The effects of several aliphatic alcohols on sodium currents were examined in the intracellularly perfused squid giant axon when the same concentration of alcohol was applied on both sides of the membrane. 2. An irreversible suppression of sodium currents, accompanied by anaesthesia at high alcohol concentration, was examined in detail using four aliphatic alcohols, that is, ethanol, 1-propanol, 1-butanol and 1-pentanol. 3. This irreversible effect seemed to be attributable to the sequential denaturation of sodium channels, because the kinetics, the current-voltage relation and the sodium channel activation-voltage curve did not change after the sodium current decreased. 4. The time course of the remaining sodium conductance was measured as a function of the sum of the alcohol application time by repeating the process of applying and completely washing out alcohol. The remaining sodium conductance decayed as a function of time in a single exponential manner. This decay time constant depended strongly on the concentration of alcohol and could be assumed to be the denaturation time constant of the sodium channel. 5. The denaturation time constant decreased as the alcohol concentration increased. This time constant is proportional to the Nth power of the alcohol concentration. The N values are 4.3, 4.5, 5.8 and 7.6 for ethanol, 1-propanol, 1-butanol and 1-pentanol, respectively. This implies that alcohol molecules bind to a restricted number of specific sites in the sodium channel protein to cause the denaturation. 6. The concentration of alcohol which caused the same amount of denaturation is related to the exponential function of the carbon number of the alcohol. Considering the partition coefficient of alcohol between lipid and aqueous solution, the concentration of alcohol in the membrane which denatured half of the sodium channels in 2 h can be calculated to be 0.5 M for all alcohols.
