{{Short description|Group of neurotoxins}} {{missing information|genetic and architectural classification (ConoServer and PMC4278219)|date=April 2019}} {{Infobox protein family | Symbol = Toxin_8 | Name = Alpha conotoxin precursor | image = alpha-Conotoxin from Conus pennaceus 1AKG.png | width = | caption = α-Conotoxin PnIB from ''C. pennaceus'', disulfide bonds shown in yellow. From the University of Michigan's Orientations of Proteins in Membranes database, {{PDB|1AKG}}. | Pfam= PF07365 | InterPro= IPR009958 | SMART= | PROSITE = PDOC60004 | SCOP = 1mii | TCDB = | OPM family = 148 | OPM protein = 1akg | PDB = }} {{Infobox protein family | Symbol = Conotoxin | Name = Omega conotoxin | image =Ziconotide 1DW5.png | width = | caption =Schematic diagram of the three-dimensional structure of ω-conotoxin MVIIA (ziconotide). Disulfide bonds are shown in gold. From {{PDB|1DW5}}. | Pfam= PF02950 | InterPro= IPR004214 | SMART= | PROSITE = | SCOP = 2cco | TCDB = | OPM family= 112 | OPM protein= 1fyg | PDB= }} 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.<ref name="pmid14715910">{{cite journal | vauthors = Terlau H, Olivera BM | title = Conus venoms: a rich source of novel ion channel-targeted peptides | journal = Physiol. Rev. | volume = 84 | issue = 1 | pages = 41–68 | year = 2004 | pmid = 14715910 | doi = 10.1152/physrev.00020.2003 | bibcode = 2004PhyRv..84...41T }}</ref> Over the last few decades conotoxins have been the subject of pharmacological interest.<ref name="pmid17932414">{{cite journal| vauthors=Olivera BM, Teichert RW| title=Diversity of the neurotoxic Conus peptides: a model for concerted pharmacological discovery. | journal=Molecular Interventions | year= 2007 | volume= 7 | issue= 5 | pages= 251–60 | pmid=17932414 | doi=10.1124/mi.7.5.7 }}</ref>
The LD<sub>50</sub> of conotoxin ranges from 5-25 μg/kg.<ref>{{cite web |url=http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf |title=PEAC Hazard Analysis & Emergency Response Resources |access-date=2017-03-31 |url-status=live |archive-url=https://web.archive.org/web/20170829050422/http://www.aristatek.com/Newsletter/MAY08/TechSpeak.pdf |archive-date=2017-08-29 }}</ref><ref>{{cite web |title=Biological Agent Reference Sheet - Conotoxin |url=https://www.ehso.emory.edu/content-guidelines/BARS_Conotoxin.pdf |publisher=Emory University}}</ref><ref>{{cite web |last1=Baker |first1=A.L. |url=http://cfb.unh.edu/phycokey/Choices/Toxins/Toxin%20ld50s/toxin%20ld50%20list.htm |website=PhycoKey |title=toxin ld50 list}}</ref>
==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.<ref name="pmid22954218">{{cite journal | vauthors = Olivera BM, Watkins M, Bandyopadhyay P, Imperial JS, de la Cotera EP, Aguilar MB, Vera EL, Concepcion GP, Lluisma A | title = Adaptive radiation of venomous marine snail lineages and the accelerated evolution of venom peptide genes | journal = Ann. N. Y. Acad. Sci. | volume = 1267 | issue = 1| pages = 61–70 |date=September 2012 | pmid = 22954218 | pmc = 3488454 | doi = 10.1111/j.1749-6632.2012.06603.x | bibcode = 2012NYASA1267...61O }}</ref> 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.<ref name="pmid22285376">{{cite journal | vauthors = Wong ES, Belov K | title = Venom evolution through gene duplications | journal = Gene | volume = 496 | issue = 1 | pages = 1–7 |date=March 2012 | pmid = 22285376 | doi = 10.1016/j.gene.2012.01.009 }}</ref> 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'').<ref name="pmid21511358">{{cite journal | vauthors = Liow LH, Van Valen L, Stenseth NC | title = Red Queen: from populations to taxa and communities | journal = Trends Ecol. Evol. | volume = 26 | issue = 7 | pages = 349–58 |date=July 2011 | pmid = 21511358 | doi = 10.1016/j.tree.2011.03.016 | bibcode = 2011TEcoE..26..349L }}</ref>
==Disulfide connectivity== Types of conotoxins also differ in the number and pattern of disulfide bonds.<ref name="PUB00016617">{{cite journal |vauthors=Jones RM, McIntosh JM |title=Cone venom--from accidental stings to deliberate injection |journal=Toxicon |volume=39 |issue=10 |pages=1447–1451 |year=2001 |pmid=11478951 |doi=10.1016/S0041-0101(01)00145-3|bibcode=2001Txcn...39.1447M }}</ref> The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.<ref name="PUB00016622">{{cite journal |vauthors=Sato K, Kini RM, Gopalakrishnakone P, Balaji RA, Ohtake A, Seow KT, Bay BH |title=lambda-conotoxins, a new family of conotoxins with unique disulfide pattern and protein folding. Isolation and characterization from the venom of Conus marmoreus |journal=J. Biol. Chem. |volume=275 |issue=50 |pages=39516–39522 |year=2000 |pmid=10988292 |doi=10.1074/jbc.M006354200|doi-access=free }}</ref>
==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.<ref name="pmid15182346">{{cite journal | vauthors = Nicke A, Wonnacott S, Lewis RJ | title = Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes | journal = Eur. J. Biochem. | volume = 271 | issue = 12 | pages = 2305–2319 | year = 2004 | pmid = 15182346 | doi = 10.1111/j.1432-1033.2004.04145.x | doi-access = free }}</ref> * δ-conotoxin inhibits fast inactivation of voltage-dependent sodium channels.<ref name="pmid15990094">{{cite journal | vauthors = Leipold E, Hansel A, Olivera BM, Terlau H, Heinemann SH | title = Molecular interaction of delta-conotoxins with voltage-gated sodium channels | journal = FEBS Lett. | volume = 579 | issue = 18 | pages = 3881–3884 | year = 2005 | pmid = 15990094 | doi = 10.1016/j.febslet.2005.05.077 | doi-access = free | bibcode = 2005FEBSL.579.3881L }}</ref> * κ-conotoxin inhibits potassium channels.<ref name="pmid9417043">{{cite journal | vauthors = Shon KJ, Stocker M, Terlau H, Stühmer W, Jacobsen R, Walker C, Grilley M, Watkins M, Hillyard DR, Gray WR, Olivera BM | title = kappa-Conotoxin PVIIA is a peptide inhibiting the shaker K+ channel | journal = J. Biol. Chem. | volume = 273 | issue = 1 | pages = 33–38 | year = 1998 | pmid = 9417043 | doi = 10.1074/jbc.273.1.33 | doi-access = free }}</ref> * μ-conotoxin inhibits voltage-dependent sodium channels in muscles.<ref name="pmid15246758">{{cite journal | vauthors = Li RA, Tomaselli GF | title = Using the deadly mu-conotoxins as probes of voltage-gated sodium channels | journal = Toxicon | volume = 44 | issue = 2 | pages = 117–122 | year = 2004 | pmid = 15246758 | doi = 10.1016/j.toxicon.2004.03.028 | pmc = 2698010 | bibcode = 2004Txcn...44..117L }}</ref> * ω-conotoxin inhibits N-type voltage-dependent calcium channels.<ref name="pmid10822250">{{cite journal | vauthors = Nielsen KJ, Schroeder T, Lewis R | title = Structure-activity relationships of omega-conotoxins at N-type voltage-sensitive calcium channels | journal = J. Mol. Recognit. | volume = 13 | issue = 2 | pages = 55–70 | year = 2000 | pmid = 10822250 | doi = 10.1002/(SICI)1099-1352(200003/04)13:2<55::AID-JMR488>3.0.CO;2-O| url = http://www3.interscience.wiley.com/cgi-bin/abstract/72502378/ABSTRACT | archive-url = https://archive.today/20110813050839/http://www3.interscience.wiley.com/cgi-bin/abstract/72502378/ABSTRACT | url-status = dead | archive-date = 2011-08-13 | format = abstract| url-access = subscription }}</ref> 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.<ref name="pmid9792182">{{cite journal | vauthors = Bowersox SS, Luther R | title = Pharmacotherapeutic potential of omega-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus | journal = Toxicon | volume = 36 | issue = 11 | pages = 1651–1658 | year = 1998 | pmid = 9792182 | doi = 10.1016/S0041-0101(98)00158-5 | bibcode = 1998Txcn...36.1651B }}</ref> Therefore, a synthetic version of ω-conotoxin M VII A has found application as an analgesic drug ziconotide (Prialt).<ref name="pmid16845440">{{cite journal | author = Prommer E | title = Ziconotide: a new option for refractory pain | journal = Drugs Today | volume = 42 | issue = 6 | pages = 369–78 | year = 2006 | pmid = 16845440 | doi = 10.1358/dot.2006.42.6.973534 }}</ref>
=== Characterization === Considering conotoxins have become an area of interest for pharmaceutical leads, there has been an increased drive to characterize newly founded conotoxins.<ref name=":4">{{Cite journal |last1=Robinson |first1=Samuel D. |last2=Norton |first2=Raymond S. |date=2014-12-17 |title=Conotoxin gene superfamilies |journal=Marine Drugs |volume=12 |issue=12 |pages=6058–6101 |doi=10.3390/md12126058 |doi-access=free |issn=1660-3397 |pmc=4278219 |pmid=25522317}}</ref> There are 3 ways: gene superfamily, cysteine framework, and pharmaceutical family.<ref name=":4" /> Much of the research on them before was focused on isolating the venom directly, which works for classifying the conotoxins for pharmacological family and cysteine framework.<ref name=":4" /> Pharmacological family classification is based on the receptor target and interaction of the conotoxin while the cysteine residues are the primary structure, which 26 main frameworks have been found as of present<ref name=":4" />.
===Alpha- Super Family=== Alpha conotoxins have two types of cysteine arrangements,<ref name="PUB00017022">{{cite journal |vauthors=Gray WR, Olivera BM, Zafaralla GC, Ramilo CA, Yoshikami D, Nadasdi L, Hammerland LG, Kristipati R, Ramachandran J, Miljanich G |year=1992 |title=Novel alpha- and omega-conotoxins from Conus striatus venom |journal=Biochemistry |volume=31 |issue=41 |pages=11864–11873 |doi=10.1021/bi00156a009 |pmid=1390774}}</ref> 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.<ref name=":4" />. This is a part of a diverse group of conotoxins which share a single peptide sequence and have a type 1 cysteine framework which tend to target an array of neuromuscular subtypes.<ref name=":4" />.
==== α-conotoxin PnIB ==== A conotoxin which consists of 16 residual peptides isolated from the molluscivorous snail ''Conus pennaceus<ref name=":0">{{Cite journal |last1=Hu |first1=Shu-Hong |last2=Gehrmann |first2=John |last3=Alewood |first3=Paul F. |last4=Craik |first4=David J. |last5=Martin |first5=Jennifer L. |date=1997-09-01 |title=Crystal Structure at 1.1 Å Resolution of α-Conotoxin PnIB: Comparison with α-Conotoxins PnIA and GI |url=https://pubs.acs.org/doi/10.1021/bi9713052 |journal=Biochemistry |language=en |volume=36 |issue=38 |pages=11323–11330 |doi=10.1021/bi9713052 |pmid=9298951 |issn=0006-2960}}</ref>. a-conotoxin PnIA inhibits neuronal nicotinic acetylcholine receptor (nAChR) with two disulfide bonds<ref name=":0" />'''<ref name=":1">{{Cite journal |last1=Hogg |first1=Ron C. |last2=Miranda |first2=Les P. |last3=Craik |first3=David J. |last4=Lewis |first4=Richard J. |last5=Alewood |first5=Paul F. |last6=Adams |first6=David J. |date=December 1999 |title=Single Amino Acid Substitutions in α-Conotoxin PnIA Shift Selectivity for Subtypes of the Mammalian Neuronal Nicotinic Acetylcholine Receptor |journal=Journal of Biological Chemistry |language=en |volume=274 |issue=51 |pages=36559–36564 |doi=10.1074/jbc.274.51.36559 |doi-access=free |pmid=10593955 }}</ref>.'''''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<ref>{{Cite journal |last=Olivera |first=Baldomero M. |date=November 2002 |title=Conus Venom Peptides: Reflections from the Biology of Clades and Species |url=https://www.annualreviews.org/doi/10.1146/annurev.ecolsys.33.010802.150424 |journal=Annual Review of Ecology and Systematics |language=en |volume=33 |issue=1 |pages=25–47 |doi=10.1146/annurev.ecolsys.33.010802.150424 |bibcode=2002AnRES..33...25O |issn=0066-4162}}</ref>.
=== B-Conotoxin Superfamily === Conantokin-G, also known as the sleeper peptide, was isolated from the venom of ''Conus geographus''<ref name=":4" />. It has the ability to induce a sleep like phenomenon and was the first conotoxin to not have any cysteine residues, which is unusual because this is one of the key characteristics of conotoxin classification.
===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.<ref name="PUB00016617" />{{Infobox protein family | Symbol = Mu-conotoxin | Name = Mu-conotoxin | image = PDB 1r9i EBI.jpg | width = | caption = nmr solution structure of piiia toxin, nmr, 20 structures | Pfam = PF05374 | Pfam_clan = CL0083 | InterPro = IPR008036 | SMART = | PROSITE = | MEROPS = | SCOP = 1gib | TCDB = | OPM family = 112 | OPM protein = 1ag7 | CAZy = | CDD = }} ===Mu=== Mu-conotoxins have two types of cysteine arrangements, but the knottin scaffold is not observed.<ref name="pmid12006587">{{cite journal | vauthors = Nielsen KJ, Watson M, Adams DJ, Hammarström AK, Gage PW, Hill JM, Craik DJ, Thomas L, Adams D, Alewood PF, Lewis RJ | title= Solution structure of mu-conotoxin PIIIA, a preferential inhibitor of persistent tetrodotoxin-sensitive sodium channels| journal = J. Biol. Chem. | volume = 277 | issue = 30 | pages = 27247–55 |date=July 2002 | pmid = 12006587 | doi = 10.1074/jbc.M201611200 | url = https://researchonline.jcu.edu.au/266/1/thomas_1.pdf| doi-access = free }}</ref> Mu-conotoxins target the muscle-specific voltage-gated sodium channels,<ref name="PUB00016617" /> and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.<ref name="pmid12006587" /><ref name="PUB00017021">{{cite journal |vauthors=Zeikus RD, Gray WR, Cruz LJ, Olivera BM, Kerr L, Moczydlowski E, Yoshikami D |title=Conus geographus toxins that discriminate between neuronal and muscle sodium channels |journal=J. Biol. Chem. |volume=260 |issue=16 |pages=9280–8 |year=1985 |doi=10.1016/S0021-9258(17)39364-X |pmid=2410412|doi-access=free }}</ref> Mu-conotoxins target the voltage-gated sodium channels, preferentially those of skeletal muscle,<ref name="PUB00016617" /> and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.<ref name="pmid2410412">{{cite journal | vauthors = Cruz LJ, Gray WR, Olivera BM, Zeikus RD, Kerr L, Yoshikami D, Moczydlowski E | title = Conus geographus toxins that discriminate between neuronal and muscle sodium channels | journal = J. Biol. Chem. | volume = 260 | issue = 16 | pages = 9280–8 |date=August 1985 | doi = 10.1016/S0021-9258(17)39364-X | pmid = 2410412 | doi-access = free }}</ref>
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.<ref name="pmid12878039">{{cite journal| author=Floresca CZ| title=A comparison of the mu-conotoxins by [3H]saxitoxin binding assays in neuronal and skeletal muscle sodium channel. | journal=Toxicol Appl Pharmacol | year= 2003 | volume= 190 | issue= 2 | pages= 95–101 | pmid=12878039 | doi= 10.1016/s0041-008x(03)00153-4}}</ref>
=== 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<ref name=":5">{{Cite web |title=ConoServer |url=https://www.conoserver.org/ |access-date=2026-04-28 |website=www.conoserver.org}}</ref>. 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<ref name=":5" />. To help understand conotoxins further, the database provides statistics about relationships between conopeptide classifications, the sequence between signal peptides and the super family, the number of entries for each of the snail species studied<ref name=":5" />.
==== Genus Conus ==== thumb|Conus geographus, a cone snail capable of producing conotoxins to stun their prey.This snail is found in reef in the Indo-pacific, along the shores of Australia. It hunts small fish by injecting prey with its proboscis<ref>{{Cite web |title=Conus geographus (geography cone snail) {{!}} INFORMATION {{!}} Animal Diversity Web |url=https://animaldiversity.org/accounts/Conus_geographus/ |access-date=2026-04-21 |website=animaldiversity.org}}</ref>. The snail hunts by injecting conotoxin through the proboscis and hollow radular tooth<ref name=":2">{{Cite web |title=Conus geographus (geography cone snail) {{!}} INFORMATION {{!}} Animal Diversity Web |url=https://animaldiversity.org/accounts/Conus_geographus/ |access-date=2026-04-21 |website=animaldiversity.org}}</ref>. The venom is created in the snails venom glands where it also makes digestive enzymes<ref name=":2" />.
=== Conotoxin Effects === Divers handle cone snails without knowing their mechanisms of envenomation. The some causes of envenomation of a cone snail are paralysis, respiratory failure, and muscle pains<ref name=":3">{{Citation |last1=Kapil |first1=Sasha |title=Cone Snail Toxicity |date=2026 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK470586/ |access-date=2026-04-21 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=29262115 |last2=Hendriksen |first2=Stephen |last3=Cooper |first3=Jeffrey S.}}</ref>. At the envenomation site there could be numbness, ischemia, cyanosis, and necrosis in either localized or entire regions of the body<ref name=":3" /> Due to the complexity and multitude of conotoxins that block different pathways, little progress has been made to make an anti-venom <ref name=":3" />.
=== Treatment === Intervention for a cone snail envenomation involves seeking care at a hospital to ensure the patient's airway and circulation is working properly. Methods like pressure immobilization could prevent venom from spreading into other areas of the body to prevent further injury. <ref name=":3" />
=== Other applications === Considering conotoxins affect so many ion channels, they are currently being explored to provide pain relief for intractable pain<ref name=":3" />.
==See also== * Conolidine * Contryphan, members of "conotoxin O2" * Conantokins, also known as "conotoxin B"
==References== {{InterPro content|IPR004214|IPR008036}} {{reflist|30em}} ==External links== * {{MeshName|Conotoxins}} * {{cite web|url=https://www.ibiology.org/archive/conus-peptides/|title=Conus Peptides|author=Baldomero "Toto" Olivera's Short Talk}} * {{cite web | url = http://www.conoserver.org/ | title = ConoServer | vauthors = Kaas Q, Westermann JC, Halai R, Wang CK, Craik DJ | publisher = Institute of Molecular Bioscience, The University of Queensland, Australia| quote = A database for conopeptide sequences and structures| access-date = 2009-06-02}}
{{Protein tertiary structure}} {{Toxins}} {{Ion channel modulators}} {{Nicotinic acetylcholine receptor modulators}}
Category:Snail toxins Category:Ion channel toxins Category:Neurotoxins Category:Nicotinic antagonists Category:Peripheral membrane proteins Category:Cysteine-rich proteins