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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.[1]
Over the last few decades conotoxins have been the subject of pharmacological interest.[2]
The LD50 of conotoxin ranges from 5-25 μg/kg.[3][4][5]
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.[6] 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.[7] 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).[8]
Disulfide connectivities
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]
Types and biological activities
As of 2005, five biologically active conotoxins have been identified. Each of the five conotoxins attacks a different target:
ω-conotoxin inhibits N-type voltage-dependent calcium channels.[15] 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.[16] Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).[17]
Alpha
Alpha conotoxins have two types of cysteine arrangements,[18] and are competitive nicotinic acetylcholine receptor antagonists.
Delta, kappa, and omega
Omega, delta and kappa families of conotoxins have a knottin or inhibitor 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
Protein family
Mu-conotoxin
nmr solution structure of piiia toxin, nmr, 20 structures
Mu-conotoxins have two types of cysteine arrangements, but the knottin 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-gated sodium channels, preferentially those of skeletal muscle,[9] and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.[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.
^"Archived copy"(PDF). Archived(PDF) from the original on 2017-08-29. Retrieved 2017-03-31.{{cite web}}: CS1 maint: archived copy as title (link)
^Bowersox SS, Luther R (1998). "Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus". Toxicon. 36 (11): 1651–1658. Bibcode:1998Txcn...36.1651B. doi:10.1016/S0041-0101(98)00158-5. PMID9792182.
^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. Retrieved 2009-06-02. A database for conopeptide sequences and structures
