Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 24, Pages 18545-18554Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.125211
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Funding
- Federal Agency for Education of the Russian Federation [P1388]
- Program of Cell and Molecular Biology of the Russian Academy of Sciences
- Russian Foundation for Basic Research [05-04-50828, BIL05/50]
- F.W.O. Vlaanderen) [G.0257.08, G.0330.06]
- K.U. Leuven [OT-05-64]
- Interuniversity Attraction Poles Program, Belgian State, Belgian Science Policy [UA P6/31]
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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-likeaction). 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.
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