PHYSIOLOGICAL SYNERGISM BETWEEN CONOTOXINS

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In the last grant period, we obtained evidence that the prey-capture strategy of fish-hunting cone snails involves the use of a combination drug strategy. All fish hunting cone snails interfere with neuromuscular transmission by using multiple peptides which target important receptors and ion channels in the motor circuitry (the motor cabal). However, many fish hunting Conus species apparently also have a set of toxins in their venom which elicits excitotoxic shock in the prey, resulting in a very rapid, rigid paralysis (the lightning-strike cabal). The lightning-strike and motor cabals of two fish-hunting Conus species, Conus purpurascens and Conus magus will be analyzed in detail, and the pharmacological specificity of each Conus peptide involved will be determined. Our data suggest that individual peptides not only diverge structurally but may target different sites if two venoms are compared. We have presented preliminary evidence that fish-hunting cone snails that use a net strategy (instead of the more common hook-and-line method for catching fish) do not have the lightning-strike cabal, but instead elicit anesthetic and sedative-like effects in prey before the motor cabal acts to disrupt neuromuscular transmission. The group of peptides which generally suppress sensory systems are hypothesized to belong to the nirvana cabal, which may facilitate capture of small schools of fish by a single snail. Of exceptional interest within the nirvana cabal are the conantokins, subtype-specific NMDA receptor antagonists which have recently been shown to be potent anticonvulsants with a high protective index. Thus, the characterization of the Conus peptides which belong to the nirvana cabal may provide novel tools for suppressing the activity of the nervous system.