δ-Atracotoxins from Australian funnel-web spiders compete with scorpion α-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, Graham M. Nicholson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

δ-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 α-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 α-toxin II from the venom of the scorpion Leiurus quinquestriatus hebraeus) binding and on alkaloid toxin-stimulated 22Na+ uptake in rat brain synaptosomes. δ- 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 α-toxins. Unlike the inhibition of batrachotoxin-activated 22Na+ uptake, δ-atracotoxins increased veratridine-stimulated 22Na+ uptake by converting veratridine from a partial to a full agonist, analogous to scorpion α-toxins. Hence, δ- 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 δ-atracotoxins. Despite these actions, low concentrations of δ-atracotoxins completely inhibited the binding of the scorpion α-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 δ-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.

Original languageEnglish
Pages (from-to)27076-27083
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number42
DOIs
Publication statusPublished - 16 Oct 1998
Externally publishedYes

Fingerprint

Dive into the research topics of 'δ-Atracotoxins from Australian funnel-web spiders compete with scorpion α-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels'. Together they form a unique fingerprint.

Cite this