Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes

Frank Bosmans, Lachlan Rash, Shunyi Zhu, Sylvie Diochot, Michel Lazdunski, Pierre Escoubas, Jan Tytgat

Research output: Contribution to journalArticlepeer-review

Abstract

Four novel peptide toxins that act on voltage-gated sodium channels have been isolated from tarantula venoms: ceratotoxins 1, 2, and 3 (CcoTx1, CcoTx2, and CcoTx3) from Ceratogyrus cornuatus and phrixotoxin 3 (PaurTx3) from Phrixotrichus auratus. The pharmacological profiles of these new toxins were characterized by electrophysiological measurements on six cloned voltage-gated sodium channel subtypes expressed in Xenopus laevis oocytes (Na v1.1/β1, Nav1.2/β1, Nav1.3/β1, Nav1.4/β1, Nav1.5/β1, and Nav1.8/β1). These novel toxins modulate voltage-gated sodium channels with properties similar to those of typical gating-modifier toxins, both by causing a depolarizing shift in gating kinetics and by blocking the inward component of the sodium current. PaurTx3 is one of the most potent peptide modulators of voltage-gated sodium channels described thus far from spider venom, modulating Nav1.2 with an IC50 value of 0.6 ± 0.1 nM. CcoTx1 and CcoTx2, differing by only one amino acid, are potent modulators of different voltagegated sodium channel subtypes from the central nervous system, except for Nav1.3, which is only affected by CcoTx2. The potency of CcoTx3 is lower, although this toxin seems to be more selective for the tetrodotoxin-resistant channel subtype Nav1.5/β1 (IC50 = 447 ± 32 nM). In addition to these results, molecular modeling indicates that subtle differences in toxin surfaces may relate to their different pharmacological profiles. Furthermore, an evolutionary trace analysis of these toxins and other structurally related three-disulfide spider toxins provides clues for the exploration of toxin-channel interaction and future structure-function research.

Original languageEnglish (US)
Pages (from-to)419-429
Number of pages11
JournalMolecular Pharmacology
Volume69
Issue number2
DOIs
StatePublished - Jan 27 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Fingerprint Dive into the research topics of 'Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes'. Together they form a unique fingerprint.

Cite this