Conantokins
Encyclopedia
Conantokins are a small family of helical peptides, rich in γ-carboxyglutamate
(Gla) amino acid residues. They are derived from the venom of predatory marine snails of the genus Conus
. Conantokins act as potent and specific antagonists of the 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 .
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 and excitotoxic brain injury, neuronal apoptosis
, pain, epilepsy
, and as a research tool in drug addiction and Alzheimer’s disease. 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.
. This peptide has 4 residues of Gla. Con-T acts by inhibiting NMDAR-mediated Ca2+ influx in neurons in the central nervous system.
compound, derived from Conus radiatus
.
. 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.
. 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.
and Conus ermineus
, respectively). Con-P differs from the other known conantokins in that it contains a long disulfide
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 NR2C
and NR2D
. Con-E is very similar in structure to Con-P, and is likely to have a similar function.
, is unique among the conantokins in having two distinct conformational states between which it equilibriates. 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-R1-A by Lys. Con-R1-A discriminates more effectively than any other known ligand between the NR2B and NR2C subunits of NMDAR.
), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR .
or a lysine
residue, or the serine
at position 16 is replaced with a tyrosine
residue, respectively. Con-G[γ7A] is fourfold more potent than the native peptide, Con-G, while Con-G[γ7K] is as potent as Con-G. The first two peptides appear to distinguish NMDAR subtypes in mid-frontal gyri
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
-enhanced [3H]MK-801 binding. Con-G[γ7K] and Con-G[S16Y] also show positive results in morphine withdrawal.
and lack of cysteine
residues. Conantokins typically lack disulfide bond
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.
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.
Carboxyglutamate
Carboxyglutamic acid , is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium...
(Gla) amino acid residues. They are derived from the venom of predatory marine snails of the genus Conus
Conus
Conus is a large genus of small to large predatory sea snails, marine gastropod molluscs, with the common names of cone snails, cone shells or cones. This genus is placed in the subfamily Coninae within the family Conidae. Geologically speaking, the genus is known from the Eocene to the Recent ...
. Conantokins act as potent and specific antagonists of the 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 .
Conantokin-G (Con-G)
Also known as the “sleeper peptide” or CGX-1007, Con-G is a small peptidePeptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
isolated from the fish-hunting snail, Conus geographus
Conus geographus
Cnous geographus, common name the geography cone, is a species of predatory sea snail, a marine gastropod mollusk in the family Conidae, the cone snails, cone shells or cones. Although all cone snails hunt and kill prey using venom, the venom of this species is known to be especially potent...
. It is the best-characterized conantokin, and acts as a functional inhibitor of NMDAR.
Con-G shows potential as a neuroprotective agent in ischemic and excitotoxic brain injury, neuronal apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, pain, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
, and as a research tool in drug addiction and Alzheimer’s disease. 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
Therapeutic window
The Therapeutic window of a drug is the range of drug dosages which can treat disease effectively while staying within the safety range. In other words, it is the dosages of a medication between the amount that gives an effect and the amount that gives more adverse effects than desired effects...
. Con-G can reverse established allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
and can also fully reverse thermal hypersensitivity induced by nerve injury.
Conantokin-T (Con-T)
Con-T is purified from the venom of the fish-hunting cone-snail, Conus tulipaConus tulipa
Conus tulipa is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous...
. 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 (Con-R)
Con-R is a highly potent anticonvulsantAnticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
compound, derived from Conus radiatus
Conus radiatus
Conus radiatus is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous. They are capable of "stinging" humans, therefore live ones should be handled carefully or...
.
Conantokin-L (Con-L)
Con-L is an efficient anticonvulsant compound, derived from Conus lynceusConus lynceus
Conus lynceus, common name the lynceus cone, is a species of predatory sea snail, a marine gastropod mollusk in the family Conidae, the cone snails, cone shells or cones.-Distribution:...
. 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 (Con-Pr1, Con-Pr2 and Con-Pr3)
Each peptide in this group is derived from the same species, Conus pariusConus parius
Conus parius is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous. They are capable of "stinging" humans, therefore live ones should be handled carefully or not...
. 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
GRIN2B
Glutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
subunits of the NMDAR.
Conantokin-P (Con-P) and Conantokin-E (Con-E)
Con-P and Con-E were isolated from the only two fish-hunting cone snails of the Americas (Conus purpurascensConus purpurascens
Conus purpurascens is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous. They are capable of "stinging" humans, therefore live ones should be handled carefully...
and Conus ermineus
Conus ermineus
Conus ermineus is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous...
, respectively). Con-P differs from the other known conantokins in that it contains a long disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
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 NR2C
GRIN2C
Glutamate [NMDA] receptor subunit epsilon-3 is a protein that in humans is encoded by the GRIN2C gene.-Interactions:GRIN2C has been shown to interact with DLG4 and DLG3....
and NR2D
GRIN2D
Glutamate [NMDA] receptor subunit epsilon-4 is a protein that in humans is encoded by the GRIN2D gene.-Interactions:GRIN2D has been shown to interact with Interleukin 16....
. Con-E is very similar in structure to Con-P, and is likely to have a similar function.
Conantokin-R1-A (Con-R1-A)
Con-R1-A, derived from the venom of Conus rolaniConus rolani
Conus rolani is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous. They are capable of "stinging" humans, therefore live ones should be handled carefully or not...
, is unique among the conantokins in having two distinct conformational states between which it equilibriates. 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-R1-A by Lys. Con-R1-A discriminates more effectively than any other known ligand between the NR2B and NR2C subunits of NMDAR.
Conantokin-Br (Con-Br)
Con-Br is isolated from Conus brettinghami (aka Conus sulcatusConus sulcatus
Conus sulcatus is a species of sea snail, a marine gastropod mollusk in the family Conidae, the cone snails and their allies.Like all species within the genus Conus, these snails are predatory and venomous. They are capable of "stinging" humans, therefore live ones should be handled carefully or...
), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR .
Con-G synthetic peptides
Con-G[γ7A] Con-G[γ7K] and Con-G[S16Y] are synthetic Con-G peptides, where the Gla residue at position 7 is replaced with an alanineAlanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
or a lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
residue, or the serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
at position 16 is replaced with a tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
residue, respectively. Con-G[γ7A] is fourfold more potent than the native peptide, Con-G, while Con-G[γ7K] is as potent as Con-G. The first two peptides appear to distinguish NMDAR subtypes in mid-frontal gyri
Middle frontal gyrus
The middle frontal gyrus makes up about one-third of the frontal lobe of the human brain....
from those in superior temporal gyri
Superior temporal gyrus
The superior temporal gyrus is one of three gyri in the temporal lobe of the human brain, which is located laterally to the head, situated somewhat above the external ear.The superior temporal gyrus is bounded by:* the lateral sulcus above;...
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
Spermine is a polyamine involved in cellular metabolism found in all eukaryotic cells. Formed from spermidine, it is found in a wide variety of organisms and tissues and is an essential growth factor in some bacteria. It is found as a polycation at physiological pH...
-enhanced [3H]MK-801 binding. Con-G[γ7K] and Con-G[S16Y] also show positive results in morphine withdrawal.
Con-T synthetic peptides
Con-T[K7γ] is 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 the presence of Mg2+.Chemistry
Biochemically, conantokins have distinctively high content of γ-carboxyglutamateCarboxyglutamate
Carboxyglutamic acid , is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium...
and lack of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues. Conantokins typically lack disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
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
GRIN1
Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.-Further reading:...
/ NR2A
GRIN2A
Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene.-Interactions:GRIN2A has been shown to interact with FYN, DLG4, DLG3, DLG1, Src, PTK2B and Interleukin 16.-Further reading:...
/ NR2B
GRIN2B
Glutamate [NMDA] receptor subunit epsilon-2 also known as N-methyl D-aspartate receptor subtype 2B is a protein that in humans is encoded by the GRIN2B gene.- Function :...
) 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.