The plasma membrane of all electrically excitable cells such as neurons contain voltage gated cation channels which are responsible for generating an action potential which is a traveling wave of electrical excitation. An action potential is generated by a depolorization or shift in the membrane potential of the plasma membrane to a less negative value.

In nerve and skeletal muscle cells, a stimulus that causes sufficient depolarization promptly causes voltage gated Na+channels to open, allowing a small amount of Na+ to enter the cell down its electrochemical gradient. The influx of + charge depolarizes the membrane thereby opening more Na+ channels causing further depolarization. This process continues within a fraction of a millisecond until the electrical potential has shifted from its resting value of about -70 mV to almost as far as the Na+ equilibrium potential of about +50 mV. At this point, when the net electrochemical driving force for the flow of Na+ is almost zero, the cell would come to a new resting state but this does not occur because Na+ channels are inactivated and K+channels are opened. When K+ channels are opened, the transient influx of Na+ is overwhelmed by the efflux of K+ which quickly drives the membrane back toward the K+ equilibrium potential.

How do Na+ channels go from an initial closed to an open and then inactivated state? One model proposed is the so called “ball-and-chain” model. When the membrane is at rest (highly polarized), the closed conformation has the lowest free energy and is therefore most stable. When the membrane is depolarized, the energy of the open conformation is lower so the channel has a high probability of opening. The free energy of the inactivated conformation is even lower so that after a randomly variable period spent in the open state, the channel becomes inactivated. The model is called “ball and chain” because the occlusion of the channel is thought to occur by a ball like structure that is linked to the channel through a chain.