Two novel alpha-neurotoxins isolated from the taipan snake, Oxyuranus scutellatus, exhibit reduced affinity for nicotinic acetylcholine receptors in brain and skeletal muscle.
Three novel toxic peptides were purified to homogeneity from the venom of the Australian taipan snake, Oxyuranus scutellatus scutellatus. On the basis of complete amino acid sequence analyses, two of these toxins belong to the family of short-chain alpha-neurotoxins found in elapid and hydrophid snake venoms and are the first postsynaptic neurotoxins identified in taipan venom. Radioligand binding studies confirm that taipan toxins 1 and 2 inhibit the binding of [125I]-alpha-bungarotoxin to nicotinic acetylcholine receptors in skeletal muscle with IC50 values of 2.4-2.5 nM but are 5-fold less potent in this assay than alpha-bungarotoxin or the two short-chain alpha-neurotoxins erabutoxin a and erabutoxin b. Taipan toxins 1 and 2 do not antagonize [125I]-alpha-bungarotoxin binding to central neuronal nicotinic receptors at concentrations up to 3 microM. We find that erabutoxin a and erabutoxin b do inhibit the binding of [125I]-alpha-bungarotoxin to central neuronal nicotinic receptors but are over 350-fold less potent than long-chain alpha-neurotoxins at these receptors. The novel alpha-neurotoxins from taipan venom do not inhibit the binding of [3H]nicotine to high-affinity nicotine receptors in brain, a property they share with alpha-bungarotoxin and the erabutoxins. The results demonstrate that at least two neuromuscular junction-blocking peptides are present in taipan venom. Nonconservative substitutions at position 32 in both taipan toxin 1 and 2 may be responsible for the observed decreases in affinities of the toxins of 5-fold for muscle receptors (compared to alpha-bungarotoxin) and over 10-fold for alpha-bungarotoxin-sensitive nicotinic receptors in brain (compared to the structurally similar short-chain alpha-neurotoxins erabutoxin a and erabutoxin b).
Zamudio
F
F
Department of Molecular Recognition and Structural Biology, Universidad Nacional Autonoma de Mexico, Cuernavaca, Mexico.
Wolf
K M
KM
Martin
B M
BM
Possani
L D
LD
Chiappinelli
V A
VA
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002038:Bungarotoxins / Q000378:metabolism; D002642:Chick Embryo; D017124:Conserved Sequence; D004546:Elapid Venoms / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D007700:Kinetics; D007928:Lethal Dose 50; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D002038:Bungarotoxins; D004546:Elapid Venoms; D009498:Neurotoxins; D011978:Receptors, Nicotinic