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Mechanistic insights on spider neurotoxins

  • Andreas Luch
Part of the Experientia Supplementum book series (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.

Keywords

Sodium Channel Venom Gland Spider Venom Cone Snail Black Widow Spider 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Birkhäuser Verlag/Switzerland 2010

Authors and Affiliations

  • Andreas Luch
    • 1
  1. 1.Department of Product Safety, Center for Alternatives to Animal ExperimentsFederal Institute for Risk AssessmentBerlinGermany

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