Peptide Neurotoxins from Fish-Hunting Cone Snails

TLDR

Fish‑hunting cone snails secrete small, disulfide‑rich conotoxins that sequentially block presynaptic calcium entry, postsynaptic acetylcholine receptors, and muscle sodium channels, producing synergistic paralysis of their prey. The study reports five newly identified ω‑conotoxins that inhibit presynaptic voltage‑gated calcium channels. These ω‑conotoxins display differential potency across vertebrate classes and synapse types, being active at fish and amphibian peripheral synapses, ineffective on mouse targets, yet still affecting the mammalian central nervous system, highlighting their utility for probing presynaptic calcium channels.

Abstract

To paralyze their more agile prey, the venomous fish-hunting cone snails ( Conus ) have developed a potent biochemical strategy. They produce several classes of toxic peptides (conotoxins) that attack a series of successive physiological targets in the neuromuscular system of the fish. The peptides include presynaptic ω-conotoxins that prevent the voltage-activated entry of calcium into the nerve terminal and release of acetylcholine, postsynaptic α-conotoxins that inhibit the acetylcholine receptor, and muscle sodium channel inhibitors, the μ-conotoxins, which directly abolish muscle action potentials. These distinct peptide toxins share several common features: they are relatively small (13 to 29 amino acids), are highly cross-linked by disulfide bonds, and strongly basic. The fact that they inhibit sequential steps in neuromuscular transmission suggests that their action is synergistic rather than additive. Five new ω-conotoxins that block presynaptic calcium channels are described. They vary in their activity against different vertebrate classes, and also in their actions against different synapses from the same animal. There are susceptible forms of the target molecule in peripheral synapses of fish and amphibians, but those of mice are resistant. However, the mammalian central nervous system is clearly affected, and these toxins are thus of potential significance for investigating the presynaptic calcium channels.