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J Biol Chem, Vol. 273, Issue 42, 27076-27083, October 16, 1998

-Atracotoxins from Australian Funnel-web Spiders Compete with Scorpion -Toxin Binding but Differentially Modulate Alkaloid Toxin Activation of Voltage-gated Sodium Channels

Michelle J. Little, Cathy Zappia, Nicolas Gilles^§, Mark Connor^¶, Margaret I. Tyler, Marie-France Martin-Eauclaire, Dalia Gordon^§, and Graham M. Nicholson

From the  Department of Health Sciences, University of Technology, Sydney, Broadway, New South Wales 2007, Australia, the ^¶ Department of Pharmacology, University of Sydney, New South Wales 2006, Australia,  Deakin Research Ltd., CSIRO Division of Food Processing, North Ryde, New South Wales 2113, Australia,  UMR 6560 CNRS, Laboratoire de Biochimie, Université de la Mediterranée, I. F. R. Jean Roche, 13916 Marseille, Cedex 20, France, and ^§ CEA, C. E. Saclay, Département d'Ingénierie et d'Etudes des Protéines, Gif-sur-Yvette F-91911, France

-Atracotoxins from the venom of Australian funnel-web spiders are a unique group of peptide toxins that slow sodium current inactivation in a manner similar to scorpion -toxins. To analyze their interaction with known sodium channel neurotoxin receptor sites, we studied their effect on [³H]batrachotoxin and ¹²⁵I-Lqh II (where Lqh is -toxin II from the venom of the scorpion Leiurus quinquestriatus hebraeus) binding and on alkaloid toxin-stimulated ²²Na⁺ uptake in rat brain synaptosomes. -Atracotoxins significantly increased [³H]batrachotoxin binding yet decreased maximal batrachotoxin-activated ²²Na⁺ uptake by 70-80%, the latter in marked contrast to the effect of scorpion -toxins. Unlike the inhibition of batrachotoxin-activated ²²Na⁺ uptake, -atracotoxins increased veratridine-stimulated ²²Na⁺ uptake by converting veratridine from a partial to a full agonist, analogous to scorpion -toxins. Hence, -atracotoxins are able to differentiate between the open state of the sodium channel stabilized by batrachotoxin and veratridine and suggest a distinct sub-conductance state stabilized by -atracotoxins. Despite these actions, low concentrations of -atracotoxins completely inhibited the binding of the scorpion -toxin, ¹²⁵I-Lqh II, indicating that they bind to similar, or partially overlapping, receptor sites. The apparent uncoupling between the increase in binding but inhibition of the effect of batrachotoxin induced by -atracotoxins suggests that the binding and action of certain alkaloid toxins may represent at least two distinguishable steps. These results further contribute to the understanding of the complex dynamic interactions between neurotoxin receptor site areas related to sodium channel gating.

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