Grant: Operating Grant

Elaborately patterned cone shells house predatory snails, which are specialized to live on unlikely seeming prey ranging from fish to other mollusks or marine worms, depending on the species of snail. Cone snails have adapted to these life styles by using a combination of stealth and venoms, which contain a deadly array of neuromuscular toxins and are injected via microscopic harpoons. Individual conotoxins target various ion channel and receptor proteins which underlie signaling in the nervous system, and trigger muscle contraction. Some toxins inhibit signaling activity while others enhance it. These conotoxins, in some cases deadly to humans, are peptides (small proteins), whose well-defined structures are keyed to bind tightly to the targeted proteins and modify their essential signaling functions. For example, members of the µ-conotoxin family (µCTXs) inhibit sodium channels that generate the impulses which convey rapid signals along nerve and muscle fibres. Recent work shows that some µCTXs (e.g. µCTX GIIIA) preferentially block the sodium channels in muscle, while others selectively inhibit the closely related, but distinct, forms of sodium channel in pain-sensing nerves (e.g. µCTX KIIIA). The proposed work will define the molecular lock-and-key structures on toxin and channel responsible for these remarkably selective actions, with the a long-term vision of developing safer, better targeted strategies to combat pain, and perhaps other hyper-excitability disorders.