Properties of the voltage sensor for the opening and closing of the sodium channels in the squid giant axon

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Abstract
A combination of data from standard I--V curves, and from steps applied either at the initial current peak or in the inactivated steady state, yielded values of the total probability of the two open states of the sodium channel, multiplied by a constant scaling factor, as a function of membrane potential. The probability function PF$_{\text{peak}}$ was found to reach a maximum for pulses to 40-50 mV, but for larger test potentials it underwent a slight decline. The curve for its rise was shifted in a positive direction by several millivolts when the temperature was raised. Measurements of the probability function PF$_{\text{ss}}$ in the final steady condition, when almost the whole population of channels was inactivated, but a small flow of Na$^{+}$ current persisted, showed that the voltage sensor responsible for the actual opening of the channels carried 0.8 electronic charges, and that its equilibrium potential had been shifted nearly 100 mV by inactivation to lie close to 50 mV. The charge carried by the C$\leftrightharpoons $O voltage sensor was the same for all the dialysis and bathing solutions that were tested, but when dialysing with 350 mM NaF and bathing with full Na seawater plus 16 nM TTX, the equilibrium potential in the inactivated state was increased by about 25 mV. The results provide further support for the proposal of Keynes (1992) that the S4 voltage-sensing units of the homology domains are responsible only for the transitions between the several resting, activated and inactivated states of the channels in which it remains closed, and a separate C$\leftrightharpoons $O voltage sensor controls the transitions to and from the two open states. Inactivation of the channel involves conformational changes that lower the probability of opening by shifting the equilibrium potential of the C$\leftrightharpoons $O voltage sensor to a more positive value, and that affect the properties of the open channel in various other ways.