An integrated view of the molecular toxinology of sodium channel gating in excitable cells.

The neurotoxins that modify Na channels have actions that are characterized by different degrees of specificity (Table 2). These specificities can be correlated with their chemical properties. For example, guanidinium toxins, which are small charged ligands, appear only to "block" Na channels by binding to a site on the external surface. Peptide toxins, which are also positively charged and relatively small, also act from the external solution to modify channel activation and inactivation processes but do not alter ion selectivity. The lipophilic toxins, hydrophobic, neutral drugs, act from either side of the membrane and modify all the functions of Na channels. From such differences, and from the independence of toxin binding as well as toxin action, separate binding sites for these agents have been classified (Catterall 1980). Recent findings reviewed here suggest that all these toxins share certain features: They differentiate between various states of the channel. Effects of lipophilic activators, polypeptide toxins, and, indeed, even STX and TTX are enhanced or reversed in fractions of seconds under voltage clamp by patterns of membrane potential that selectively populate the channel open state, or the slow or fast inactivated states. Other assays--such as the binding of radiolabeled ligands or the changes of steady-state Na flux that require seconds to minutes of toxin-channel interaction--reveal interactions of the toxins with states of the channel not detected in the usual voltage-clamp analysis. Pharmacological probes may thus reveal channel states or transitions previously unrecognized. The bound toxins appear to interact with one another. The well-documented synergism at equilibrium of alpha-toxins with lipophilic activators provided a model for allosteric interactions between two separate binding sites (Catterall 1979, 1980). The other toxin interactions are more ephemeral and are characterized by kinetic variations that reflect the availability of reactive channel states. For example, the appearance of beta-toxin induced modifications of Na currents is accelerated in the presence of alpha-toxin (Wang & Strichartz 1983), whereas the modifications of inactivation by alpha-toxins are prevented by concurrent incubation with tetrodotoxin, although such modifications, once effected, are not reversed by the subsequent addition of TTX. Modifications of gating by lipophilic toxins confer a selective voltage-dependence on STX and TTX inhibition of open channels that is not observed in drug-free channels.(ABSTRACT TRUNCATED AT 400 WORDS)