Conantokin – Wikipedia Wikipedia

Conantokins are a small family of helical peptides that 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). ^[first] 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) of gamma-carboxyglutamyl (Gla) residues, generated by the post-translational modification of glutamyl (Glu) residues. These Gla residues induce a conformational change from a 3 10 helix to an alpha helix on binding to Calcium. ^[6] In the broader scheme of genetic conotoxin classification, Conanotokins are also known as “Conotoxin Superfamily B.” ^[7]

The word “conantokin” is derived from the Filipino word antokin , meaning sleepy. ^[8]

Subtypes [ edit ]

Conantokin are in general named after the specific epithet of the Conus species it is found in, using single-letter abbreviations if possible. A conantokin from Conus radiant is called Conantokin-R, but the latter-discovered ones from Conus rolani are called Canontokin-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 [ edit ]

Also known as the “sleeper peptide” ^[9] or CGX-1007, ^[ten] Curved ( P07231 ) is a small peptide 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 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. ^{[11] [twelfth]} Con-G blocks NMDAR-mediated excitatory postsynaptic currents (EPSCs). Con-G reduces the strength of excitotoxic intracellular Ca ²⁺ actions and blocks different neuronal injuries in vitro. ^[ten] In certain injuries Con-G shows an exceptional prolongation of the therapeutic window. ^[ten] Con-G can reverse established allodynia and can also fully reverse thermal hypersensitivity induced by nerve injury. ^[4]

Conantokin-T [ edit ]

Con-T P17684 ) is purified from the venom of the fish-hunting cone-snail, Conus came . This peptide has 4 residues of Gla. Con-T acts by inhibiting NMDAR-mediated Ca ²⁺ influx in neurons in the central nervous system. ^[8]

Conantokin-R and -L [ edit ]

Con-R ( P58806 ) is a highly potent anticonvulsant compound, derived from Conus radiant .

Con-L P69745 ) is an efficient anticonvulsant compound, derived from Cone 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]

Conantokin-Pr1, -Pr2 and –Pr3 [ edit ]

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 Mg ²⁺ and Ca ²⁺ , but otherwise are generally unstructured. Conantokin-Pr3 always adopts an α-helical conformation. ^[twelfth]

These peptides have highest potency for the NR2B subunits of the NMDAR. ^[twelfth]

Conantokin-P and -E [ edit ]

Con-P ( P0C8E3 ) and Con-E ( P0C8D9 ) 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 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. ^[first]

Conantokin-Rl-A [ edit ]

Con-Rl-A ( P0dky9 ), derived from the venom of Conus rolani , 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-Rl-A by Lys. Con-R1-A discriminates more effectively than any other known ligand between the NR2B and NR2C subunits of NMDAR. ^[13]

Conantokin-Br or -S1 [ edit ]

Con-Br (or Con-S1, P0CG46 ) is isolated from Conus Bretinghami (now Cone grooved ), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR. ^[14]

Synthetic derivatives [ edit ]

Con-G-based [ edit ]

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 alanine 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. ^[3] 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 [ ³ H]MK-801 binding. ^{[3] [15]} Con-G[γ7K] and Con-G[S16Y] also show positive results in morphine withdrawal. ^[3]

Con-T-based [ edit ]

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 Mg ²⁺ than for Ca ²⁺ , but does not dimerize in the presence of Mg ²⁺ . ^[16]

Chemistry [ edit ]

Biochemically, conantokins have a distinctive high γ-carboxyglutamate content and low cysteine content. Conantokins typically lack disulfide bonds, 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 [ edit ]

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.

Toxicity [ edit ]

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]

References [ edit ]

External links [ edit ]