W-Conotoxins

In vertebrates, the spectrum of w-conotoxin targets is dependent not only on the species of animal being studied, but on the w-conotoxin being used. In chicks and frogs all synapses tested are almost completely inhibited by w-conotoxin GVIA, while in rodents, w-conotoxin GVIA does not inhibit the neuromuscular synapse, and only a fraction of CNS synapses tested are blocked. In contrast, w-conotoxin MVIIA acts much more reversibly and with a much reduced affinity for many amphibian, and some mammalian, synapses. 

In the periphery, there are no obvious biological effects from w-conotoxin when injected into an adult rodent. However, when injected into a neonatal rodent, a slow depression in respiration takes place suggesting that inhibition of some o -conotoxin binding site in the periphery may result in a dysfunction in respiratory control (J. M. McIntosh, unpublished results). 

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characterized using a different assay, the induction of highly aberrant behavior upon ic injection of mice (L. J. Cruz, unpublished data). 

The cysteine motifs in this polydnavirus gene family are structurally analogous to the cysteine motifs of the >-conotoxins. The a>-conotoxins are high-affinity ligands with different receptor specificity for voltage-sensitive ion channels (64, 65). The mature w-conotoxins have three... 

In the tail flick assay -conotoxin GVIA in combination with morphine leads to an additive effect similar to the combination of morphine with SNX-111 in the formalin test. But when -conotoxin GVIA was applied 24 h before morphine, antinociception was greatly reduced. In morphine-dependent rats, w-conotoxin GVIA given i.c.v. 15 min before naloxone challenge (2 mg/kg i.p.), significantly attenuated the withdrawal symptoms (Table 4, Basilico et al., 1992). 

The w-conotoxins, which bind to voltage-sensitive calcium channel, are perhaps the most extensively studied members of the conotoxin family and comprise a six-cysteine/four-loop framework. They are exemplified in Fig. 23 by our... 

Fig. 23. w-conotoxins MVIIA and MVIIC. The three disulfide bonds that make up the cystine-knot motif are indicated, as are the four loops in the peptide backbone. Note the small difference in the orientation of loops 2 and 4 between the two molecules. 

The uKxmotoxins have attracted much recent interest owing to their potential application in the treatment of chronic pain, exemplified by the success of w-conotoxin MVIIA (Ziconotide) in phase III clinical trials initiated by the US pharmaceutical company Neurex. Ziconotide also has potential applications in other conditions associated with regulation of calcium channels. As with all peptides, though, bioavailability considerations and possible side-effects mean that the mode of delivery needs careful consideration. In the current pain trials, an infusion pump is used for delivery of peptide direct into... 

There is a great pharmaceutical interest in w-conotoxins such as w-conotoxin MVIIA that selectively inhibit N-type calcium channels. The N-type VSCCs play integral roles in the release of neurotransmitters in the spinal cord, the inhibition of which causes attenuation of neuropathic pain response with subjects less prone to tolerance when compared to morphine. ... 

The ability of conotoxins to selectively block ion channels and neuronal receptors has led to their development into therapeutic agents. So far, most conotoxin applications as therapeutics have been concentrated on the treatment of different forms of pain. The first drug of marine origin is based on the w-conotoxin MVIIA for the treatment of chronic pain (see helow). Other therapeutic applications of conotoxins include treatment of schizophrenia, epilepsy, neuromuscular disorders, certain types of cancer, urinary dysfunction, Parkinson s disease, Alzheimer s disease, stroke, and related hrain injuries. Other uses include muscle relaxants, anesthetics, and antiseizure compounds. As the demand for new painkillers and other neuropharmacological agents is expected to increase, the value of the discovery and testing of new conotoxins is expected to continue to expand. 

Figure 2 Three-dimensional structures of the a-conotoxin El, T-superfamily conotoxins e-TxlX and x-mrIA, mini-M mr3a, w-conotoxin MVIIIA, and /i-conotoxin GIIIA. The ribbon representation of the backbone is in blue. Disulfide bridges are shown in orange.

Besides their therapeutic applications, conotoxins have exhibited great potential for the development of neurological probes. Conotoxins are currently being used in hundreds of research laboratories for a wide variety of physiological investigations. Some conotoxins have become well-established neurobiological tools. They can also be used as antagonists of specific subtypes in functional studies for example, w-conotoxin MVIIA is used as a specific N-type calcium channel blocker. Conotoxins are also utilized in research to provide information on the role and distribution of different receptor subtypes. Undoubtedly, these research applications will continue to expand. 

Sodium nitroprusside (SNP), hydrocortisone 21-hemisuccinate, desipra-mine hydrochloride, L-arginine hydrochloride, and w-conotoxin GVIA were purchased from Sigma Chemical Company (St. Louis, MO). Acid-washed alumina, sodium octyl sulfate, and catecholamine standards were purchased... 

Jones, O. T., Kunze, D. L., and Angelides, K. J. (1989) Localization and mobility of w-conotoxin-sensitive Ca+ channels in hippocampal CAl neurons. Science 244,1189. 

Cay2 channels (N-type) control the release of neurotransmitters at the presynaptic level. It selective blocker, ziconotide, a synthetic peptide analog of an w-conotoxin. 

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