CAS  PubMed  Google Scholar 

  35. Volynski KE, Meunier FA, Lelianova VG, Dudina EE, Volkova TM, Rahman MA, Manser C, Grishin EV, Dolly JO, Ashley RH, Ushkaryov YA (2000) Latrophilin, neurexin, and their signaling-deficient mutants facilitate α-latrotoxin insertion into membranes but are not involved in pore formation. J Biol Chem 275: 41175–41183

    CAS  PubMed  Google Scholar 

  36. Ashton AC, Rahman MA, Volynski KE, Manser C, Orlova EV, Matsushita H, Davletov BA, van Heel M, Grishin EV, Ushkaryov YA (2000) Tetramerisation of α-latrotoxin by divalent cations is responsible for toxin-induced non-vesicular release and contributes to the Ca2+-dependent vesicular exocytosis from synaptosomes. Biochemie 82: 453–468

    CAS  Google Scholar 

  37. Volynski KE, Capogna M, Ashton AC, Thompson D, Orlova EV, Manser CF, Ribchester RR, Ushkaryov YA (2003) Mutant α-latrotoxin (LTXN4C) does not form pores and causes secretion by receptor stimulation: This action does not require neurexins. J Biol Chem 278: 31058–31066

    CAS  PubMed  Google Scholar 

  38. Capogna M, Volynski KE, Emptage NJ, Ushkaryov YA (2003) The α-latrotoxin mutant LTXN4C enhances spontaneous and evoked transmitter release in CA3 pyramidal neurons. J Neurosci 23: 4044–4053

    CAS  PubMed  Google Scholar 

  39. Finkelstein A, Rubin LL, Tzeng MC (1976) Black widow spider venom: Effect of purified toxin on lipid bilayer membranes. Science 193: 1009–1011

    CAS  PubMed  Google Scholar 

  40. Grasso A, Alemà S, Rufini S, Senni MI (1980) Black widow spider toxin-induced calcium fluxes and transmitter release in a neurosecretory cell line. Nature 283: 774–776

    CAS  PubMed  Google Scholar 

  41. Petrenko AG, Kovalenko VA, Shamotienko OG, Surkova IN, Tarasyuk TA, Ushkaryov YA, Grishin EV (1990) Isolation and properties of the α-latrotoxin receptor. EMBO J 9: 2023–2027

    CAS  PubMed  Google Scholar 

  42. Van Renterghem C, Iborra C, Martin-Moutot N, Lelianova V, Ushkaryov Y, Seagar M (2000) α-Latrotoxin forms calcium-permeable membrane pores via interactions with latrophilin or neurexin. Eur J Neurosci 12: 3953–3962

    PubMed  Google Scholar 

  43. Khvotchev M, Südhof TC (2000) α-Latrotoxin triggers transmitter release via direct insertion into the presynaptic plasma membrane. EMBO J 19: 3250–3262

    CAS  PubMed  Google Scholar 

  44. Rohou A, Nield J, Ushkaryov YA (2007) Insecticidal toxins from black widow spider venom. Toxicon 49: 531–549

    CAS  PubMed  Google Scholar 

  45. Ushkaroyov YA, Petrenko AG, Geppert M, Südhof TC (1992) Neurexins. Synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257: 50–56

    Google Scholar 

  46. Missler M, Südhof TC (1998) Neurexins: Three genes and 1001 products. Trends Genet 14: 20–26

    CAS  PubMed  Google Scholar 

  47. Davletov BA, Krasnoperov V, Hata Y, Petrenko AG, Südhof TC (1995) High affinity binding of α-latrotoxin to recombinant neurexin Iα. J Biol Chem 270: 23903–23905

    CAS  PubMed  Google Scholar 

  48. Davletov BA, Shamotienko OG, Lelianova VG, Grishin EV, Ushkaryov YA (1996) Isolation and biochemical characterization of a Ca2+-independent α-latrotoxin-binding protein. J Biol Chem 271: 23239–23245

    CAS  PubMed  Google Scholar 

  49. Lelianova VG, Davletov BA, Sterling A, Rahman MA, Grishin EV, Totty NF, Usaharyov YA (1997) α-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. J Biol Chem 272: 21504–21508

    CAS  PubMed  Google Scholar 

  50. Sugita S, Ichtechenko K, Khvotchev M, Südhof TC (1998) α-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. J Biol Chem 273: 32715–32724

    CAS  PubMed  Google Scholar 

  51. Krasnoperov VG, Bittner MA, Beavis R, Kuang Y, Salnikow KV, Chepurny OG, Little AR, Plotnikov AN, Wu D, Holz RW, Petrenko AG (1997) α-Latrotoxin stimulates exocytosis by the interaction with a neuronal G-protein-coupled receptor. Neuron 18: 925–937

    CAS  PubMed  Google Scholar 

  52. Volynski KE, Silva JP, Lelianova VG, Rahman MA, Hopkins C, Ushkaryov YA (2004) Latrophilin fragments behave as independent proteins that associate and signal on binding of LTXN4C. EMBO J 23: 4423–4433

    CAS  PubMed  Google Scholar 

  53. Ichtchenko K, Bittner MA, Krasnoperov V, Little AR, Chepurny O, Holz RW, Petrenko AG (1999) A novel ubiquitously expressed α-latrotoxin receptor is a member of the CIRL family of G-protein-coupled receptors. J Biol Chem 274: 5491–5498

    CAS  PubMed  Google Scholar 

  54. Matsushita H, Lelianova VG, Ushkaryov YA (1999) The latrophilin family: Multiply spliced G protein-coupled receptors with differential tissue distribution. FEBS Lett 443: 348–352

    CAS  PubMed  Google Scholar 

  55. Krasnoperov VG, Bittner MA, Mo W, Buryanovsky L, Neubert TA, Holz RW, Ichtchenko K, Petrenko AG (2002) Protein-tyrosine phosphatase-σ is a novel member of the functional family of α-latrotoxin receptors. J Biol Chem 277: 35887–35895

    CAS  PubMed  Google Scholar 

  56. Tobaben S, Südhof TC, Stahl B (2002) Genetic analysis of α-latrotoxin receptors reveals functional interdependence of CIRL/latrophilin 1 and neurexin Iα. J Biol Chem 277: 6359–6365

    CAS  PubMed  Google Scholar 

  57. Rosenthal L, Meldolesi J (1989) α-Latrotoxin and related toxins. Pharmacol Ther 42: 115–134

    CAS  PubMed  Google Scholar 

  58. Khvotchev M, Lonart G, Südhof TC (2000) Role of calcium in neurotransmitter release evoked by α-latrotoxin or hypertonic sucrose. Neuroscience 101: 793–802

    CAS  PubMed  Google Scholar 

  59. Matteoli M, Haimann C, Torri-Tarelli F, Polak JM, Ceccarelli B, de Camilli P (1988) Differential effect of α-latrotoxin on exocytosis from small synaptic vesicles and from large dense-core vesicles containing calcitonin gene-related peptide at the frog neuromuscular junction. Proc Natl Acad Sci USA 85: 7366–7370

    CAS  PubMed  Google Scholar 

  60. Ashton AC, Volynski KE, Lelianova VG, Orlova EV, van Renterghem C, Canepari M, Seagar M, Ushkaryov YA (2001) α-Latrotoxin, acting via two Ca2+-dependent pathways, triggers exocytosis of two pools of synaptic vesicles. J Biol Chem 276: 44695–44703

    CAS  PubMed  Google Scholar 

  61. Li G, Lee D, Wang L, Khvotchev M, Chiew SK, Arunachalam L, Collins T, Feng ZP, Sugita S (2005) N-terminal insertion and C-terminal ankyrin-like repeats of α-latrotoxin are critical for Ca2+-dependent exocytosis. J Neurosci 25: 10188–10197

    CAS  PubMed  Google Scholar 

  62. Deák F, Liu X, Khvotchev M, Li G, Kavalali ET, Sugita S, Südohf TC (2009) α-Latrotoxin stimulates a novel pathway of Ca2+-dependent synaptic exocytosis independent of the classical synaptic fusion machinery. J Neurosci 29: 8639–8648

    PubMed  Google Scholar 

  63. Gray MR (1998) Aspects of the systematics of the Australian funnel-web spiders (Araneae: Hexathelidae: Atracinae) based upon morphological and electrophoretic data. In: AD Austin, NW Heather (eds): Australian Arachnology. The Australian Entomological Society, Brisbane, Australia, 113–125

    Google Scholar 

  64. Torda TA, Loong E, Greaves I (1980) Severe lung oedema and fatal consumption coagulopathy after funnel-web spider bite. Med J Aust 2: 442–444

    CAS  PubMed  Google Scholar 

  65. Sutherland SK (1983) Genus Atrax Cambridge, the funnel-web spiders. In: SK Sutherland (ed.): Australian Animal Toxins. Oxford University Press, Melbourne, Australia, 255–298

    Google Scholar 

  66. White J, Carduso JL, Fan HW (1995) Clinical toxicology of spider bites. In: J Meier, J White (eds): Handbook of Clinical Toxicology of Animal Venoms and Poisons. CRC Press, New York, 259–329

    Google Scholar 

  67. Sutherland SK, Tibballs J (2001) The genera Atrax and Hadronyche, funnel-web spiders. In: SK Sutherland, J Tibballs (eds): Australian Animal Toxins: The Creatures, Their Toxins and Care of the Poisoned Patient. Oxford University Press, Melbourne, Australia, 402–464

    Google Scholar 

  68. Sutherland SK (1980) Antivenom to the venom of the male Sydney funnel-web spider Atrax robustus. Preliminary report. Med J Aust 2: 437–441

    CAS  PubMed  Google Scholar 

  69. Graudins A, Wilson D, Alewood PF, Broady KW, Nicholson GM (2002) Cross-reactivity of Sydney funnel-web spider antivenom: Neutralization of the in vitro toxicity of other Australian funnel-web (Atrax and Hadronyche) spider venoms. Toxicon 40: 259–266

    CAS  PubMed  Google Scholar 

  70. Miller MK, Whyte IM, White J, Keir PM (2000) Clinical features and management of Hadronyche envenomation in man. Toxicon 38: 409–427.

    CAS  PubMed  Google Scholar 

  71. Isbister GK, Gray MR (2004) Bites by Australian mygalomorph spiders (Araneae, Mygalomorphae), including funnel-web spiders (Atracinae) and mouse spiders (Actinopodidae: Missulena spp). Toxicon 43: 133–140

    CAS  PubMed  Google Scholar 

  72. Nicholson GM, Graudins A, Wilson HI, Little M, Broady KW (2006) Arachnid toxinology in Australia: From clinical toxicology to potential applications. Toxicon 48: 872–898

    CAS  PubMed  Google Scholar 

  73. Wiener S (1957) The Syndney funnel-web spider (Atrax robustus). I Collection of venom and its toxicity in animals. Med J Aust 44: 377–382

    CAS  PubMed  Google Scholar 

  74. Duncan AW, Tibballs J, Sutherland SK (1980) Effects of funnel-web spider envenomation in monkeys, and their clinical implications. Med J Aust 2: 429–435

    CAS  PubMed  Google Scholar 

  75. Mylecharane EJ, Spence I, Gregson RP (1984) In vivo actions of atraxin, a protein neurotoxin from the venom glands of the funnel-web spider (Atrax robustus). Comp Biochem Physiol C 79: 395–399

    CAS  PubMed  Google Scholar 

  76. Sheumack DD, Baldo BA, Carroll PR, Hampson F, Howden ME, Skorulis A (1984) A comparative study of properties and toxic constituents of funnel-web spider (Atrax) venoms. Comp Biochem Physiol C 78: 55–68

    CAS  PubMed  Google Scholar 

  77. Brown MR, Sheumack DD, Tyler MI, Howden MEH (1988) Amino acid sequence of versutoxin, a lethal neurotoxin from the venom of the funnel-web spider Atrax versutus. Biochem J 250: 401–405

    CAS  PubMed  Google Scholar 

  78. Mylecharane EJ, Spence I, Sheumack DD, Claassens R, Howden MEH (1989) Actions of robustoxin, a neurotoxic polypeptide from the venom of the male funnel-web spider (Atrax robustus), in anaesthetized monkeys. Toxicon 27: 481–492

    CAS  PubMed  Google Scholar 

  79. Sheumack DD, Claassens R, Whiteley NM, Howden MEH (1985) Complete amino acid sequence of a new type of lethal neurotoxin from the venom of the funnel-web spider Atrax robustus. FEBS Lett 181: 154–156

    CAS  PubMed  Google Scholar 

  80. Szeto TH, Birinyi-Strachan LC, Smith R, Connor M, Christie MJ, King GF, Nicholson GM (2000) Isolation and pharmacological characterisation of δ-atracotoxin-Hvlb, a vertebrate-selective sodium channel to xin. FEBS Lett 470: 293–299

    CAS  PubMed  Google Scholar 

  81. Pallaghy PK, Alewood D, Alewood PF, Norton RS (1997) Solution structure of robustoxin, the lethal neurotoxin from the funnelweb spider Atrax robustus. FEBS Lett 419: 191–196

    CAS  PubMed  Google Scholar 

  82. Pallaghy PK, Neilsen KJ, Craik DJ, Norton RS (1994) A common structural motif, incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides. Protein Sci 3: 1833–1839

    CAS  PubMed  Google Scholar 

  83. Norton RS, Pallaghy PK (1998) The cystine knot structure of ion channel toxins and related polypeptides. Toxicon 36: 1573–1583

    CAS  PubMed  Google Scholar 

  84. Nicholson GM, Little MJ, Birinyi-Strachan LC (2004) Structure and function of δ-atracotoxins: Lethal neurotoxins targeting the voltage-gated sodium channel. Toxicon 43: 587–599

    CAS  PubMed  Google Scholar 

  85. Grolleau F, Stankiewicz M, Birinyi-Strachan L, Wang XH, Nicholson GM, Pelhate M, Lapied B (2001) Electrophysiological analysis of the neurotoxic action of a funnel-web spider toxin, δ-atracotoxin-Hvla, on insect voltage-gated Na+ channels. J Exp Biol 204: 711–721

    CAS  PubMed  Google Scholar 

  86. Alewood D, Birinyi-Strachan LC, Pallaghy PK, Norton RS, Nicholson GM, Alewood PF (2003) Synthesis and characterization of δ-atracotoxin-Arla, the lethal neurotoxin from venom of the Sydney funnel-web spider (Atrax robustus). Biochemistry 42: 12933–12940

    CAS  PubMed  Google Scholar 

  87. Nicholson GM, Walsh R, Little MJ, Tyler MI (1998) Characterisation of the effects of robustoxin, the lethal neurotoxin from the Sydney funnel-web spider Atrax robustus, on sodium channel activation and inactivation. Pflügers Arch 436: 117–126

    CAS  PubMed  Google Scholar 

  88. Nicholson GM, Little MJ, Tyler M, Narahashi T (1996) Selective alteration of sodium channel gating by Australian funnel-web spider toxins. Toxicon 34: 1443–1453

    CAS  PubMed  Google Scholar 

  89. Little MJ, Wilson H, Zappia C, Cestèle S, Tyler MI, Martin-Eauclaire MF, Gordon D, Nicholson GM (1998) δ-Atracotoxins from Australian funnel-web spiders compete with scorpion α-toxin binding on both rat brain and insect sodium channels. FEBS Lett 439: 246–252

    CAS  PubMed  Google Scholar 

  90. Little MJ, Zappia C, Gilles N, Connor M, Tyler MI, Martin-Eauclaire MF, Gordon D, Nicholson GM (1998) δ-Atracotoxins from Australian funnel-web spiders compete with scorpion α-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels. J Biol Chem 273: 27076–27083

    CAS  PubMed  Google Scholar 

  91. Gordon D (1997) Sodium channels as targets for neurotoxins: Mode of action and interaction of neurotoxins with receptor sites on sodium channels. In: P. Lazarowici, Y Gutman (eds): Toxins and Signal Transduction. Harwood Press, Amsterdam, The Netherlands, 119–149

    Google Scholar 

  92. Gilles N, Harrison G, Karbat I, Gurevitz M, Nicholson GM, Gordon D (2002) Variations in receptor site-3 on rat brain and insect sodium channels highlighted by binding of a funnel-web spider δ-atracotoxin. Eur J Biochem 269: 1500–1510

    CAS  PubMed  Google Scholar 

  93. Cestèle S, Catterall WA (2000) Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82: 883–892

    PubMed  Google Scholar 

  94. Blumenthal KM, Seibert AL (2003) Voltage-gated sodium channel toxins. Cell Biochem Biophys 38: 215–237

    CAS  PubMed  Google Scholar 

  95. Catterall WA, Cestèle S, Yarov-Yarovoy V, Yu FH, Konoki K, Scheuer T (2007) Voltage-gated ion channels and gating modifier toxins. Toxicon 49: 124–141

    CAS  PubMed  Google Scholar 

  96. Eitan M, Fowler E, Hermann R, Duval A, Pelhate M, Zlotkin E (1990) A scorpion venom neurotoxin paralytic to insects that affects sodium current inactivation: Purification, primary structure, and mode of action. Biochemistry 29: 5941–5947

    CAS  PubMed  Google Scholar 

  97. Rogers JC, Qu Y, Tanada TN, Scheuer T, Catterall WA (1996) Molecular determinants of high affinity binding of α-scorpion toxin and sea anemone toxin in the S3-S4 extracellular loop in domain IV of the Na+ channel α subumit. J Biol Chem 271: 15950–15962

    CAS  PubMed  Google Scholar 

  98. Fletcher JI, Chapman BE, Mackay JP, Howden MEH, King GF (1997) The structure of versutoxin (δ-atracotoxin-Hv1): Implications for binding of site-3 toxins to the voltage-gated sodium channel. Structure 5: 1525–1535

    CAS  PubMed  Google Scholar 

  99. Gilles N, Leipold E, Chen H, Heinemann SH, Gordon D (2001) Effect of depolarization on binding kinetics of scorpion α-toxin highlights conformational changes of rat brain sodium channels. Biochemistry 40: 14576–14584

    CAS  PubMed  Google Scholar 

  100. Fletcher JI, Smith R, O’Donoghue SI, Nilges M, Connor M, Howden ME, Christie MJ, King GF (1997) The structure of a novel insecticidal neurotoxin, ε-atracotoxin-Hv1, from the venom of an Australian funnel-web spider. Nat Struct Biol 4: 559–566

    CAS  PubMed  Google Scholar 

  101. Wang XH, Connor M, Wilson D, Wilson HI, Nicholson GM, Smith R, Shaw D, Mackay JP, Alewood PF, Christie MJ, King GF (2001) Discovery and structure of a potent and highly specific blocker of insect calcium channels. J Biol Chem 276: 40306–40312

    CAS  PubMed  Google Scholar 

  102. Wang X, Connor M, Smith R, Maciejewski MW, Howden ME, Nicholson GM, Christie MJ, King GF (2000) Discovery and characterization of a family of insecticidal neurotoxins with a rare vicinal disulfide bridge. Nat Struct Biol 7: 505–513

    CAS  PubMed  Google Scholar 

  103. Gunning SJ, Maggio F, Windley MJ, Valenzuela SM, King GF, Nicholson GM (2008) The Janus-faced atracotoxins are specific blockers of invertebrate Kca channels. FEBS J 275: 4045–4059

    CAS  PubMed  Google Scholar 

  104. King GF, Tedford HW, Maggio F (2002) Structure and function of insecticidal neurotoxins from Australian funnel-web spiders. J Toxicol Toxin Rev 21: 359–389

    CAS  Google Scholar 

  105. Tedford HW, Sollod BL, Maggio F, King GF (2004) Australian funnel-web spiders: Master insecticide chemists. Toxicon 43: 601–618

    CAS  PubMed  Google Scholar 

  106. Catterall WA (1992) Cellular and molecular biology of voltage-dependent sodium channels. Physiol Rev 72: S15–48

    Google Scholar 

  107. Catterall WA (2000) From ionic currents to molecular mechanisms: The structure and function of voltage-gated sodium channels. Neuron 26: 13–25

    CAS  PubMed  Google Scholar 

  108. Yang N, George AL Jr, Horn R (1996) Molecular basis of charge movement in voltage-gated sodium channels. Neuron 16: 113–122

    PubMed  Google Scholar 

  109. Nicholson GM (2007) Insect-selective spider toxins targeting voltage-gated soidum channels. Toxicon 49: 490–512

    CAS  PubMed  Google Scholar 

  110. Dudley SC Jr, Todt H, Lipkind G, Fozzard HA (1995) A μ-conotoxin-insensitive Na+ channel mutant: Possible localization of a binding site at the outer vestibule. Biophys J 69: 1657–1665

    CAS  PubMed  Google Scholar 

  111. Martin-Moutot N, Mansuelle P, Alcaraz G, Dos Santos RG, Cordeiro MN, De Lima ME, Seagar M, van Renterghem C (2006) Phoneutria nigriventer toxin 1: A novel, state-dependent inhibitor of neuronal sodium channels that interacts with μ conotoxin binding sites. Mol Pharmacol 69: 1931–1937

    CAS  PubMed  Google Scholar 

  112. Chahine M, Chen LQ, Fotouhi N, Walsky R, Fry D, Santarelli V, Horn R, Kallen RG (1995) Characterizing the μ-conotoxin binding site on voltage-sensitive sodium channels with toxin anlogs and channel mutations. Receptors Channels 3: 161–174

    CAS  PubMed  Google Scholar 

  113. Nicholson GM, Lewis RJ (2006) Ciguatoxins: Cyclic polyether modulators of voltage-gated ion channel function. Mar Drugs 4: 82–118

    CAS  Google Scholar 

  114. Smith JJ, Blumenthal KM (2007) Site-3 anemone toxins: Molecular probes of gating mechanisms in voltage-dependent sodium channels. Toxicon 49: 159–170

    CAS  PubMed  Google Scholar 

  115. Srinivasan KN, Gopalakrishnakone P, Tan PT, Chew KC, Cheng B, Kini RM, Koh JL, Seah SH, Brusic V (2002) SCORPION, a molecular database of scorpion toxins. Toxicon 40: 23–31

    CAS  PubMed  Google Scholar 

  116. Tan PT, Veeramani A, Srinivasan KN, Ranganathan S, Brusic V (2006) SCORPION2: A database for structure-function analysis of scorpion toxins. Toxicon 47: 356–363

    CAS  PubMed  Google Scholar 

  117. Catterall WA (1979) Binding of scorpion toxin to receptor sites associated with sodium channels in frog muscle. Correlation of voltage-dependent binding with activation. J Gen Physiol 74: 375–391

    CAS  PubMed  Google Scholar 

  118. Cestèle S, Khalifa RB, Pelhate M, Rochat H, Gordon D (1995) α-Scorpion toxins binding on rat brain and insect sodium channels reveal divergent allosteric modulations by brevetoxin and veratridine. J Biol Chem 270: 15153–15161

    PubMed  Google Scholar 

  119. Sheets MF, Kyle JW, Kallen RG, Hanck DA (1999) The Na channel voltage sensor associated with inactivation is localized to the external charged residues of domain IV, S4. Biophys J 77: 747–757

    CAS  PubMed  Google Scholar 

  120. Hasson A, Fainzilber M, Gordon D, Zlotkin E, Spira ME (1993) Alteration of sodium currents by new peptide toxins from the venom of a molluscivorous Conus snail. Eur J Neurosci 5: 56–64

    CAS  PubMed  Google Scholar 

  121. Fainzilber M, Kofman O, Zlotkin E, Gordon D (1996) A new neurotoxin receptor site on sodium channels is identified by a conotoxin that affects sodium channel inactivation in molluscs and acts as an antagonist in rat brain. J Biol Chem 269: 2574–2580

    Google Scholar 

  122. Leipold E, Hansel A, Olivera BM, Terlau H, Heinemann SH (2005) Molecular interaction of δ-conotoxins with voltage-gated sodium channels. FEBS Lett 579: 3881–3884

    CAS  PubMed  Google Scholar 

  123. Cestèle S, Qu Y, Rogers JC, Rochat H, Scheuer T, Catterall WA (1998) Voltage-sensor-trapping: Enhanced activation of sodium channels by β-scorpion toxin bound to the S3-S4 loop in domain II. Neuron 21: 919–931

    PubMed  Google Scholar 

  124. Cestèle S, Yarov-Yarovoy V, Qu Y, Sampieri F, Scheuer T, Catterall WA (2006) Structure and function of the voltage sensor of sodium channels probed by a β-scorpion toxin. J Biol Chem 281: 21332–21344

    PubMed  Google Scholar 

  125. Ushakaryov YA, Rohou A, Sugita S (2008) α-Latrotoxin and its receptors. Handb Exp Pharmacol 184: 171–206

    Google Scholar 

  126. Lewis RJ, Garcia ML (2003) Therapeutic potential of venom peptides. Nat Rev Drug Discov 2: 790–802

    CAS  PubMed  Google Scholar 

  127. Han TS, Teichert RW, Olivera BM, Bulaj G (2008) Conus vennoms — A rich source of peptidebased therapeutics. Curr Pharm Des 14: 2462–2479

    CAS  PubMed  Google Scholar 

  128. Lewis RJ (2009) Conotoxins: Molecular and therapeutic targets. Prog Mol Subcell Biol 46: 45–65

    CAS  PubMed  Google Scholar 

  129. Escoubas P, King GF (2009) Venomics as a drug discovery platform. Expert Rev Proteomics 6: 221–224

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Product Safety, Center for Alternatives to Animal Experiments, Federal Institute for Risk Assessment, Thielallee 88-92, 14195, Berlin, Germany

    Andreas Luch

Authors
  1. Andreas Luch
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Federal Institute for Risk Assessment, Thielallee 88-92, 14195, Berlin, Germany

    Andreas Luch

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Birkhäuser Verlag/Switzerland

About this chapter

Cite this chapter

Luch, A. (2010). Mechanistic insights on spider neurotoxins. In: Luch, A. (eds) Molecular, Clinical and Environmental Toxicology. Experientia Supplementum, vol 100. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8338-1_8

Download citation

Publish with us

Policies and ethics

Search

Navigation