The Paradox of Scorpion Toxin Interactions with Portable Nav Receptors

Scorpion venom is rich in proteinaceous toxins that affect excitability by impeding ion channel gating. Channel blockers interact with the external region of the pore and obstruct ion conductance, whereas channel modifiers interact with the voltage sensor module hindering the activation or inactivation processes [1-3]. Scorpion toxin modifiers of voltage-gated sodium channels (Navs) are divided by their mode of action to alpha and beta classes [4], and further to distinct pharmacological groups by their binding features (Figure 1) [5-7]. Alpha toxins that prolong channel inactivation bind at the pharmacologically defined receptor site 3, whereas beta toxins that affect channel activation bind at receptor site 4 [4-12]. Although the study of the mode of action, binding features, three-dimensional structure and bioactive surface of these toxins encompasses more than four decades, it markedly accelerated once ways for toxin expression in heterologous systems (Escherichia coli, Saccharomyces cerevisiae) have been developed [9,13-15]. Of particular use was the efficient expression system of Esherichia coli which expedited the examination of the effects of any single or multiple amino acid substitutions on toxin binding and action. The considerable large quantities of pure recombinant toxins enabled also crystallization and determination of the structures of wild type and mutant derivatives. Undoubtedly, the simplification of toxin production and analysis accelerated the study of their bioactive surfaces, as shown for toxin representatives of all pharmacological groups [13,16-24]. These studies have shown that the bioactive surfaces are generally divided between two domains in both alpha and beta toxins (Figure 1 upper as an example), where one domain is associated with the molecule core and the other domain includes residues of the intertwining N and C tails. This division suggested that the ‘mirror face’ channel receptors might be composed as well of two distinct sites complementary to the toxin bioactive surfaces. Moreover, the ability of both alpha and beta toxins to modify channel gating has suggested that they interact, at least in part, with the voltage sensor module. Backed by this rationale and the available expression systems for both toxins (using E. coli) and Navs (expressed either in frog oocytes or cultured cell lines) a molecular study of the interaction between the toxins and the channels has been established.