Conotoxin

Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced ([[endogenous]]ly) but act on other organisms.{{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 }} 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.{{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 }} Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus [[cone snail]]s are under constant selective pressure to maintain [[Polymorphism (biology)|polymorphism]] in these genes because failing to evolve and adapt will lead to extinction (''[[Red Queen hypothesis]]'').{{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 }}

Conotoxins are hypervariable even within the same species. They do not act within a body where they are produced ([[endogenous]]ly) but act on other organisms.{{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 }} 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.{{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 }} Variability in conotoxin components reduces the likelihood that prey organisms will develop resistance; thus [[cone snail]]s are under constant selective pressure to maintain [[Polymorphism (biology)|polymorphism]] in these genes because failing to evolve and adapt will lead to extinction (''[[Red Queen hypothesis]]'').{{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 }}

==Disulfide connectivities==

==Disulfide connectivity==

Types of conotoxins also differ in the number and pattern of disulfide bonds.{{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 }} The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.{{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 }}

Types of conotoxins also differ in the number and pattern of disulfide bonds.{{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 }} The disulfide bonding network, as well as specific amino acids in inter-cysteine loops, provide the specificity of conotoxins.{{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 }}

Alpha conotoxins have two types of cysteine arrangements,{{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}} and are competitive nicotinic acetylcholine receptor antagonists.

Alpha conotoxins have two types of cysteine arrangements,{{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}} and are competitive nicotinic acetylcholine receptor antagonists.

=== α-conotoxin PnIB ===

==== α-conotoxin PnIB ====

A conotoxin which consists of 16 residual peptides isolated from the [[Molluscivore|molluscivorous snail]] ''[[Conus pennaceus]]{{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}}. a-conotoxin PnIA inhibits neuronal nicotonic acetylcholine receptor (nAChR) with two disulfide bonds'''{{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 }}.'''''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{{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}}. Conotoxins can be used to alleviate pain with out intense side effect and there is much evidence supporting a-conotoxins being a conotoxin of interest for its analgesic effect due to the GABABRs inhibition of Cav channels{{Cite journal |last=Munasinghe |first=Nehan R. |last2=Christie |first2=MacDonald J. |date=2015-12-10 |title=Conotoxins That Could Provide Analgesia through Voltage Gated Sodium Channel Inhibition |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC4690140/ |journal=Toxins |volume=7 |issue=12 |pages=5386–5407 |doi=10.3390/toxins7124890 |issn=2072-6651 |pmc=4690140 |pmid=26690478}}.

A conotoxin which consists of 16 residual peptides isolated from the [[Molluscivore|molluscivorous snail]] ''[[Conus pennaceus]]{{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}}. a-conotoxin PnIA inhibits neuronal nicotonic acetylcholine receptor (nAChR) with two disulfide bonds'''{{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 }}.'''''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{{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}}. Conotoxins can be used to alleviate pain with out intense side effect and there is much evidence supporting a-conotoxins being a conotoxin of interest for its analgesic effect due to the GABABRs inhibition of Cav channels{{Cite journal |last=Munasinghe |first=Nehan R. |last2=Christie |first2=MacDonald J. |date=2015-12-10 |title=Conotoxins That Could Provide Analgesia through Voltage Gated Sodium Channel Inhibition |url=https://pmc.ncbi.nlm.nih.gov/articles/PMC4690140/ |journal=Toxins |volume=7 |issue=12 |pages=5386–5407 |doi=10.3390/toxins7124890 |issn=2072-6651 |pmc=4690140 |pmid=26690478}}.

=== Genus Conus ===

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{{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}}. The snail hunts by injecting conotoxin through the proboscis and hollow radular tooth{{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}}. The venom is created in the snails venom glands where it also makes digestive enzymes>{{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>.

[[File:Conus geographus 60092276.jpg|thumb|Conus geographus, a cone snail capable of producing conotoxins to stun their prey.]]

===Delta, kappa, and omega ===

===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.

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.{{Infobox protein family

===Mu===

{{Infobox protein family

| Symbol = Mu-conotoxin

| Symbol = Mu-conotoxin

| Name = Mu-conotoxin

| Name = Mu-conotoxin

| CDD =

| CDD =

}}

}}

===Mu===

Mu-conotoxins have two types of cysteine arrangements, but the [[Trefoil knot fold|knottin scaffold]] is not observed.{{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 }} Mu-conotoxins target the muscle-specific voltage-gated sodium channels, and are useful probes for investigating voltage-dependent sodium channels of excitable tissues.{{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 }} Mu-conotoxins target the voltage-gated [[sodium]] channels, preferentially those of [[skeletal muscle]], and are useful probes for investigating [[voltage-dependent sodium channels]] of excitable [[tissue (biology)|tissue]]s.{{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 }}

Mu-conotoxins have two types of cysteine arrangements, but the [[Trefoil knot fold|knottin scaffold]] is not observed.{{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 }} Mu-conotoxins target the muscle-specific voltage-gated sodium channels, and are useful probes for investigating voltage-dependent sodium channels of excitable tissues. />{{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 }} Mu-conotoxins target the voltage-gated [[sodium]] channels, preferentially those of [[skeletal muscle]], and are useful probes for investigating [[voltage-dependent sodium channels]] of excitable [[tissue (biology)|tissue]]s.{{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 }}

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.{{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}}

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.{{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}}

=== Genus Conus ===

[[File:Conus geographus 60092276.jpg|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{{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}}. The snail hunts by injecting conotoxin through the proboscis and hollow radular tooth 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}}. The venom is created in the snails venom glands where it also makes digestive enzymesname=":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{{Citation |last=Kapil |first=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.}}. Due to the complexity and multitude of conotoxins that block different pathways, little progress has been made to make an anti-venom .

==See also==

==See also==