Scorpion toxins specific for Na+-channels

Na+-channel specific scorpion toxins are peptides of 60-76 amino acid resid ues in length, tightly bound by four disulfide bridges. The complete amino acid sequence of 85 distinct peptides are presently known. For some toxins, the three-dimensional structure has been solved by X-ray diffraction and N MR spectroscopy. A constant structural motif has been found in all of them, consisting of one or two short segments of alpha-helix plus a triple-stran ded beta-sheet, connected by variable regions forming loops (turns). Physio logical experiments have shown that these toxins are modifiers of the gatin g mechanism of the Na+-channel function, affecting either the inactivation (alpha-toxins) or the activation (beta-toxins) kinetics of the channels. Ma ny functional Variations of these peptides have been demonstrated, which in clude not only the classical alpha- and beta-types, but also the species sp ecificity of their action. There are peptides that bind or affect the funct ion of Na+-channels from different species (mammals, insects or crustaceans ) or are toxic to more than one group of animals. Based on functional and s tructural features of the known toxins, a classification containing 10 diff erent groups of toxins is proposed in this review. Attempts have been made to correlate the presence of certain amino acid residues or 'active sites' of these peptides with Na+-channel functions. Segments containing positivel y charged residues in special locations, such as the five-residue turn, the turn between the second and the third beta-strands, the C-terminal residue s and a segment of the N-terminal region from residues 2-11, seems to be im plicated in the activity of these toxins. However, the uncertainty, and the limited success obtained in the search for the site through which these pe ptides bind to the channels, are mainly due to the lack of an easy method f or expression of cloned genes to produce a well-folded, active peptide. Man y scorpion toxin coding genes have been obtained from cDNA libraries and fr om polymerase chain reactions using fragments of scorpion DNAs, as template s. The presence of an intron at the DNA level, situated in the middle of th e signal peptide, has been demonstrated.