Conantokin

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]

Conantokin
Identifiers
SymbolConantokin
PfamPF10550
InterProIPR005918
PROSITEPS60025
SCOP21ONT / SCOPe / SUPFAM

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 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

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. Gowd KH, Twede V, Watkins M, Krishnan KS, Teichert RW, Bulaj G, Olivera BM (August 2008). "Conantokin-P, an unusual conantokin with a long disulfide loop". Toxicon. 52 (2): 203–13. doi:10.1016/j.toxicon.2008.04.178. PMC 2630528. PMID 18586049.
  2. Mena EE, Gullak MF, Pagnozzi MJ, Richter KE, Rivier J, Cruz LJ, Olivera BM (October 1990). "Conantokin-G: a novel peptide antagonist to the N-methyl-D-aspartic acid (NMDA) receptor". Neuroscience Letters. 118 (2): 241–4. doi:10.1016/0304-3940(90)90637-O. PMID 2177176.
  3. Wei J, Dong M, Xiao C, Jiang F, Castellino FJ, Prorok M, Dai Q (September 2006). "Conantokins and variants derived from cone snail venom inhibit naloxone-induced withdrawal jumping in morphine-dependent mice". Neuroscience Letters. 405 (1–2): 137–41. doi:10.1016/j.neulet.2006.06.040. PMID 16859831.
  4. Malmberg AB, Gilbert H, McCabe RT, Basbaum AI (January 2003). "Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T". Pain. 101 (1–2): 109–16. doi:10.1016/S0304-3959(02)00303-2. PMID 12507705.
  5. Jimenez EC, Donevan S, Walker C, Zhou LM, Nielsen J, Cruz LJ, Armstrong H, White HS, Olivera BM (September 2002). "Conantokin-L, a new NMDA receptor antagonist: determinants for anticonvulsant potency". Epilepsy Research. 51 (1–2): 73–80. doi:10.1016/S0920-1211(02)00101-8. PMID 12350383.
  6. Rigby AC, Baleja JD, Li L, Pedersen LG, Furie BC, Furie B (December 1997). "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. doi:10.1021/bi9718550. PMID 9398296.
  7. Robinson SD, Norton RS (December 2014). "Conotoxin gene superfamilies". Marine Drugs. 12 (12): 6058–101. doi:10.3390/md12126058. PMC 4278219. PMID 25522317.
  8. Haack JA, Rivier J, Parks TN, Mena EE, Cruz LJ, Olivera BM (April 1990). "Conantokin-T. A gamma-carboxyglutamate containing peptide with N-methyl-d-aspartate antagonist activity". The Journal of Biological Chemistry. 265 (11): 6025–9. PMID 2180939.
  9. Olivera BM, McIntosh JM, Clark C, Middlemas D, Gray WR, Cruz LJ (1985). "A sleep-inducing peptide from Conus geographus venom". Toxicon. 23 (2): 277–82. doi:10.1016/0041-0101(85)90150-3. PMID 4024137.
  10. Williams AJ, Ling G, McCabe RT, Tortella FC (May 2002). "Intrathecal CGX-1007 is neuroprotective in a rat model of focal cerebral ischemia". NeuroReport. 13 (6): 821–4. doi:10.1097/00001756-200205070-00017. PMID 11997694.
  11. Alex AB, Baucum AJ, Wilcox KS (September 2006). "Effect of Conantokin G on NMDA receptor-mediated spontaneous EPSCs in cultured cortical neurons". Journal of Neurophysiology. 96 (3): 1084–92. doi:10.1152/jn.01325.2005. PMID 16760339.
  12. Teichert RW, Jimenez EC, Twede V, Watkins M, Hollmann M, Bulaj G, Olivera BM (December 2007). "Novel conantokins from Conus parius venom are specific antagonists of N-methyl-D-aspartate receptors". The Journal of Biological Chemistry. 282 (51): 36905–13. doi:10.1074/jbc.M706611200. PMID 17962189.
  13. Gowd KH, Watkins M, Twede VD, Bulaj GW, Olivera BM (August 2010). "Characterization of conantokin Rl-A: molecular phylogeny as structure/function study". Journal of Peptide Science. 16 (8): 375–82. doi:10.1002/psc.1249. PMC 4136950. PMID 20572027.
  14. Twede VD, Teichert RW, Walker CS, Gruszczyński P, Kaźmierkiewicz R, Bulaj G, Olivera BM (May 2009). "Conantokin-Br from Conus brettinghami and selectivity determinants for the NR2D subunit of the NMDA receptor". Biochemistry. 48 (19): 4063–73. doi:10.1021/bi802259a. PMC 3955384. PMID 19309162.
  15. Ragnarsson L, Mortensen M, Dodd PR, Lewis RJ (May 2002). "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. 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. 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". Journal of Biological Inorganic Chemistry. 15 (5): 667–75. doi:10.1007/s00775-010-0633-2. PMC 3693470. PMID 20195692.
  17. Donevan SD, McCabe RT (September 2000). "Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors". Molecular Pharmacology. 58 (3): 614–23. doi:10.1124/mol.58.3.614. PMID 10953056.
  18. Huang L, Balsara RD, Sheng Z, Castellino FJ (October 2010). "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. doi:10.1016/j.mcn.2010.06.007. PMC 2923249. PMID 20600930.
  • Kohn AJ, Anderson TR. "The conus biodiversity website". Burke Museum of Natural and History and Culture. Retrieved 2011-10-17. A part of a National Science Foundation-sponsored project aimed at expanding knowledge of systematics of the unusually diverse marine gastropod genus Conus
  • Kaas Q, Westermann JC, Halai R, Wang CK, Craik DJ. "ConoServer". Institute of Molecular Bioscience, The University of Queensland, Australia. Retrieved 2011-10-17. A database for conopeptide sequences and structures
  • "conotoxin+B+superfamily" Uniprot family: "conotoxin b superfamily" - List of curated Conantokins in UniProt
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