Facilitation of recovery from inactivation by external Na+ and location ofthe activation gate in neuronal Na+ channels

Fast inactivation of the Na+ channel presumably is produced by binding of t he inactivating peptide (the "hinged lid") to the internal pore mouth of th e activated channel. It has been shown that recovery from inactivation in N a+ channels begins with a delay, which corresponds to deactivation of the c hannel, and is then followed by an exponential phase, which corresponds to unbinding of the inactivating peptide. We found that the exponential phase is similar to 1.6- fold faster in 150 mM than in 0 mM external Na+, but the initial delays are the same. External Na+ also increases the late steady-s tate Na+ current during a step depolarization and shifts the inactivation c urve accordingly but has no effect on the activation and deactivation kinet ics of the current. Quantitative analysis of the data reveals that external Na+ has the same facilitation effect on the unbinding of the bound inactiv ating peptide whether the channel is activated or deactivated but has no ef fect on the other gating processes of the channel. These findings suggest t hat permeating Na+ ions directly knock off the bound inactivating peptide a nd that channel activation or deactivation does not affect the accessibilit y of the bound inactivation peptide to external Na+. The activation gate (t he key gating change transforming a Na+-nonconducting pore into a Na+ condu cting one) therefore should not be located external to the inactivation gat e, which presumably is already located close to the internal end of the por e.