Scorpion neurotoxins

The nomenclature of scorpion toxins recognizes two general classes, alpha-and beta-toxins. The division being not whether they are insect or mammalian specific but rather their effect upon sodium channels. Scorpion alpha-toxins induce a prolongation of the action potential of nerves and muscles by slowing down the inactivation of the sodium channel with receptor affinity dependent upon membrane potential, while beta-toxins bind to a receptor site distinct from that of the alpha toxins with binding being independent of voltage. Scorpion alpha- and beta-toxins are sometimes called 'Androctonus-like' and 'Centruroides-like' toxins after the genera from which they were first isolated, these two genera being representative of Old World and New World species respectively.

Both alpha- and beta-toxins further fall into two subgroups with the difference in specificity being the discrimination between mammalian or insect voltage-dependent sodium channels from excitable tissues. This specificity of action is likely to be due to the relative position of the C-terminal peptide in relation to the hydrophobic surface common to all scorpion toxins. The structural motif of the surface of these compounds is an aromatic cluster surrounded by long hydrophobic side-chain residues with protruding loops.

Scorpion alpha-and beta-toxins have been found in both Old and New World species so the division is not definitive along geographical lines, nor is the division between insect and mammalian specific toxins quite so firm. An example is CsE-V from the Central American scorpion Centruroides suffusus. This alpha toxin is significant in that it structurally and functionally represents a transition between New World and Old World scorpion alpha toxins. Another example is the isolated toxin AaHIT4, from the northern African species Androctonus australis that binds to the sodium channels of insects as well as mammals. Further, this toxin competes in binding to a mammal sodium channel with both alpha-type and beta-type anti-mammal scorpion toxins. As such, this toxin could be the first member of a new class of toxins to have ancestral structural features and a wide toxicity range.

Tityustoxin-VII from Tityus serrulatus venom is a peptide that binds to both insect and mammalian nervous tissues. Tityustoxin-VII has a much more flexible structure than the anti-insect toxin AaHIT2 (Androctonus australis hector) or the anti-mammal toxin CssII (Centruroides sculpturatus sculpturatus), allowing it to compete with both of these proteins in binding to the sodium channels of insects and also mammals. This is similar to the situation seen with spiders and conotoxins, where subtle scaffold modifications radically change the specificity of action.

Toxins from different venoms that bind to the same site are quite useful. For example, the scorpion toxin charybdotoxin, which causes concentration dependent contraction, blocks the same receptor on voltage-dependent K+ channels as the snake toxin dendrotoxin, as does the mast cell degranulating peptide from bee venom. The Mexican scorpion Centruroides noxius contains primarily beta toxins, which block voltage-gated K+ channels binding to a site different to that of other beta toxins. A significant activity of noxiustoxin from this species is displacement of bound dendrotoxin (a potent mamba toxin) from synaptosomal membranes from a rat brain, indicating obvious shared pharmacological properties. The common target of these two rather different peptides makes them useful for comparative studies of potassium channels.