The proposed study utilizes internally-perfused, voltage-clamped, crayfish giant axons to investigate effects of selected pharmacologic agents on the gating mechanisms of the sodium and potassium channels. Using computer analysis of signal-averaged, linear capacity-subtracted gating current records, three major kinetic components can be identified within the gating currents. A detailed sequence of studies is proposed by which I expect to determine: a) whether the "fast" component of gating current is an artifact or a reflection of very fast molecular transitions within the sodium channel gating mechanism; b) whether the "intermediate" component of gating current is an intimate reflection of sodium activation; c) whether the "slow" component of gating current reflects sodium inactivation or potassium activation and, d) to what extent these components are affected by changes in holding potential. The results to be obtained will help to confirm or discredit a model for the sodium conductance control mechanism involving physically-distinct, though interactive, voltage sensors for sodium activation and inactivation. They should also clarify the contribution of the potassium gating mechanism to the total gating current in crayfish giant axons. Pharmacologic agents, which will be used within carefully chosen experimental protocols to help answer these questions, will be methylene blue, veratrine, aconitine, Leiurus venom, Condylactis toxin, gallic acid, trypsin and pronase.