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. 1997 Nov;8(11):2101-9.
doi: 10.1091/mbc.8.11.2101.

E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology

B M Olivera  1
Affiliations
Free PMC article

E.E. Just Lecture, 1996. Conus venom peptides, receptor and ion channel targets, and drug design: 50 million years of neuropharmacology

B M Olivera. Mol Biol Cell. 1997 Nov.
Free PMC article
No abstract available

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Figures

Figure 1
Figure 1
Ten different cone snails. Shown are the shells of ten Conus species including, top row: the cloth-of-gold cone, Conus textile; the cone of the magi, Conus magus. Second row, left to right: the circumcision cone, Conus circumcisus; the geography cone, Conus geographus; Dusavel’s cone, Conus dusaveli. Third row, left to right: the glory-of-the-sea cone, Conus gloriamaris, the glory-of-India cone, Conus milneedwardsi. Bottom row, left to right: the admiral cone, Conus ammiralis; the banded marble cone, Conus bandanus vidua; Hirasei’s cone, Conus hirasei. The geography cone, C. geographus is responsible for the majority of human fatalities. This species, along with C. magus, C. circumcisus, and C. dusaveli, are all likely to be fish hunting. The other Conus shown all hunt other gastropod molluscs, except for C. hirasei, which is probably a vermivorous species, although its biology has not been studied.
Figure 2
Figure 2
The venom apparatus and harpoon-like tooth of Conus purpurascens. Upper panel, a representation of the venom apparatus of C. purpurascens. The venom apparatus in all cone snails comprises: vb, a venom bulb which pushes the venom out; vd, the venom duct where the venom is actually made and stored; rs, a radula sac where the harpoon-like teeth are stored; h, harpoon-like teeth; p, pharynx; pr, proboscis, which is used to deliver the harpoon and venom to the prey. The radula sac has been shown in cross-section, to make the harpoons visible. Each harpoon is used only once; in the radula sac they are found in various stages of assembly. Lower panel, a close-up electron micrograph of a single harpoon-like tooth. Venom is ejected through the tooth.
Figure 3
Figure 3
A cartoon representing the hook-and-line (top panel) and the net strategy (bottom panel) of fish-hunting cone snails. Conus striatus, magus, and purpurascens are examples of hook-and-line piscivores. Species such as Conus tulipa and Conus geographus use a net strategy.
Figure 4
Figure 4
Mechanism of blocking neuromuscular transmission. The “motor cabal” of toxins (see text) targets multiple components in the neuromuscular circuit (top panel). Three different toxins (ω-, α- and μ-conotoxins) act on three different target components: 1) presynaptic Ca2+ channels; 2) nicotinic acetylcholine receptors; and 3) voltage-gated skeletal muscle Na+ channels. Bottom panel, synergy in Conus venoms is achieved both by inhibiting multiple components as well as multiple sites in a single macromolecular component. Two unrelated toxins (α- and Ψ-conotoxins) inhibit one receptor, the postsynaptic nicotinic acetylcholine receptor at different sites.
Figure 5
Figure 5
Diverse structures of peptides from different cone snails which inhibit the nicotinic acetylcholine receptor at the postsynaptic terminus of the neuromuscular junction. The first four compounds [α-Gi (Gray et al., 1981); α-Ei (Martinez et al., 1995); α-Sii (Ramilo et al., 1992); αA-Piva (Hopkins et al., 1995)] are all competitive antagonists of the receptor. The fifth peptide, Ψ-piiie (Shon et al., 1997a) acts at a different site on the receptor complex and is a noncompetitive antagonist. Note the lack of sequence similarity between all of these peptides which are all produced in the venom ducts of fish-hunting Conus species.  ^, free C-terminus; #, amidated e-terminus; O, hydroxyproline.
Figure 6
Figure 6
A comparison of the precursor sequences of two ω-conotoxins, Gvia (top sequence) and Mviia (bottom sequence) from Conus geographus and Conus magus, respectively. Both of these toxins block the N-type voltage-gated calcium channel and compete with each other for binding. The entire precursor sequence is shown. The red amino acids comprise the signal sequence, whereas the solid arrow indicates the proteolytic site which generates the mature toxin. The mature toxin region is shown in capital letters, and the cysteine residues involved in disulfide bonding are shown bold. All loci where the two sequences differ are indicated by asterisks. It is notable that although the signal sequences are entirely identical, the vast majority of the non-Cys amino acids of mature ω-conotoxin Gvia are different from the corresponding ω-conotoxin Mviia residues; in contrast, the Cys residues in this region are completely conserved.
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References

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