Inactivation of sodium channels: second order kinetics in myelinated nerve

1. Kinetics of inactivation of sodium channels in myelinated nerve from Rana pipiens were studied at 4.5 degrees C using the voltage clamp technique of Dodge & Frankenhaeuser (1958).2. Potassium currents were blocked by cutting the internodes in 20 mM-TEA-Cl + 100 mM-KCl and by adding 12 mM-TEA-Cl to the external Ringer. Leakage and capacitative currents were subtracted electronically.3. Kinetics of recovery from inactivation of the sodium channels were studied by inactivating the channels with a large depolarizing prepulse and allowing the channels to recover at different potentials; the extent of recovery was measured by applying a test pulse at various times after the prepulse.4. Kinetics of development of inactivation were studied by two different methods. The first was to measure the decay of sodium current under a maintained depolarization. The second method was to measure the decay of the peak sodium current in a test pulse as a function of time after the onset of a maintained depolarization. These two methods yielded similar results for the kinetics of inactivation development.5. Contrary to expectations of the Hodgkin-Huxley formalism, the time course of recovery from and development of inactivation is not strictly exponential. Rather, recovery from complete inactivation shows an initial delay which depends on recovery potentials. Development of inactivation at a fixed potential exhibits at least two exponentials.6. The steady-state inactivation curve h(infinity)(E) is asymmetrical and is fitted better by 1/[1+exp (A(1)E+B(1)) +exp (A(2)E+B(2))] than by 1/[1+exp (AE+B)].7. Most of the above kinetic observation on inactivation can be fitted by the following modification of the h system of the Hodgkin-Huxley formalism: [Formula: see text]8. In the analysis it was not necessary to modify the concept of two separate processes, activation and inactivation, governing the opening and closing of the sodium channels.