Conantokins

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]

The word "conantokin" is derived from the Filipino word antokin, meaning sleepy.[6]

Subtypes

Conantokin-G (Con-G)

Also known as the “sleeper peptide”[7] or CGX-1007,[8] Con-G 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.[9]

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.[9][10] 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.[8] In certain injuries Con-G shows an exceptional prolongation of the therapeutic window.[8] Con-G can reverse established allodynia and can also fully reverse thermal hypersensitivity induced by nerve injury.[4]

Conantokin-T (Con-T)

Con-T 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.[6]

Conantokin-R (Con-R)

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

Conantokin-L (Con-L)

Con-L 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 (Con-Pr1, Con-Pr2 and Con-Pr3)

Each peptide in this group is derived from the same species, Conus parius. 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[10]

These peptides have highest potency for the NR2B subunits of the NMDAR.[10]

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 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)

Con-Rl-A, 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.[11]

Conantokin-Br (Con-Br)

Con-Br is isolated from Conus brettinghami (aka Conus sulcatus), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR.[12]

Modifications (synthetic peptides)

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 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][13] Con-G[γ7K] and Con-G[S16Y] also show positive results in morphine withdrawal.[3]

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+.[14]

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.[9][15] It can attenuate both the amplitude and the decay time constant of NMDA-mediated EPSCs[16] 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.[9]

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 2 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. 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.” Neurosci. Lett. 118, 241-244. PMID 2177176
  3. 1 2 3 4 5 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.” Neurosci. Lett. 405:137–41. PMID 16859831
  4. 1 2 3 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, 101:109–116. PMID 12507705
  5. 1 2 3 4 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 Res. 51:73–80. PMID 12350383
  6. 1 2 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”. J Biol Chem. 265:6025–6029. PMID 2180939
  7. ↑ 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. PMID 4024137
  8. 1 2 3 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. PMID 11997694
  9. 1 2 3 4 Alex AB, Baucum AJ, Wilcox KS. (September 2006) “Effect of Conantokin G on NMDA receptor-mediated spontaneous EPSCs in cultured cortical neurons.” J Neurophysiol 96(3):1084-92. PMID 16760339
  10. 1 2 3 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.” J Biol Chem. 282(51):36905-13. PMID 17962189
  11. ↑ Gowd KH, Watkins M, Twede VD, Bulaj GW, Olivera BM. (August 2010) “Characterization of conantokin Rl-A: molecular phylogeny as structure/function study.” J Pept Sci. 16(8):375-82. PMID 20572027
  12. ↑ Twede VD, Teichert RW, Walker CS, Gruszczynski P, Kazmierkiewicz 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):4063–4073. PMID 19309162
  13. ↑ 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.” J Neurochem. 81(4):765-79. PMID 12065636
  14. ↑ 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. PMID 20195692
  15. ↑ Donevan SD, McCabe RT. (September 2000) “Conantokin G is an NR2B-selective competitive antagonist of N-methyl-D-aspartate receptors.” Mol Pharmacol. 58(3):614-23. PMID 10953056
  16. ↑ 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.” Mol Cell Neurosci. 45(2):163-72. PMID 20600930
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