On the slowly rising phase of the sodium gating current in the squid giant axon.

High-resolution records of the sodium gating current in the squid giant axon demonstrate the existence of a slowly rising phase that is first apparent at pulse potentials slightly below zero, and becomes increasingly pronounced at more positive potentials. At +80 mV the current reaches its peak with a delay of 30 microseconds at 10 degrees C. It is suggested that this current is generated by the first two steps labelled R-->P and P-->A in the S4 units of all four domains of the series-parallel gating system, activating the channel before its opening by the third steps A-->B in domains I, II and III in conjunction with hydration. The kinetics of the slowly rising phase can only be explained by the incorporation of an appropriate degree of voltage-dependent cooperativity between the S4 voltage-sensors for their two initial transitions.