Conantokins are a small family of helical

peptides Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Dalton (unit), Da or more are called proteins. Chains of fewer t ...

that are derived from the venom of predatory marine snails of the genus ''

Conus ''Conus'' is a genus of venomous and predatory cone snails.Bouchet, P.; Gofas, S. (2015). Conus Linnaeus, 1758. In: MolluscaBase (2015). Accessed through: World Register of Marine Species at http://www.marinespecies.org/aphia.php?p=taxdetails&i ...

''. Conantokins act as potent and specific

antagonists An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.N-methyl-D-aspartate receptor (NMDAR). They are the only naturally-derived peptides to do so. The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes. Chemically, conantokins are unique in that they possess a number (generally 4 or 5) of gamma-carboxyglutamyl (Gla) residues, generated by the

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

of glutamyl (Glu) residues. These Gla residues induce a conformational change from a 3 10 helix to an alpha helix on binding to Calcium. In the broader scheme of genetic

conotoxin 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. C ...

classification, Conanotokins are also known as "Conotoxin Superfamily B." The word "conantokin" is derived from the Filipino word ''antokin'', meaning sleepy.

Subtypes

Conantokin are in general named after the

specific epithet In Taxonomy (biology), taxonomy, binomial nomenclature ("two-term naming system"), also called binary nomenclature, is a formal system of naming species of living things by giving each a name composed of two parts, both of which use Latin gramm ...

of the ''Conus'' species it is found in, using single-letter abbreviations if possible. A conantokin from ''Conus radiatus'' is called Conantokin-R, but the latter-discovered ones from ''Conus rolani'' are called Conantokin-Rl. If a species makes multiple conantokins, numbers or letters are suffixed to the names. The abbreviation for "Conantokin" in these names is always "Con".

Conantokin-G

Also known as the “sleeper peptide” or CGX-1007, Con-G () is a small

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

isolated from the fish-hunting snail, '' Conus geographus''. It is the best-characterized conantokin, and acts as a functional inhibitor of NMDAR. Con-G shows potential as a neuroprotective agent in

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems ...

and excitotoxic brain injury, neuronal

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

, pain,

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

, and as a research tool in

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

and

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

. Con-G blocks NMDAR-mediated excitatory postsynaptic currents (EPSCs). Con-G reduces the strength of excitotoxic intracellular Ca²⁺ actions and blocks different neuronal injuries in vitro. In certain injuries Con-G shows an exceptional prolongation of the therapeutic window. Con-G can reverse established allodynia and can also fully reverse thermal hypersensitivity induced by nerve injury.

Conantokin-T

Con-T () is purified from the venom of the fish-hunting cone-snail, '' Conus tulipa''. This peptide has 4 residues of Gla. Con-T acts by inhibiting NMDAR-mediated Ca²⁺ influx in neurons in the central nervous system.

Conantokin-R and -L

Con-R () is a highly potent

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

compound, derived from '' Conus radiatus''. Con-L () is an efficient anticonvulsant compound, derived from '' Conus lynceus''. It differs from Con-R mainly in the C-terminal amino acids and, like Con-R, it induces sleep-like symptoms in young mice, with faster onset and for a longer duration. Con-L blocks NMDA-evoked currents in a powerful way, which is only slowly reversible upon washout, similar to Con-R and Con-G.

Conantokin-Pr1, -Pr2 and –Pr3

Each peptide in this group is derived from the same species, '' Conus parius''. Con-Pr3 () has three different post-translational modifications. Con-Pr1 () and –Pr2 () adopt α-helical conformations in the presence of Mg²⁺ and Ca²⁺, but otherwise are generally unstructured. Conantokin-Pr3 always adopts an α-helical conformation. These peptides have highest potency for the NR2B subunits of the NMDAR.

Conantokin-P and -E

Con-P () and Con-E () were isolated from the only two fish-hunting cone snails of the Americas ('' Conus purpurascens'' and '' Conus ermineus'', respectively). Con-P differs from the other known conantokins in that it contains a long

disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

loop with two Gla residues. It is less helical (estimated 44% helical content), but unlike con-G, it does not require calcium for stability of this structure. Another notable distinction is the increased discrimination for NR2B. Con-E is very similar in structure to Con-P, and is likely to have a similar function.

Conantokin-Rl-A

Con-Rl-A (), derived from the venom of '' Conus rolani'', is unique among the conantokins in having two distinct conformational states between which it equilibrates. Like Con-P and Con-E, its helical structure (estimated at 50%) does not depend on the presence or absence of calcium. This is likely due to the fact that two of the five Gla residues present in con-G are replaced in con-Rl-A by Lys. Con-R1-A discriminates more effectively than any other known ligand between the NR2B and NR2C subunits of NMDAR.

Conantokin-Br or -S1

Con-Br (or Con-S1, ) is isolated from ''Conus brettinghami'' (now '' Conus sulcatus''), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR.

Synthetic derivatives

Con-G-based

Con-G �7ACon-G �7Kand Con-G 16Yare synthetic Con-G peptides, where the Gla residue at position 7 is replaced with an

alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group sid ...

or a

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

residue, or the

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

at position 16 is replaced with a

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

residue, respectively. Con-G �7Ais fourfold more potent than the native peptide, Con-G, while Con-G �7Kis as potent as Con-G. The first two peptides appear to distinguish NMDAR subtypes in mid-frontal

gyri In neuroanatomy, a gyrus (: gyri) is a ridge on the cerebral cortex. It is generally surrounded by one or more sulcus (neuroanatomy), sulci (depressions or furrows; : sulcus). Gyri and sulci create the folded appearance of the brain in huma ...

from those in superior temporal gyri in human brain tissue. Both of them are being researched in relation to Alzheimer's disease (AD) and all three evoked 100% inhibition of

spermine Spermine is a polyamine involved in cellular metabolism that is found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is an essential growth factor in some bacteria as well. It is found as a p ...

-enhanced sup>3HK-801 binding. Con-G �7Kand Con-G 16Yalso show positive results in morphine withdrawal.

Con-T-based

Con-T 7γis a synthetic Con-T peptide, where the serine at position 7 is replaced with Gla residue. Like Con-G, it has higher affinity for Mg²⁺ than for Ca²⁺, but does not

dimerize In chemistry, dimerization is the process of joining two identical or similar Molecular entity, molecular entities by Chemical bond, bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dim ...

in the presence of Mg²⁺.

Chemistry

Biochemically, conantokins have a distinctive high γ- carboxyglutamate content and low

cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...

content. Conantokins typically lack

disulfide bond In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inor ...

s, in contrast to most families of conotoxins, which have an unusually high density of disulfide cross-links. The inhibition of NMDAR-mediated spontaneous EPSCs (sEPSCs) and NMDA-gated currents in cortical neurons might be a result of actions on both diheteromeric (NR1/NR2B) and triheteromeric ( NR1/ NR2A/ NR2B) NMDAR.

Mode of action

Con-G does not act directly at the glycine binding site. It can attenuate both the amplitude and the decay time constant of NMDA-mediated EPSCs and significantly and reversibly affect other different properties of NMDAR-mediated sEPSCs in cultured neurons. The effect of Con-G on the frequency of the sEPSCs most likely relates to antagonizing the NMDAR.

Target

Conantokins target NMDAR. Each subtype selectively targets different subunits of the receptor.

Toxicity

Some of these peptide effects are age-dependent, such as the induction of sleep-like state in young mice and hyperactive behavior in older mice. Intrathecal administration of doses greater than 300 pmol produced motor impairment in mice.
Con-G, Con-R and Con-L cause behavioral toxicity at similar doses. Thus the difference in the C-terminal sequence might affect the anticonvulsant and behavioral toxicity profile.

References

External links

* *
Uniprot family: "conotoxin b superfamily"
- List of curated Conantokins in UniProt {{Ionotropic glutamate receptor modulators Ion channel toxins Neurotoxins Snail toxins NMDA receptor antagonists