Chemistry:Conantokin

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Conantokin
Identifiers
SymbolConantokin
PfamPF10550
InterProIPR005918
PROSITEPS60025
SCOP21ONT / SCOPe / SUPFAM

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).[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) 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

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 radiatus 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

Also known as the “sleeper peptide”[9] or CGX-1007,[10] Con-G (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][12] 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.[10] In certain injuries Con-G shows an exceptional prolongation of the therapeutic window.[10] Con-G can reverse established allodynia and can also fully reverse thermal hypersensitivity induced by nerve injury.[4]

Conantokin-T

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]

Conantokin-R and -L

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

Con-L (P69745) is an efficient anticonvulsant compound, derived from Conus 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

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 the NR2B subunits of the NMDAR.[12]

Conantokin-P and -E

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.[1]

Conantokin-Rl-A

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 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]

Conantokin-Br or -S1

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

Synthetic derivatives

Con-G-based

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

Con-T-based

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+.[16]

Chemistry

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

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]

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.[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

  1. ↑ 1.0 1.1 "Conantokin-P, an unusual conantokin with a long disulfide loop". Toxicon 52 (2): 203–13. August 2008. doi:10.1016/j.toxicon.2008.04.178. PMID 18586049. 
  2. ↑ "Conantokin-G: a novel peptide antagonist to the N-methyl-D-aspartic acid (NMDA) receptor". Neuroscience Letters 118 (2): 241–4. October 1990. doi:10.1016/0304-3940(90)90637-O. PMID 2177176. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice". Neuroscience Letters 405 (1–2): 137–41. September 2006. doi:10.1016/j.neulet.2006.06.040. PMID 16859831. 
  4. ↑ 4.0 4.1 4.2 "Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T". Pain 101 (1–2): 109–16. January 2003. doi:10.1016/S0304-3959(02)00303-2. PMID 12507705. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Conantokin-L, a new NMDA receptor antagonist: determinants for anticonvulsant potency". Epilepsy Research 51 (1–2): 73–80. September 2002. doi:10.1016/S0920-1211(02)00101-8. PMID 12350383. 
  6. ↑ "Role of gamma-carboxyglutamic acid in the calcium-induced structural transition of conantokin G, a conotoxin from the marine snail Conus geographus". Biochemistry 36 (50): 15677–84. December 1997. doi:10.1021/bi9718550. PMID 9398296. 
  7. ↑ "Conotoxin gene superfamilies". Marine Drugs 12 (12): 6058–101. December 2014. doi:10.3390/md12126058. PMID 25522317. 
  8. ↑ 8.0 8.1 "Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity". The Journal of Biological Chemistry 265 (11): 6025–9. April 1990. doi:10.1016/S0021-9258(19)39285-3. PMID 2180939. 
  9. ↑ "A sleep-inducing peptide from Conus geographus venom". Toxicon 23 (2): 277–82. 1985. doi:10.1016/0041-0101(85)90150-3. PMID 4024137. 
  10. ↑ 10.0 10.1 10.2 "Intrathecal CGX-1007 is neuroprotective in a rat model of focal cerebral ischemia". NeuroReport 13 (6): 821–4. May 2002. doi:10.1097/00001756-200205070-00017. PMID 11997694. 
  11. ↑ 11.0 11.1 11.2 11.3 "Effect of Conantokin G on NMDA receptor-mediated spontaneous EPSCs in cultured cortical neurons". Journal of Neurophysiology 96 (3): 1084–92. September 2006. doi:10.1152/jn.01325.2005. PMID 16760339. 
  12. ↑ 12.0 12.1 12.2 "Novel conantokins from Conus parius venom are specific antagonists of N-methyl-D-aspartate receptors". The Journal of Biological Chemistry 282 (51): 36905–13. December 2007. doi:10.1074/jbc.M706611200. PMID 17962189. 
  13. ↑ "Characterization of conantokin Rl-A: molecular phylogeny as structure/function study". Journal of Peptide Science 16 (8): 375–82. August 2010. doi:10.1002/psc.1249. PMID 20572027. 
  14. ↑ "Conantokin-Br from Conus brettinghami and selectivity determinants for the NR2D subunit of the NMDA receptor". Biochemistry 48 (19): 4063–73. May 2009. doi:10.1021/bi802259a. PMID 19309162. 
  15. ↑ "Spermine modulation of the glutamate(NMDA) receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex". Journal of Neurochemistry 81 (4): 765–79. May 2002. doi:10.1046/j.1471-4159.2002.00872.x. PMID 12065636. 
  16. ↑ Cnudde SE, Prorok M, Castellino FJ, Geiger JH. (June 2010) “Metal ion determinants of conantokin dimerization as revealed in the X-ray crystallographic structure of the Cd(2+)/Mg (2+)-con-T[K7gamma] complex.” J Biol Inorg Chem.15(5):667-75. "Metal ion determinants of conantokin dimerization as revealed in the X-ray crystallographic structure of the Cd(2+)/Mg (2+)-con-T[K7gamma complex"]. Journal of Biological Inorganic Chemistry 15 (5): 667–75. June 2010. doi:10.1007/s00775-010-0633-2. PMID 20195692. 
  17. ↑ "Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors". Molecular Pharmacology 58 (3): 614–23. September 2000. doi:10.1124/mol.58.3.614. PMID 10953056. 
  18. ↑ "Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation". Molecular and Cellular Neurosciences 45 (2): 163–72. October 2010. doi:10.1016/j.mcn.2010.06.007. PMID 20600930. 

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