title: Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes.
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(v)1.1/beta(1), Na(v)1.2/beta(1), Na(v)1.3/beta(1), Na(v)1.4/beta(1), Na(v)1.5/beta(1), and Na(v)1.8/beta(1)). 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 Na(v)1.2 with an IC(50) value of 0.6 +/- 0.1 nM. CcoTx1 and CcoTx2, differing by only one amino acid, are potent modulators of different voltage-gated sodium channel subtypes from the central nervous system, except for Na(v)1.3, 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 Na(v)1.5/beta(1) (IC(50) = 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.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire Centre National de la Recherche Scientifique Unité Mixte de Recherche, Valbonne, France.
authors.forename: Frank
authors.initials: F
authors.lastname: Bosmans
authors.forename: Lachlan
authors.initials: L
authors.lastname: Rash
authors.forename: Shunyi
authors.initials: S
authors.lastname: Zhu
authors.forename: Sylvie
authors.initials: S
authors.lastname: Diochot
authors.forename: Michel
authors.initials: M
authors.lastname: Lazdunski
authors.forename: Pierre
authors.initials: P
authors.lastname: Escoubas
authors.forename: Jan
authors.initials: J
authors.lastname: Tytgat
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001097:Arachnida / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019143:Evolution, Molecular; D020128:Inhibitory Concentration 50; D015640:Ion Channel Gating / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000187:drug effects; D009865:Oocytes / Q000187:drug effects; D011487:Protein Conformation; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*; D013111:Spider Venoms / Q000737:chemistry*; D014118:Toxins, Biological / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013111:Spider Venoms; D014118:Toxins, Biological; D002118:Calcium