Veratridine causes Na+ channels to stay open during a sustained membrane depolarization by abolishing inactivation. The consequential Na+ influx, either by itself or by causing a maintained depolarization, leads to many secondary effects such as increasing pump activity, Ca2+ influx, and in turn exocytosis. If the membrane is voltage clamped in the presence of the alkaloid, a lasting depolarizing impulse induces, following the "normal" transient current, another much more slowly developing Na+ current that reaches a constant level after a few seconds. Repolarization then is followed by an inward tail current that slowly subsides. Development of these slow currents is enhanced by additional treatment with agents that inhibit inactivation. Most of these phenomena can be satisfactorily explained by assuming that Na+ channels must open before veratridine binds to them, and that the slow current changes reflect the kinetics of binding and unbinding. It is unclear, however, where the alkaloid stays when it is not bound. Although the effect sets in promptly, once this pool is filled, access to it from outside must be impeded since in most preparations veratridine can only partially be washed out. Cooling acts as if the available concentration is reduced, but this reversible "reduction" takes much longer to develop than the cold-induced changes in kinetics. Several authors assume that the binding site, site 2, is accessed from the lipid phase of the membrane. Considerations of this kind are often based on experiments with batrachotoxin, the widely used site-2 ligand which has a much higher affinity and acts as a full agonist in contrast to the partial agonist veratridine. Batrachotoxin thus lends itself to binding studies using radiolabeled derivatives. Such experiments may eventually lead to the characterization of neurotoxin site 2; the first promising steps have been taken. Modern techniques of molecular biology will almost certainly be successful, and one hopes for point-mutated channels with distinctly different reactions also to veratridine. A considerable amount of research is still required to clarify the structural basis for the numerous allosteric interactions with other sites, the mechanism of the very large potential shift of activation, the reduced single-channel conductance and selectivity, and the chemical nature of the different affinities of the site-2 toxins. Note Added in Proof. A report on point mutations with effects on neurotoxin site 2 (see Sect. 8) has just appeared: Wang S-Y, Wang GK (1988) Point mutations in segment I-S6 render voltage-gated Na+ channels resistant to batrachotoxin. Proc Natl Acad USA 95:2653-2658. In microliter muscle Na+ channels expressed in mammalian cells, mutation Asn434Lys leads to complete, Asn434Ala to partial insensitivity to 5 mM batrachotoxin. (Asn434 corresponds to Asn419 of Trainer et al. 1996). The mutant channel displays almost normal current kinetics and in the presence of veratridine little, if any, slow tail current. However, veratridine inhibits peak Na+ currents in the mutant which may point to a complex structure of site 2.