Now let us summarize the events that take place during an action potential. The action potential can be divided into five phases (Fig. 2): (1) depolarization to and beyond threshold, (2) overshoot, (3) peak, (4) repolarization, and (5) hyperpolarizing afterpotential (or simply hyperpolarization) (Fig. 2). Let’s consider each of these events in detail.

As mentioned above, if the initial depolarization does not reach the threshold voltage, no action potential will result. However, if depolarization is large enough such that the membrane potential reaches −50 mV, a complete all-or-nothing action potential will result. As will be discussed below, unique voltage-gated ion channels, namely voltage-gated Na⁺ and K⁺ channels, respond to membrane depolarization to or beyond the threshold voltage. Remarkably, all of the features of the action potential can be explained by understanding the molecular properties of these voltage-gated ion channels, and the electrochemical gradients of Na⁺ and K⁺ across the neuronal plasma membrane.

The uncontrolled depolarization that takes place (also referred to as the spike phase of the action potential; 1 in Fig. 2) is strictly a function of voltage-gated Na⁺ channels in neurons. At rest (−70 mV), the voltage-gated Na⁺ channels are closed, but begin to open at membrane potentials ranging from −40 to −50 mV (threshold voltage, V_th). Opening of Na⁺ channels leads to the entry of a large amount of Na⁺ ions into the cell. Remember that a very large driving force (~100 mV) acts on Na⁺ ions favoring their movement into the cell through now open Na⁺ channels. This Na⁺ influx is brought about both by the Na⁺ concentration gradient, and the inside negative membrane potential. Entry of Na⁺ into the cell brings about further depolarization. Membrane depolarization further activates additional Na⁺ channels which, in turn, leads to the entry of more Na⁺ into the cell. Therefore, a positive feedback loop is established, which leads to increasing entry of Na⁺ into the cell. This positive feedback loop is called the Hodgkin cycle (Fig. 3), so named because of the investigator who pioneered most of what we know today about electrical activity in neurons. Thus, the Hodgkin cycle is responsible for the spike phase of the action potential.

The continued entry of Na⁺ into the cell leads to rapid depolarization of the cell (< 1 ms). Because rapid opening of Na⁺ channels leads to a rapid rise in membrane permeability to Na⁺, the membrane potential reverses its sign (goes from negative to positive) and approaches the equilibrium potential for Na⁺ (about +50 mV). Remember from the previous lecture on the resting membrane potential that the movement of an ion down its electrochemical gradient tends to move the membrane potential towards the equilibrium potential for that ion. In this case, Na⁺ entry into the cell through voltage-gated Na⁺ channels takes the membrane potentials close to the Na⁺ equilibrium potential (V_Na). Reversal of the sign where the membrane potential becomes positive is referred to as overshoot (2 in Fig. 2). Whereas at rest, the relative permeabilities of K⁺ (p_K) and Na⁺ (p_Na) are 1 : 0.05 (p_K : p_Na), at the peak of the action potential, the p_K : p_Na ratio is about 1 : 12. However, keep in mind that at the peak of the action potential the absolute value of p_K is also larger than its value at rest (see Fig. 5 below). At the peak of the action potential p_Na is about 600 times greater than its resting value, whereas p_K is about 3 times its resting value. If you use the Goldman-Hodgkin-Katz (GHK) equation and the permeability values at the peak of the action potential (p_K : p_Na ratio of 1 : 12), you can convince yourself that V_m approaches V_Na. While the maximum p_Na is observed at the peak of the action potential, the maximum value of p_K is observed shortly after the peak of the action potential (see Fig. 5 below).

At the peak of the action potential, the membrane potential is close to V_Na, but it never reaches V_Na (3 in Fig. 2). There are two reasons for this. First, the voltage-gated Na⁺ channels begin to inactivate spontaneously very rapidly after opening. Channel inactivation "plugs" the pore of the channel so that Na⁺ ions can no longer pass through the channel permeation pathway. A cytosolic region of the Na⁺ channel actually blocks the Na⁺ permeation pathway of the channel. This has been referred to as the ball-and-chain model of inactivation (Fig. 4). Ball refers to a globular cytoplasmic portion of channel protein that is tethered to the rest of the protein by a linker (or chain) part. A schematic representation of this process is shown in Fig. 4.

The second reason for the fact that the peak of the action potential does not reach V_Na is that neurons also have voltage-gated K⁺ channels that become activated by membrane depolarization (also at around the threshold voltage of −40 to −50 mV). Activation of the voltage-gated K⁺ channels, however, is much slower than that of voltage-gated Na⁺ channels (Fig. 5). For this reason, these K⁺ channels are referred to as delayed rectifiers. Therefore, at the peak of the action potential, p_K is greater than its value when the neuron is at rest, and movement of K⁺ out of the cell opposes the depolarization caused by the movement of Na⁺ into the cell (Fig. 5)

Once the peak of the action potential is reached, Na⁺ channels inactivate, and as a result p_Na falls rapidly with time, and approaches its value at rest (Fig. 5). At this time, however, because of the delayed response of the voltage-gated K⁺ channels to membrane depolarization, p_K is still becoming larger. Now the balance of ion flow across the membrane is in favor of K⁺ moving out of the cell. Movement of K⁺ out of the cell brings about rapid repolarization of the membrane back to the resting value (4 in Fig. 2). However, p_K remains elevated for some time even after V_m has reached the resting value (Fig. 5). Therefore, continued movement of K⁺ out of the cell causes a membrane hyperpolarization (i.e., more negative than V_rest). This phase is commonly referred to as the hyperpolarizing afterpotential or simply hyperpolarization (5 in Fig. 2). This is also sometimes referred to as undershoot. This occurs because during this time p_Na is at its resting value, but p_K is higher than its resting value. Therefore, K⁺ movement out of the cell will tend to move the V_m closer to V_K. Finally, p_K returns to its value at rest, and at this time the membrane potential also returns to baseline at its resting value of about −70 mV. It is important to note that K⁺ channels do not inactivate. They close simply because the membrane potential becomes more negative than the threshold potential (the potential at which Na⁺ and K⁺ channels become activated). Thus, the repolarization and hyperpolarization that is caused by movement of K⁺ out of the cell through the voltage-gated K⁺ channels, also causes the closing of the same voltage-gated K⁺ channels.