Toxins that modulate the sodium channel gating mechanism.

A variety of toxins and chemicals has been shown to modulate the gating kinetics of the sodium channel. Studies of batrachotoxin, grayanotoxins and pyrethroids are summarized here as examples. Batrachotoxin and grayanotoxins eliminate the sodium channel inactivation thereby causing a prolonged, steady-state sodium current to flow during a depolarizing step. The sodium channel activation kinetics are not affected markedly. Batrachotoxin appears to bind to a site in the sodium channel to which the inactivation gate normally binds, thus causing an inhibition of sodium inactivation. Single channel recording experiments have shown that the mean open time of individual sodium channels is greatly prolonged by batrachotoxin. It appears that individual sodium channels are modified by batrachotoxin in an all-or-none manner. Pyrethroids which are synthetic derivatives of pyrethrins also modify the kinetics of sodium channels in a very drastic manner. In the presence of type I pyrethroids which lack a cyano group at the alpha position (e.g., allethrin and tetramethrin), a large steady-state sodium current appears during a step depolarization and a large slowly decaying sodium tail current appears upon repolarization. Thus both the activation and inactivation kinetics are slowed. Type II pyrethroids which contain an alpha-cyano group (e.g., deltamethrin, cyphenothrin, and fenvalerate) exert effects on sodium channels qualitatively similar to those of type I pyrethroids. However, the amplitudes of the steady-state sodium current and sodium tail current are smaller and the time constant of tail current decay is much longer. The mean open time of single sodium channels is greatly prolonged by the pyrethroids, and the effect is much more pronounced in type II than in type I pyrethroids. A high degree of stereospecificity has been found among four isomers of tetramethrin, (+)-trans and (+)-cis isomers being highly active and (-)-trans and (-)-cis isomers almost totally inactive. The inactive isomers bind to the sodium channel sites, thus preventing the action of the active isomers. Because of the unique action of pyrethroids in modulating the sodium channels, they are becoming useful tools for channel physiology and pharmacology.