Conantokins are a small family of helicalpeptides that are derived from the venom of predatory marine snails of the genusConus. Conantokins act as potent and specificantagonists of theN-methyl-D-aspartate receptor (NMDAR).^[1] They are the only naturally-derived peptides to do so.^[2] 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.^[3][4][5]

Chemically, conantokins are unique in that they possess a number (generally 4 or 5) ofgamma-carboxyglutamyl (Gla) residues, generated by thepost-translational modification of glutamyl (Glu) residues. These Gla residues induce a conformational change from a3₁₀ helix to an alpha helix on binding to Calcium.^[6] In the broader scheme of geneticconotoxin classification, Conanotokins are also known as "Conotoxin Superfamily B."^[7]

The word "conantokin" is derived from theFilipino wordantokin, meaning sleepy.^[8]

Conantokin are in general named after thespecific epithet of theConus species it is found in, using single-letter abbreviations if possible. A conantokin fromConus radiatus is called Conantokin-R, but the latter-discovered ones fromConus 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".

Also known as the “sleeper peptide”^[9] or CGX-1007,^[10]Conantokin G (P07231) is a smallpeptide isolated from the fish-hunting snail,Conus geographus. It is the best-characterized conantokin, and acts as a functional inhibitor of NMDAR.^[11]

Con-G shows potential as aneuroprotective agent inischemic andexcitotoxic brain injury, neuronalapoptosis, pain,epilepsy, and as a research tool indrug addiction andAlzheimer's disease.^[11][12] Con-G blocks NMDAR-mediated excitatory postsynaptic currents (EPSCs). Con-G reduces the strength ofexcitotoxic intracellular Ca²⁺ actions and blocks different neuronal injuries in vitro.^[10] In certain injuries Con-G shows an exceptional prolongation of thetherapeutic window.^[10] Con-G can reverse establishedallodynia and can also fully reverse thermal hypersensitivity induced by nerve injury.^[4]

Con-T (P17684) 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.^[8]

Con-R (P58806) is a highly potentanticonvulsant compound, derived fromConus radiatus.

Con-L (P69745) is an efficient anticonvulsant compound, derived fromConus lynceus.^[5] 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.^[5]

Con-L blocks NMDA-evoked currents in a powerful way, which is only slowly reversible upon washout, similar to Con-R and Con-G.^[5]

Each peptide in this group is derived from the same species,Conus parius. Con-Pr3 (P0C8E2) has three different post-translational modifications. Con-Pr1 (P0C8E0) and –Pr2 (P0C8E1) adopt α-helical conformations in the presence of Mg²⁺ and Ca²⁺, but otherwise are generally unstructured. Conantokin-Pr3 always adopts an α-helical conformation.^[12]

These peptides have highest potency for theNR2B subunits of the NMDAR.^[12]

Con-P (P0C8E3) and Con-E (P0C8D9) were isolated from the only two fish-hunting cone snails of the Americas (Conus purpurascens andConus ermineus, respectively). Con-P differs from the other known conantokins in that it contains a longdisulfide 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 forNR2B. Con-E is very similar in structure to Con-P, and is likely to have a similar function.^[1]

Con-Rl-A (P0DKY9), derived from the venom ofConus 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.^[13]

Con-Br (or Con-S1,P0CG46) is isolated fromConus brettinghami (nowConus sulcatus), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR.^[14]

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 analanine or alysine residue, or theserine at position 16 is replaced with atyrosine 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.^[3] The first two peptides appear to distinguish NMDAR subtypes in mid-frontalgyri from those insuperior 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 ofspermine-enhanced [³H]MK-801 binding.^[3][15] Con-G[γ7K] and Con-G[S16Y] also show positive results in morphine withdrawal.^[3]

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 notdimerize in the presence of Mg²⁺.^[16]

Biochemically, conantokins have a distinctive high γ-carboxyglutamate content and lowcysteine content. Conantokins typically lackdisulfide bonds, in contrast to most families ofconotoxins, 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.

Con-G does not act directly at the glycine binding site.^[11][17] It can attenuate both the amplitude and the decay time constant of NMDA-mediated EPSCs^[18] 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.^[11]

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

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.^[3]

Intrathecal administration of doses greater than 300 pmol produced motor impairment in mice.^[4]
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.^[5]

• Ion channel toxins
• Neurotoxins
• Snail toxins
• NMDA receptor antagonists

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