Cobratoxin

α-Cobratoxin is a substance of the venom of certain Naja cobras. It is a muscle-type nicotinic acetylcholine receptor (nAChR) antagonist, which causes paralysis by preventing the binding of acetylcholine to the nAChR.

Source

α-Cobratoxin is a neurotoxin from the venom of certain Naja cobras, such as Naja atra and Naja siamensis (the monocled cobra) (Yang 1965)

Chemistry

α-Cobratoxin consists of 71 amino acid residues and 5 disulfide bridges (Zeng et al. 2002). It is also known as long neurotoxin 1, neurotoxin 3, or CbTx. It belongs to the type II alpha-neurotoxin subfamily, which also includes alpha-bungarotoxin.

Target

Cobratoxin binds with high affinity to ligand gated nicotinic acetylcholine receptor (nAChR) , which play an important role in synaptic transmission both in the central nervous system and at the neuromuscular junction (NMJ) (Konstantakaki et al. 2007). It has an affinity for the chick neuronal α7 nAChR of 6 nM and for the nAchR from the Torpedo NMJ of 39 pM (Servent 2000)).

Mode of action

Cobratoxin binds to the ligand-binding pocket between the α/γ or α/δ nAChR subunits (Chen et al. 2006). It causes a postsynaptic block at the NMJ nAChRs by preventing the binding of acetylcholine to its receptor. Long neurotoxins like Cobratoxin also block neuronal α7 nAChRs (Hue et al. 2007), but it is unclear how effectively the long neurotoxin can reach the central nervous system (CNS).

Toxicity

The lethal dose (LD₅₀) of cobratoxin in mice is 4 µg/kg (Lipps 2001).

Treatment

Researchers are trying to develop a vaccine against the toxin by using a replicant-deficient adenovirus containing mutated cobratoxin (Pergolizzi et al. 2005).

References

• Yang, C.C. (1965), "Crystallization and Properties of Cobrotoxin from Formosan Cobra Venom", J. Biol. Chem. 240: 1616–8, PMID 14285499 .
• Zeng, D.; Hawrot, E. (2002), "NMR-based binding screen and structural analysis of the complex formed between alpha-cobratoxin and an 18-mer cognate peptide derived from the alpha 1 subunit of the nicotinic acetylcholine receptor from Torpedo californica", J. Biol. Chem. 277 (40): 37439–45, doi:10.1074/jbc.M205483200, PMID 12133834 .
• Konstantakaki, M.; Changeux, J.P; Taly, A (2007), "Docking of alpha-cobratoxin suggests a basal conformation of the nicotinic receptor", Biochem. Biophys. Res. Commun. 359 (3): 413–8, doi:10.1016/j.bbrc.2007.05.126, PMID 17555709 .
• Servent, D.; Antil-Delbeke, S; Gaillard, C; Corringer, PJ; Changeux, JP; Ménez, A (2000), "Molecular characterization of the specificity of interactions of various neurotoxins on two distinct nicotinic acetylcholine receptors", Eur. J. Pharmacol. 393 (1–3): 197–204, doi:10.1016/S0014-2999(00)00095-9, PMID 10771013 .
• Chen, Z.X; Zhang, HL; Gu, ZL; Chen, BW; Han, R; Reid, PF; Raymond, LN; Qin, ZH (2006), "A long-form alpha-neurotoxin from cobra venom produces potent opioid-independent analgesia", Acta Pharmacol. Sin. 27 (4): 402–8, doi:10.1111/j.1745-7254.2006.00293.x, PMID 16539838 .
• Hue, B.; et al., SD; Buckingham, D; Sattelle, DB (2007), "Actions of snake neurotoxins on an insect nicotinic cholinergic synapse", Invert. Neurosci. 7 (3): 173–8, doi:10.1007/s10158-007-0053-3, PMID 17710455 .
• Lipps, B.V. (2001), "Production of polyclonal antibodies in mice against cobratoxin, botulinum toxin and ricin without altering their toxicity or use of adjuvant", J. Nat. Toxins 10 (1): 27–32, PMID 11288726 .
• Pergolizzi, R.G; et al., R; Ropper, AE; Menez, A; Crystal, RG (2005), "Protective immunity against alpha-cobratoxin following a single administration of a genetic vaccine encoding a non-toxic cobratoxin variant", Gene. Ther. 16 (3): 292–8, doi:10.1089/hum.2005.16.292, PMID 15812224 .