This articleis missing information about genetic and architectural classification (ConoServer and PMC4278219). Please expand the article to include this information. Further details may exist on thetalk page.(April 2019)
Conotoxins, which are peptides consisting of 10 to 30amino acid residues, typically have one or moredisulfide 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 ofion channels.[1]Over the last few decades conotoxins have been the subject of pharmacological interest.[2]
TheLD50 of conotoxin ranges from 5-25 μg/kg.[3][4][5]
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.[6] Therefore, conotoxin genes experience less selection againstmutations (likegene duplication andnonsynonymous substitution), and mutations remain in the genome longer, allowing more time for potentially beneficial novel functions to arise.[7] Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thuscone snails are under constant selective pressure to maintainpolymorphism in these genes because failing to evolve and adapt will lead to extinction (Red Queen hypothesis).[8]
Types of conotoxins also differ in the number and pattern of disulfide bonds.[9] The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.[10]
ω-conotoxin inhibits N-typevoltage-dependent calcium channels.[15] Because N-type voltage-dependent calcium channels are related toalgesia (sensitivity topain) in the nervous system, ω-conotoxin has ananalgesic effect: the effect of ω-conotoxin M VII A is 100 to 1000 times that ofmorphine.[16] Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drugziconotide (Prialt).[17]
Omega, delta and kappa families of conotoxins have a knottin orinhibitor cystine knot scaffold. The knottin scaffold is a very special disulfide-through-disulfide knot, in which the III-VI disulfide bond crosses the macrocycle formed by two other disulfide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N-terminus. The cysteine arrangements are the same for omega, delta and kappa families, even though omega conotoxins are calcium channel blockers, whereas delta conotoxins delay the inactivation of sodium channels, and kappa conotoxins are potassium channel blockers.[9]
Mu-conotoxins have two types of cysteine arrangements, but theknottin scaffold is not observed.[19] Mu-conotoxins target the muscle-specific voltage-gated sodium channels,[9] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.[19][20] Mu-conotoxins target the voltage-gatedsodium channels, preferentially those ofskeletal muscle,[9] and are useful probes for investigatingvoltage-dependent sodium channels of excitabletissues.[21]
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.[22]
^Terlau H, Olivera BM (2004). "Conus venoms: a rich source of novel ion channel-targeted peptides".Physiol. Rev.84 (1):41–68.doi:10.1152/physrev.00020.2003.PMID14715910.
^Olivera BM, Teichert RW (2007). "Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery".Molecular Interventions.7 (5):251–60.doi:10.1124/mi.7.5.7.PMID17932414.
^Floresca CZ (2003). "A comparison of the mu-conotoxins by [3H]saxitoxin binding assays in neuronal and skeletal muscle sodium channel".Toxicol Appl Pharmacol.190 (2):95–101.doi:10.1016/s0041-008x(03)00153-4.PMID12878039.
Kaas Q, Westermann JC, Halai R, Wang CK, Craik DJ."ConoServer". Institute of Molecular Bioscience, The University of Queensland, Australia. Retrieved2009-06-02.A database for conopeptide sequences and structures
