Unique bell-shaped voltage-dependent modulation of Na+ channel gating by novel insect-selective toxins from the spider Agelena orientalis.
Spider venoms provide a highly valuable source of peptide toxins that act on a wide diversity of membrane-bound receptors and ion channels. In this work, we report isolation, biochemical analysis, and pharmacological characterization of a novel family of spider peptide toxins, designated beta/delta-agatoxins. These toxins consist of 36-38 amino acid residues and originate from the venom of the agelenid funnel-web spider Agelena orientalis. The presented toxins show considerable amino acid sequence similarity to other known toxins such as mu-agatoxins, curtatoxins, and delta-palutoxins-IT from the related spiders Agelenopsis aperta, Hololena curta, and Paracoelotes luctuosus. beta/delta-Agatoxins modulate the insect Na(V) channel (DmNa(V)1/tipE) in a unique manner, with both the activation and inactivation processes being affected. The voltage dependence of activation is shifted toward more hyperpolarized potentials (analogous to site 4 toxins) and a non-inactivating persistent Na(+) current is induced (site 3-like action). Interestingly, both effects take place in a voltage-dependent manner, producing a bell-shaped curve between -80 and 0 mV, and they are absent in mammalian Na(V) channels. To the best of our knowledge, this is the first detailed report of peptide toxins with such a peculiar pharmacological behavior, clearly indicating that traditional classification of toxins according to their binding sites may not be as exclusive as previously assumed.
Billen
Bert
B
Laboratory of Toxicology, University of Leuven, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49, PO Box 922, B-3000 Leuven, Belgium.
Vassilevski
Alexander
A
Nikolsky
Anton
A
Debaveye
Sarah
S
Tytgat
Jan
J
Grishin
Eugene
E
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D004220:Disulfides / Q000737:chemistry; D004594:Electrophysiology / Q000379:methods; D007313:Insecta; D007477:Ions; D013058:Mass Spectrometry / Q000379:methods; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D015222:Sodium Channels / Q000737:chemistry*; D013111:Spider Venoms / Q000737:chemistry*; D013112:Spiders; D014118:Toxins, Biological / Q000737:chemistry*; D014982:Xenopus laevis
D004220:Disulfides; D007477:Ions; D010455:Peptides; D015222:Sodium Channels; D013111:Spider Venoms; D014118:Toxins, Biological
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