Action potentials are propagated changes in the transmembrane potential that, once initiated, affect an entire excitable membrane. In a representative neuron, an action potential generally begins at the initial segment of the axon. The action potential is then propagated along the length of the axon, ultimately reaching the synaptic terminals. The action potential begins with the opening of voltage-regulated sodium ion channels at one site. The movement of sodium ions into the cell depolarizes adjacent sites, triggering the opening of additional voltage-regulated channels. The result is a chain reaction that spreads across the membrane surface like a line of falling dominoes.

The All-or-None Principle

The stimulus that initiates an action potential is a depolarization large enough to open voltage-regulated sodium channels. That opening occurs at a transmembrane potential known as the threshold. Threshold for an axon is typically between –60 mV and –55 mV, a depolarization of 10-15 mV. A stimulus that shifts the resting membrane potential from –70 mV to –62 mV will not produce an action potential, only a graded depolarization. When such a stimulus is removed, the transmembrane potential returns to the resting level. The depolarization of the initial segment of the axon is caused by local currents resulting from the graded depolarization of the axon hillock.

The initial depolarization acts like pressure on the trigger of a gun. If a slight pressure is applied, the gun will not fire. It will fire only when a certain minimum pressure is applied to the trigger. Once the trigger pressure reaches this threshold, the firing pin drops and the gun discharges. At that point, it no longer matters whether the pressure was applied gradually or suddenly, or whether it was caused by the precise movement of just one finger or by the clenching of the entire hand. The speed and range of the bullet that leaves the gun do not change, regardless of the forces that were applied to the trigger.

In the case of an axon or another area of excitable membrane, a graded depolarization is the pressure on the trigger, and the action potential is the firing of the gun. All stimuli that bring the membrane to threshold generate identical action potentials. In other words, the properties of the action potential are independent of the relative strength of the depolarizing stimulus as long as that stimulus exceeds threshold. This concept is called the all-or-none principle, because a given stimulus either triggers a typical action potential or does not produce one at all. If an action potential is produced, it will be propagated over the entire surface of the excitable membrane. The all-or-none principle applies to all excitable membranes. An action potential is generated at one site as the result of a localized depolarization. It is then propagated away from that site. We will consider each process individually.

Action Potential Generation

Figure 12-15 diagrams the steps involved in the generation of an action potential from the resting state. At the normal resting potential, the activation gates of the voltage-regulated sodium channels are closed:

step 1: Depolarization to threshold. Before an action potential can begin, an area of excitable membrane must be depolarized to threshold by local currents.

step 2: The activation of sodium channels and rapid depolarization. At threshold, the sodium activation gates open and the cell membrane becomes much more permeable to Na⁺. Driven by the large electrochemical gradient, sodium ions rush into the cytoplasm, and rapid depolarization occurs at this site. In less than a millisecond, the inner membrane surface has changed; it now contains more positive ions than negative ones, and the transmembrane potential has changed from –60 mV to positive values closer to the equilibrium potential for sodium (+66 mV).

Notice that the first two steps in action potential generation are an example of positive feedback: A small depolarization triggers the production of a larger depolarization.

step 3: The inactivation of sodium channels and the activation of potassium channels. As the transmembrane potential approaches +30 mV, the inactivation gates of the voltage-regulated sodium channels begin closing. This step is known as sodium channel inactivation. While sodium channel inactivation is under way, voltage-regulated potassium channels are opening. At a transmembrane potential of +30 mV, the cytosol along the interior of the membrane contains an excess of positive charges. Thus, in contrast to the situation in the resting membrane, both the electrical and chemical gradients favor the movement of K⁺ out of the cell. The sudden loss of positive charges then shifts the transmembrane potential back toward resting levels, and repolarization begins.

step 4: The return to normal permeability. The voltage-regulated sodium channels remain inactivated until the membrane has repolarized to threshold, about –60 mV. At this time, they regain their normal status--closed but capable of opening. The voltage-regulated potassium channels begin closing as the membrane reaches the normal resting potential (about –70 mV), but the process takes about a millisecond. Over that period, potassium ions continue to move out of the cell at a faster rate than when at rest, producing a brief hyperpolarization that brings the transmembrane potential very close to the equilibrium potential for potassium (–90 mV). As the voltage-regulated potassium channels close, the transmembrane potential returns to normal resting levels. The membrane is now in a prestimulation condition, and the action potential is over.

The Refractory Period From the time an action potential begins until the normal resting potential has stabilized, the membrane will not respond normally to additional depolarizing stimuli. This period is known as the refractory period of the membrane. From the moment the voltage-regulated sodium channels open at threshold until sodium channel inactivation ends, the membrane cannot respond to further stimulation, because all the voltage-regulated sodium channels are either already open or are inactivated. This portion of the refractory period is the absolute refractory period. The relative refractory period begins when the sodium channels regain their normal resting condition and continues until the transmembrane potential stabilizes at normal resting levels. Another action potential can begin if the membrane is depolarized to threshold, but that depolarization requires a larger-than-normal depolarizing stimulus because (1) the local current must deliver enough Na⁺ to counteract the loss of positively charged K⁺ through voltage-regulated K⁺ channels, and (2) through most of the relative refractory period, the membrane is hyperpolarized to some degree.

The Role of the Sodium–Potassium Exchange Pump In an action potential, depolarization results from the influx of Na⁺ and repolarization involves the loss of K⁺. Over time, the sodium–potassium exchange pump returns intracellular and extracellular ion concentrations to prestimulation levels. Compared with the total number of ions inside and outside the cell, however, the number involved in a single action potential is insignificant. Tens of thousands of action potentials can occur before intracellular ion concentrations change enough to disrupt the entire mechanism. Thus the exchange pump is not essential to any single action potential.

However, a maximally stimulated neuron can generate action potentials at a rate of 1000 per second. Under these circumstances, the exchange pump is needed if ion concentrations are to remain within acceptable limits over a prolonged period. The sodium–potassium exchange pump requires energy in the form of ATP. Each time the pump exchanges two extracellular potassium ions for three intracellular sodium ions, one molecule of ATP is broken down to ADP. The transmembrane protein of the exchange pump is called sodium–potassium ATPase because it splits ATP to ADP. If sodium–potassium ATPase is inactivated by a metabolic poison or if the cell runs out of ATP, a neuron will soon lose its ability to function.

Table 12-3 summarizes the process of action potential generation.

Action Potential Propagation

The sequence of events described earlier occurs in a relatively small portion of the total membrane surface. But we have already noted that, unlike graded potentials, which diminish rapidly with distance, action potentials spread to affect the entire excitable membrane. To understand the basic principle involved, imagine that you are standing by the doors of a movie theater at the start of a long line. Everyone is waiting for the doors to open. The manager steps outside and says to you, "Let everyone know that we're opening in 15 minutes." How would you spread the news? If you treated the line as an inexcitable membrane, you would shout "The doors open in 15 minutes!" as loudly as you could. The closest people in the line would hear the news very clearly, but those farther away might not hear the entire message, and those at the end of the line might not hear you at all. If you treated the crowd as an excitable membrane, you would give the message to another person in line, with instructions to pass it on. In this way, the message would travel along the line until everyone had heard the news. Such a message "moves" as each person repeats it to someone else. Distance is not a factor; the line can contain 50 people or 5000.

This situation is comparable to the way an action potential spreads across an excitable membrane. An action potential (message) is relayed from one location to another in a series of steps. At each step, the message is repeated. Because the same events take place over and over, the term propagation is preferable to the term conduction.

Continuous Propagation The basic mechanism of action potential propagation along an unmyelinated axon is shown in Figure 12-16. For convenience, we will consider the membrane as a series of adjacent segments. The action potential begins at the initial segment. For a brief moment at the peak of the action potential, the transmembrane potential becomes positive rather than negative (Figure 12-16a). A local current then develops, and sodium ions begin moving in the cytosol and in the extracellular fluid (Figure 12-16b). The local current spreads in all directions, depolarizing adjacent portions of the membrane. The axon hillock cannot respond with an action potential (like the rest of the cell body, it lacks voltage-gated channels). But when the adjacent segment of the axon is depolarized to threshold, an action potential develops there. The process then continues in a chain reaction (Figure 12-16c, d). Eventually, the most distant portions of the cell membrane will be affected. As in our "movie line" model, the message is being relayed from one location to another. At each step along the way, the message is retold, so distance has no effect on the process. The action potential reaching the synaptic knob is identical to the one generated at the initial segment, and the net effect is the same as if a single action potential had traveled across the membrane surface. This form of action potential propagation is known as continuous propagation.

Each time a local current develops, the action potential moves forward, not backward, because the previous segment of the axon is still in the absolute refractory period. As a result, an action potential always proceeds away from the site of generation and cannot reverse direction. For a second action potential to occur at the same site, a second stimulus must be applied.

In continuous propagation, an action potential appears to move across the membrane surface in a series of tiny steps. Even though the events at any one location take only about a millisecond, the sequence must be repeated at each step along the way. Continuous propagation along unmyelinated axons occurs at speeds of about 1 meter per second (approximately 2 mph).

Saltatory Propagation In a myelinated axon, the axolemma is wrapped in a myelin sheath that is complete except at the nodes. Continuous propagation cannot occur along a myelinated axon, because myelin increases resistance to the flow of ions across the membrane. Ions can readily cross the cell membrane only at the nodes. As a result, only the nodes can respond to a depolarizing stimulus.

When an action potential appears at the initial segment of a myelinated axon, the local current skips the internodes and depolarizes the closest node to threshold (Figure 12-17). Because the nodes may be 1-2 mm apart in a large myelinated axon, the action potential "jumps" from node to node rather than moving along the axon in a series of tiny steps. This process is saltatory propagation. Imagine relaying a message along a line of people spaced 5 meters apart. Each person shouts the message to the next person in line; by the time the message has been repeated four times, it has moved 20 meters. In our model of continuous propagation, in which people were closely packed, the message would have moved only a few meters by the time it had been repeated four times. Saltatory propagation in the CNS and PNS carries nerve impulses along an axon much more rapidly than does continuous propagation. It also uses proportionately less energy, because less surface area is involved and fewer sodium ions need to be pumped out of the cytoplasm.

Table 12-4 reviews key differences between graded potentials and actionpotentials.

Axon Diameter and Propagation Speed

Axon diameter, as well as myelination, affects propagation velocity. To depolarize adjacent portions of the cell membrane, ions must move through the cytoplasm. Cytoplasm offers resistance to ion movement, although the resistance is much less than that of the cell membrane. In this instance, an axon behaves like an electrical cable: The larger the diameter, the lower the resistance. (That is why motors with large current demands, such as the starter on a car, an electric stove, or a big air conditioner, use such thick wires.)

Axons are classified into three groups according to the relationships among diameter, myelination, and propagation speed:

1. Type A fibers are the largest axons, with diameters ranging from 4 to 20 µm. These are myelinated axons that carry action potentials at speeds of up to 140 meters per second, or over 300 mph.
2. Type B fibers are smaller myelinated axons, with diameters of 2-4 µm. Their propagation speeds average around 18 meters per second, or roughly 40 mph.
3. Type C fibers are unmyelinated and less than 2 µm in diameter. These axons propagate action potentials at the leisurely pace of 1 meter per second, or a mere 2 mph.

We can understand the relative importance of myelin by noting that in going from Type C to Type A fibers, the diameter increases tenfold but the propagation speed increases by 140 times!

Type A fibers carry to the CNS sensory information about position, balance, and delicate touch and pressure sensations from the skin surface. The motor neurons that control skeletal muscles also send their commands over large, myelinated Type A axons. Type B fibers and Type C fibers carry to the CNS information about temperature, pain, and general touch and pressure sensations and carry instructions to smooth muscle, cardiac muscle, glands, and other peripheral effectors.

When we need to tell a friend urgent news or receive an immediate response, we usually pick up the telephone. For general correspondence, we usually send a first-class letter or an e-mail message, both of which produce fast but not immediate responses. If we have to distribute an enormous volume of information to a huge number of people and are in no particular rush, bulk mail offers efficiency at a considerable savings. Instead of representing a compromise between time and money, information transfer in the nervous system reflects a compromise between time and space. Axons carry the information, and the larger the axon, the faster the rate of transmission. But if all sensory information were carried by Type A fibers, your peripheral nerves would be the size of garden hoses and your spinal cord would have the diameter of a garbage can. Instead, only around one-third of all axons carrying sensory information are myelinated, and most sensory information arrives over slender Type C fibers.

Myelination improves coordination and control by decreasing the time between the reception of a sensation and the initiation of an appropriate response. Myelination begins relatively late in development, and the myelination of sensory and motor fibers is not completed until early adolescence. In growing children, the pace of myelination and the pathways involved can be quite variable. This variability contributes to the observed range of physical capabilities in a given age group.

Action Potentials in Muscle Tissues

Although neurons, skeletal muscle fibers, multiunit smooth muscle cells, and cardiac muscle cells have excitable membranes, their action potentials differ in several important ways:

• The potential difference is larger in muscle cells than in axons. The resting potential of a skeletal, cardiac, or multiunit smooth muscle cell is –85 mV to –90 mV, close to the potassium equilibrium potential. Threshold values in these cells are comparable to those of axons.
• Action potentials last longer in muscle cells than in axons. An action potential in an axon may last 0.5 msec, versus 7.5 msec in a skeletal muscle fiber, 50 msec in a multiunit smooth muscle cell, and 250-300 msec in a cardiac muscle cell from one of the ventricles.
• Despite the large diameters of muscle cells, action potentials are propagated relatively slowly. Action potentials of muscle cells travel by continuous propagation at speeds of 3-5 meters per second (6-10 mph).

Visceral smooth muscle cells do not have typical excitable membranes, and most have neither stable resting potentials nor action potentials comparable to those of other muscle types. When visceral smooth muscle cells are stimulated to contract, changes in the transmembrane potential reflect primarily changes in the membrane permeability to calcium ions.

 How would a chemical that blocks the sodium channels in neuron cell membranes affect a neuron's ability to depolarize?

 What effect would decreasing the concentration of extracellular potassium ions have on the transmembrane potential of a neuron?

 One axon propagates action potentials at 50 meters per second; another carries them at 1 meter per second. Which axon is myelinated?

Potentially deadly forms of poisoning result from eating seafood containing neurotoxins, poisons that affect primarily neurons. Several neurotoxins, such as tetrodotoxin (TTX), prevent sodium from entering voltage-regulated sodium channels. The result is an inability to generate action potentials. Motor neurons cannot function under these conditions, and death by suffocation can result from paralysis of the respiratory muscles. Neurotoxins in Seafood