delta-Atracotoxins from australian funnel-web spiders compete with scorpion alpha-toxin binding but differentially modulate alkaloid toxin activation of voltage-gated sodium channels.
delta-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 alpha-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 alpha-toxin II from the venom of the scorpion Leiurus quinquestriatus hebraeus) binding and on alkaloid toxin-stimulated 22Na+ uptake in rat brain synaptosomes. delta-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 alpha-toxins. Unlike the inhibition of batrachotoxin-activated 22Na+ uptake, delta-atracotoxins increased veratridine-stimulated 22Na+ uptake by converting veratridine from a partial to a full agonist, analogous to scorpion alpha-toxins. Hence, delta-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 delta-atracotoxins. Despite these actions, low concentrations of delta-atracotoxins completely inhibited the binding of the scorpion alpha-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 delta-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.
Department of Health Sciences, University of Technology, Sydney, Broadway, New South Wales 2007, Australia.
M J
MJ
Little
C
C
Zappia
N
N
Gilles
M
M
Connor
M I
MI
Tyler
M F
MF
Martin-Eauclaire
D
D
Gordon
G M
GM
Nicholson
D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015640:Ion Channel Gating; D008297:Male; D009498:Neurotoxins / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012604:Scorpion Venoms / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000187:drug effects*; D013111:Spider Venoms / Q000378:metabolism* / Q000494:pharmacology; D013574:Synaptosomes / Q000378:metabolism; D014701:Veratridine / Q000378:metabolism
D001496:Batrachotoxins; C065190:LqhalphaIT toxin; D009498:Neurotoxins; D012604:Scorpion Venoms; D015222:Sodium Channels; D013111:Spider Venoms; C055477:versutoxin; D014701:Veratridine; C031775:batrachotoxinin A 20-alpha-benzoate; D012964:Sodium