SPider Neurotoxins Targeting Voltage-Gated Sodium Channels

Abstract

The voltage-gated sodium (Nav) channel is a target for a number of drugs, insecticides and neurotoxins. These bind to at least seven identified neurotoxin binding sites and either block conductance or modulate sodium channel gating and / or kinetics. A number of polypeptide toxins from the venoms of araneomorph and mygalomorph spiders have been isolated and characterized that interact with several of these sites. Certain huwentoxins and hainantoxins appear to target site 1 to block Nav channel conductance. The δ-atracotoxins and Magi 4 slow Nav channel inactivation via an interaction with neurotoxin site 3. The δ-palutoxins, and most likely µ-agatoxins and curtatoxins, target site 4. However their action is complex with the µ-agatoxins causing a hyperpolarizing shift the voltage-dependence of activation, an action analogous to scorpion β-toxins, but with both δ-palutoxins and µ-agatoxins slowing Nav channel inactivation, a site 3 like action. Many spider toxins target undefined sites, while others are likely to cross-react with other ion channels due to conservedstructures within domains of voltage-gated ion channels. It is already clear, however, that many spider toxins represent highly potent and specific molecular tools to define novel links between sites modulating channel activation and inactivation. Other spider toxins show phyla-specificity and are being considered as lead compounds for the development of biopesticides. Others display tissue specificity via interactions with specific Nav channel subtypes and should provide useful tools to delineate the molecular determinants to target ligands to these channel subtypes. These studies are being greatly assisted by the determination of the pharmacophore of these toxins, but without precise identification of their binding site and mode of action their potential in the above areas remains underdeveloped.!

Ciguatoxins: Cyclic Polyether Modulators of Voltage-gated Iion Channel Function

“…Ciguatoxins and brevetoxins bind with site 5 indicated in blue. Figure is adapted from Cestèle [112] and Nicholson [113]. …”

Developing novel analgesics to treat chronic pain: inhibiting voltage gated sodium channel 1.7 with spider-venom peptides

“…Moreover, even though the vast majority of spiders prey primarily on invertebrates, there is no evolutionary selection pressure to prevent spider toxins acting on vertebrate ion channels. It is therefore not surprising that many spider-venom peptides have been found to modulate the activity of vertebrate Na V channels 33,70,83 . rings of amino acid residues that form the ion-selectivity filter and constitute the proposed neurotoxin receptor site 1 for the water-soluble guanidinium toxins TTX and saxitoxin.…”

“…Indeed, four of the seven pharmacological sites on vertebrate Na V channels are defined by the binding of mollusk or arachnid toxins. Na V channel modulation is one of the major pharmacologies of spider venoms 69,70 and the spider toxins responsible have proved to be valuable tools for understanding the structure and function of Na V channels 33,71 .…”