Spider Neurotoxins Targeting Voltage-Gated Sodium Channels

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 in 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 conserved structures 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 mentioned areas remains underdeveloped.