A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.
Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Conotoxins have a variety of mechanisms of actions, most of which have not been determined. However, it appears that many of these peptides modulate the activity of ion channels.
Over the last few decades conotoxins have been the subject of pharmacological interest.
The LD<sub>50</sub> of conotoxin ranges from 5-25 μg/kg.
Hypervariability
Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced (endogenously) but act on other organisms. Therefore, conotoxin genes experience less selection against mutations (like gene duplication and nonsynonymous substitution), and mutations remain in the genome longer, allowing more time for potentially beneficial novel functions to arise. Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus cone snails are under constant selective pressure to maintain polymorphism in these genes because failing to evolve and adapt will lead to extinction (Red Queen hypothesis).
Disulfide connectivity
Types of conotoxins also differ in the number and pattern of disulfide bonds. The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.
Types and biological activities
As of 2005, five biologically active conotoxins have been identified. Each of the five conotoxins attacks a different target:
- α-conotoxin inhibits nicotinic acetylcholine receptors at nerves and muscles.
- δ-conotoxin inhibits fast inactivation of voltage-dependent sodium channels.
- κ-conotoxin inhibits potassium channels.
- μ-conotoxin inhibits voltage-dependent sodium channels in muscles.
- ω-conotoxin inhibits N-type voltage-dependent calcium channels. Because N-type voltage-dependent calcium channels are related to algesia (sensitivity to pain) in the nervous system, ω-conotoxin has an analgesic effect: the effect of ω-conotoxin M VII A is 100 to 1000 times that of morphine. Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).
Characterization
Considering conotoxins have become an area of interest for pharmaceutical leads, there has been an increased drive to characterize newly founded conotoxins. There are 3 ways: gene superfamily, cysteine framework, and pharmaceutical family. and are competitive nicotinic acetylcholine receptor antagonists. Alpha-GI is a peptide of 13 amino acids with two disulfide bonds which is a nicotinic-acetylcholine receptor antagonist that inhibits neuromuscular transmission.. a-conotoxin PnIA inhibits neuronal nicotinic acetylcholine receptor (nAChR) with two disulfide bonds.It is present in the mixture of neuro toxins produced in the venom duct and injected into prey via the radular tooth connected to the venom bulb.
B-Conotoxin Superfamily
Conantokin-G, also known as the sleeper peptide, was isolated from the venom of Conus geographus Mu-conotoxins target the muscle-specific voltage-gated sodium channels, Mu-conotoxins target the voltage-gated sodium channels, preferentially those of skeletal muscle,
Different subtypes of voltage-gated sodium channels are found in different tissues in mammals, e.g., in muscle and brain, and studies have been carried out to determine the sensitivity and specificity of the mu-conotoxins for the different isoforms.
ConoServer
A database that has the structures and sequences of peptides expressed in conopeptides, also known as conotoxins. Considering conotoxins target human ion channels the three classifications that ConoServer uses are the gene super families, cystine frameworks, and the pharmacological families. The database also has information about post-translational modifications considering conotoxins are extremely post-translationally modified, the server has both naturally and artificially introduced modifications. The snail hunts by injecting conotoxin through the proboscis and hollow radular tooth. The venom is created in the snails venom glands where it also makes digestive enzymes. At the envenomation site there could be numbness, ischemia, cyanosis, and necrosis in either localized or entire regions of the body