Conus

Conotoxins are the venoms of the marine cone snails. The >500 Conus species produce >10,000 different toxins. All are cysteine-rich peptides of 10-30 amino... 

Certain occluders also discriminate among Na channels from neuronal and skeletal muscle. But in this case the blocking ligands are small peptides, the x-conotoxins from the mollusc Conus geo aphus. This molecule binds tightly to muscle Na channels, effectively reducing Na current (55 see Figure 6A), and also can displace bound... 

Figure 15. Data from single channel experiments, plotted to show the relationship between kinetic and equilibrium parameters for several of the saxitoxins, tetrodotoxin, and Conus geographus toxin GIIIA. Compound numbering corresponds to that in Figure 1. The vertical axis is and the horizontal axis is dwell time, the reciprocal of k j. The dissociation constant, the ratio of k jj/k, therefore corresponds to distance along the diagonal. Data primarily from Ref. 95.

Several hundred species of Conus snails produce a wide array of small (12-30 AA) and mostly tightly disulfide bonded peptide ligands with high affinity for a diverse set of receptor and ion channel types. 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

It is not our intention to present a comprehensive review of the work on Conus toxins here the reader is referred to recent articles already in the literature (1-5). We have focused largely on fish-hunting Conus toxins, particularly the w-... 

The cx)ne snails are predatory, venomous molluscs which use a common general strategy to capture prey (i, 5-7). All 300-500 species of Conus have a specialized venom apparatus, diagrammed in Figure 1 (8). A venom paralytic to the prey is produced in a venom duct and injected through a disposable, harpoon-like tooth (Figure 2). Paralysis of the prey can be remarkably rapid in the case of certain piscivorous cone species, the fish prey is immobilized in less than one second. 

Conus Species Feeding lypes, Taxonomic Considerations... 

Figure 1. Diagram of the venom duct of Conus. The venom is produced in the venom duct, apparently expelled from the duct into the proboscis by contraction of the venom bulb. Simultaneously, a harpoon-like tooth is transferred from the radula sac to the proboscis. When injection takes place, the venom is pushed through the hollow tooth and flows into the prey through a hole at the tip of the tooth. Typically, fish-hunting cones will strike at a fish only once and grasp the tooth after injection has occurred, effectively harpooning their prey while injecting the paralytic venom. In contrast, snail-hunting cones will usually sting their prey several times before total paralysis occurs. (Reprinted with permission from the Second Revised Edition of Ref. 8. Copyright 1988 Darwin Press, Inc.)...

Figure 2. The harpoon-like tooth of Conus, a. An unusual photograph of a radular tooth at the tip of the proboscis of Conus pur-purascens. Normally, the tooth would not be ejected from the proboscis until the prey had been harpooned. Photograph by Alex Ker-stitch. b. A scanning electron micrograph of the tip of the radular tooth of Conus purpurascens, showing its harpoon-like form.

Figure 4. Worm-hunting and snail-hunting Conus, (a) The ver-mivorous species Conus brunneus about to sting its polychaete worm prey, (b) The molluscivorous species Conus dalli stinging the snail prey, Columhella. Both Conus species were collected in the Gulf of California. Photographs by Alex Kerstitch.

Conus. Thus, Figure 6c shows a group of fish-hunting cones, the Conus magus-striatus group. Other piscivorous species such as Conus geographus are less closely related to the species shown in Figure 6c. 

Between 6 and 10 homologous peptides have been extensively characterized for each toxin class. Although uj- and a-conotoxins have been isolated from several fish-hunting Conus species, x-conotoxins have so far been isolated only from C. geographus venom. 

Like the other paralytic toxins from Conus venom, a-conotoxins are small and very tightly folded, structural features which may be advantageous for rapid paralysis of prey (1). a-Conotoxins are typically 13 to 15 amino acids long with two disulfide bridges (see Table III). In addition to the five a-conotoxins shown, two new a-conotoxins (SIA and SIB) from C. striatus have recently been isolated, sequenced, and chemically synthesized. SIA is very unusual because it is 19 amino acid residues long and it contains 6 cysteine residues, three of which are contiguous near the amino terminus (C. Ramilo et al., unpublished results). 

The a -, /z-, and a-conotoxins are the best characterized of the peptides isolated from Conus venoms so far. However, a large number of other peptides are found in these venoms. These comprise both paralytic toxins to immobilize the prey of the cone snail, and other biologically active peptides which are not themselves directly paralytic. Only the briefest overview of these peptide components will be presented here. 

In the fish-hunting cone snail venoms, a- and w-conotoxins are ubiquitously distributed. As noted above, z-conotoxins have only been found in one species. Conus geographus. In addition to these three well-characterized classes, however, a fourth class of paralytic conotoxins has been found. In contrast to the a-, z-, and... 

Another potentially paralytic conotoxin was recently described this was a peptide purified from Conus geographus venom, which like / -conotoxin appeared to target to voltage-sensitive Na channels. However, the structure of "conotoxin GS" [nomenclature of Yanagawa et al. (J7)] was less homologous to / -conotoxins than to the w-conotoxins, which are Ca channel blockers. The same peptide was purified and characterized using a different assay, the induction of highly aberrant behavior upon ic injection of mice (L. J. Cruz, unpublished data). 

A large number of other non-paralytic but biologically active peptides have been purified and sequenced. In most cases however, the detailed mechanism of action has not yet been elucidated. Clearly, Conus venoms will be a rich source of such peptides that can be used to probe various receptor targets, particularly in the central nervous system. 

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