Na+ channels must deactivate to recover from inactivation.

We studied the kinetics of recovery from inactivation of voltage-dependent Na+ channels in rat hippocampal CA1 neurons. Recovery proceeded exponentially after an initial delay and was accompanied by a tiny ionic current. Both the delay and the time constant of recovery became shorter with increasing hyperpolarization. Negative to -170 mV, the rate of recovery saturated at approximately 4 ms-1 (22 degrees C). Recovery from block by the anticonvulsant drug diphenylhydantoin was far slower, but the pattern of voltage dependence was very similar. Our results suggest that, analogous to the coupling between Na+ channel activation and the development of inactivation, recovery from inactivation is coupled to channel deactivation. Such coupling ensures very little "leak" Na+ current during recovery and a highly voltage-sensitive repriming of Na+ channels for the next impulse.