Hodgkin and Huxley made the fundamental observations on which our current understanding of the ionic basis of the action potential is based. In their

experiments, they measured the ionic currents flowing across the membrane of a squid giant axon in response to changes in membrane voltage. This was done using the voltage-clamp apparatus, which provides a means of holding membrane potential constant in the face of changes in the ionic conductance of the axon membrane. By analyzing these ionic currents, Hodgkin and Huxley derived equations specifying both the voltage dependence and the time-course of changes in sodium and potassium conductance of the membrane. During a maintained depolarization, the sodium conductance increased rapidly, then declined, while potassium conductance showed a delayed but maintained increase. Analysis of the change in sodium conductance suggested that the conducting state of the sodium channel was controlled by a rapidly opening activation gate, called the m gate, and a slowly closing inactivation gate, called the h gate. The gates behave as though they are controlled by charged gating particles that move within the plasma membrane; when the gating particles occupy binding sites associated with the channel gating mechanism, the gates open. The kinetics of the observed gating behavior would be explained by the kinetics of the redistribution of the charged gating particles within the membrane following a step change in the transmembrane potential. The sodium activation gate appears to open when three independent binding sites are occupied by gating particles, while the inactivation gate closes when a single particle leaves a single binding site. The potassium channel is controlled by a single gate, the n gate, which opens when four binding sites are occupied. The rate at which the gating particles redistribute following a depolarization is different for the three types of gate, with sodium-activation gating being faster than sodium-inactivation or potassium-activation gating. Tiny membrane currents associated with the movement of the charged gating particles within the membrane have been detected. Experiments combining molecular biology with electrical measurements promise to establish the correspondence between Hodgkin and Huxley's gating mechanisms and actual parts of the ion-channel protein molecule.

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