TY - JOUR
T1 - Four novel tarantula toxins as selective modulators of voltage-gated sodium channel subtypes
AU - Bosmans, Frank
AU - Rash, Lachlan
AU - Zhu, Shunyi
AU - Diochot, Sylvie
AU - Lazdunski, Michel
AU - Escoubas, Pierre
AU - Tytgat, Jan
PY - 2006/1/27
Y1 - 2006/1/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=31044432475&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=31044432475&partnerID=8YFLogxK
U2 - 10.1124/mol.105.015941
DO - 10.1124/mol.105.015941
M3 - Article
C2 - 16267209
AN - SCOPUS:31044432475
VL - 69
SP - 419
EP - 429
JO - Molecular Pharmacology
JF - Molecular Pharmacology
SN - 0026-895X
IS - 2
ER -