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

Discovery of a selective Na V 1.7 inhibitor from centipede venom with analgesic efficacy exceeding morphine in rodent pain models

“…S4). This partial reversal of channel inhibition, along with the depolarizing shift in the voltage dependence of activation, is characteristic of gating modifiers that interact with the voltage-sensing domains of Na V channels (18). In contrast, as expected, inhibition of Na V 1.7 currents by the pore-blocker TTX was largely voltage-independent (Fig.…”

Analysis of the Structural and Molecular Basis of Voltage-sensitive Sodium Channel Inhibition by the Spider Toxin Huwentoxin-IV (μ-TRTX-Hh2a)

“…The mechanism of action of HwTX-IV is thought to involve binding to the voltage sensor of domain II and trapping of the voltage sensor in the inward, closed conformation (5,8). In order to determine if different interactions are responsible for binding and voltage sensor trapping, we compared the activity of the panel of alanine mutants in the functional QPatch assay (where activity is a function of affinity and efficacy) with activity in a novel radioligand binding assay (measure of binding affinity only).…”

“…2 Because the majority of spiders prey primarily on invertebrates, it is likely that these toxins target VGSCs in the insect nervous system, providing a highly efficient mechanism for spiders to incapacitate their prey. However, given the structural similarity between many insect and vertebrate sodium channels, it is not surprising that many spider venom peptides also modulate the activity of vertebrate VGSCs (5)(6)(7)(8)(9). In vertebrates, there are nine VGSC isoforms, Nav1.1-Nav1.9, with each isoform exhibiting a unique pattern of tissue distribution.…”

“…All peptides from this family were isolated from the venom of tarantulas (Theraphosidae), and they consist of [33][34][35] dues with three disulfide bridges that form an inhibitory cysteine knot (ICK) motif (14). Peptides from family 1 include huwentoxin-1 (/-TRTX-Hh1a) (16), hainantoxin-IV (-TRTXHhn1b) (9), phrixotoxin-3 (␤-TRTX-Ps1a) (5), ceratotoxin-1 (␤-TRTX-Cm1a) (5), and huwentoxin-4 (-TRTXHh2a, HwTX-IV) (8,17). All of these peptides are inhibitors of vertebrate VGSCs, and their mechanism of action probably involves a specific interaction with the voltage sensor region(s), impeding its movement and inhibiting channel activation (5,8).…”

“…Peptides from family 1 include huwentoxin-1 (/-TRTX-Hh1a) (16), hainantoxin-IV (-TRTXHhn1b) (9), phrixotoxin-3 (␤-TRTX-Ps1a) (5), ceratotoxin-1 (␤-TRTX-Cm1a) (5), and huwentoxin-4 (-TRTXHh2a, HwTX-IV) (8,17). All of these peptides are inhibitors of vertebrate VGSCs, and their mechanism of action probably involves a specific interaction with the voltage sensor region(s), impeding its movement and inhibiting channel activation (5,8). However, very little is known about the channel residues involved in these interactions.…”