Specific aspects of the cell membrane’s electrical activity interact to convey information throughout the nervous system. The movement of ions across neuronal membranes produces the electrical activity that enables this information flow.

Figure 4-9 shows how the voltage difference is recorded when one microelectrode is placed on the outer surface of an axon’s membrane and another is placed on its inner surface. In the absence of stimulation, the difference is about 70 mV. Although the charge on the outside of the membrane is actually positive, by convention it is given a charge of zero. Therefore, the inside of the membrane at rest is –70 mV relative to the extracellular side.

If we were to continue to record for a long time, the charge across the unstimulated membrane would remain much the same. The charge can change, given certain changes in the membrane, but at rest the difference in charge on the inside and outside of the membrane produces an electrical potential—the ability to use its stored power, analogous to a charged battery. The charge is thus a store of potential energy called the membrane’s resting potential.

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We might use the term potential in the same way to talk about the financial potential of someone who has money in the bank—the person can spend the money at some future time. The resting potential, then, is a store of energy that can be used later. Most of your body’s cells have a resting potential, but it is not identical on every axon. Resting potentials vary from –40 to –90 mV, depending on neuronal type and animal species.

Four charged particles take part in producing the resting potential: ions of sodium (Na⁺), potassium (K⁺), chloride (Cl^–), and large protein molecules (A^–). These are the cations and anions, respectively, defined in Section 4-1. As Figure 4-10 shows, these charged particles are distributed unequally across the axon’s membrane, with more protein anions and potassium ions in the intracellular fluid and more chloride and sodium ions in the extracellular fluid. How do the unequal concentrations arise, and how does each contribute to the resting potential?

The cell membrane’s channels, gates, and pumps maintain the resting potential. Figure 4-11, which shows the resting membrane close up, details how these three features contribute to the cell membrane’s resting charge:

Inside the Cell

Large protein anions are manufactured inside cells. No membrane channels are large enough to allow these proteins to leave the cell, and their negative charge alone is sufficient to produce transmembrane voltage, or a resting potential. Because most cells in the body manufacture these large, negatively charged protein molecules, most cells have a charge across the cell membrane.

To balance the negative charge produced by large protein anions in the intracellular fluid, cells accumulate positively charged potassium ions to the extent that about 20 times as many potassium ions cluster inside the cell as outside it. Potassium ions cross the cell membrane through open potassium channels, as shown in Figure 4-11. With this high concentration of potassium ions inside the cell, however, the potassium concentration gradient across the membrane limits the number of potassium ions entering the cell. In other words, not all the potassium ions that could enter do enter. Because the internal concentration of potassium ions is much higher than the external potassium concentration, potassium ions are drawn out of the cell by the potassium concentration gradient.

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A few residual potassium ions on the outside of the membrane are enough to contribute to the charge across the membrane. They add to the negative charge on the intracellular side of the membrane relative to the extracellular side. You may be wondering whether you read the last sentence correctly. If there are 20 times as many potassium ions inside the cell as there are outside, why should the inside of the membrane have a negative charge? Should not all those potassium ions in the intracellular fluid give the inside of the cell a positive charge instead? No, because not quite enough potassium ions are able to enter the cell to balance the negative charge of the protein anions.

Think of it this way: if the number of potassium ions that could accumulate on the intracellular side of the membrane were unrestricted, the positively charged potassium ions inside would exactly match the negative charges on the intracellular protein anions. There would be no charge across the membrane at all. But the number of potassium ions that accumulate inside the cell is limited, because when the intracellular K⁺ concentration becomes higher than the extracellular concentration, further potassium ion influx is opposed by its concentration gradient.

Outside the Cell

The equilibrium of the potassium voltage and concentration gradients results in some potassium ions remaining outside the cell. It is necessary to have only a few potassium ions outside the cell to maintain a negative charge inside the cell. As a result, potassium ions contribute to the charge across the membrane.

Sodium (Na⁺) and chloride (Cl^–) ions also take part in producing the resting potential. If positively charged sodium ions were free to move across the membrane, they would diffuse into the cell and eliminate the transmembrane charge produced by the unequal distribution of potassium ions inside and outside the cell. This diffusion does not happen, because a gate on the sodium ion channels in the cell membrane is ordinarily closed (see Figure 4-11), blocking the entry of most sodium ions. Still, given enough time, sufficient sodium ions could leak into the cell to neutralize its membrane potential. The cell membrane has a different mechanism to prevent this neutralization.

When sodium ions do leak into the neuron, they are immediately escorted out again by the action of a sodium–potassium pump, a protein molecule embedded in the cell membrane. A membrane’s many thousands of pumps continually exchange three intracellular sodium ions for two potassium ions, as shown in Figure 4-11. The potassium ions are free to leave the cell through open potassium channels, but closed sodium channels slow the reentry of the sodium ions. In this way, sodium ions are kept out to the extent that about 10 times as many sodium ions reside on the outside of the axon membrane as on its inside. The difference in sodium concentrations also contributes to the membrane’s resting potential.

Now consider the chloride ions. Unlike sodium ions, chloride ions move in and out of the cell through open channels in the membrane. The equilibrium point, at which the chloride’s concentration gradient equals its voltage gradient, is approximately the same as the membrane’s resting potential, and so chloride ions ordinarily contribute little to the resting potential. At this equilibrium point, there are about 12 times as many chloride ions outside the cell as inside it.

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The cell membrane’s semipermeability and the actions of its channels, gates, and pumps thus produce voltage across the cell membrane: its resting potential (Figure 4-12).

The resting potential provides an energy store that can be used somewhat like the water in a dam: small amounts can be released by opening gates for irrigation or to generate electricity. If the concentration of any of the ions across the unstimulated cell membrane changes, the membrane voltage changes. These graded potentials are small voltage fluctuations across the cell membrane.

Stimulating a membrane electrically through a microelectrode mimics the way the membrane’s voltage changes to produce a graded potential in the living cell. If the voltage applied to the inside of the membrane is negative, the membrane potential increases in negative charge by a few millivolts. As illustrated in Figure 4-13A, it may change from a resting potential of –70 mV to a slightly greater potential of –73 mV.

This change is a hyperpolarization because the charge (polarity) of the membrane increases. Conversely, if positive voltage is applied inside the membrane, its potential decreases by a few millivolts. As illustrated in Figure 4-13B, it may change from, say, a resting potential of –70 mV to a slightly lower potential of –65 mV. This change is a depolarization because the membrane charge decreases. Graded potentials usually last only milliseconds.

Hyperpolarization and depolarization typically take place on the soma (cell body) membrane and on neuronal dendrites. These areas contain gated channels that can open and close, changing the membrane potential as illustrated in Figure 4-13. Three channels—for potassium, chloride, and sodium ions—underlie graded potentials:

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Evidence that potassium channels have a role in hyperpolarization comes from the fact that the chemical tetraethylammonium (TEA), which blocks potassium channels, also blocks hyperpolarization. The involvement of sodium channels in depolarization is indicated by the fact that the chemical tetrodotoxin (TTX), which blocks sodium channels, also blocks depolarization. The puffer fish, considered a delicacy in some countries, especially Japan, secretes this potentially deadly poison to fend off potential predators. Skill is required to prepare this fish for dinner. It can be lethal to the guests of careless cooks because its toxin impedes the electrical activity of neurons.

Electrical stimulation of the cell membrane at resting potential produces local graded potentials. An action potential is a brief but large reversal in an axon membrane’s polarity (Figure 4-14A). It lasts about 1 ms. The voltage across the membrane suddenly reverses, making the intracellular side positive relative to the extracellular side, then abruptly reverses again to restore the resting potential. Because the action potential is brief, many action potentials can occur within a second, as illustrated in Figure 4-14B and C, where the time scales are compressed.

An action potential occurs when a large concentration of first Na⁺ and then K⁺ crosses the membrane rapidly. The depolarizing phase of the action potential is due to Na⁺ influx, and the hyperpolarizing phase, to K⁺ efflux. Sodium rushes in, then potassium rushes out. As shown in Figure 4-15, the combined flow of sodium and potassium ions underlies the action potential.

An action potential is triggered when the cell membrane is depolarized to about –50 mV. At this threshold potential, the membrane charge undergoes a remarkable further change with no additional stimulation. The relative voltage of the membrane drops to zero and continues to depolarize until the charge on the inside of the membrane is as great as +30 mV—a total voltage change of 100 mV. Then the membrane potential reverses again, becoming slightly hyperpolarized—a reversal of a little more than 100 mV. After this second reversal, the membrane slowly returns to its resting potential at –70 mV.

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The action potential normally consists of the summed current changes caused first by the inflow of sodium and then by the outflow of potassium on an axon. Experimental results reveal that if an axon membrane is stimulated electrically while the solution surrounding the axon contains the chemical TEA (to block potassium channels), the result is a smaller-than-normal ion flow due entirely to an Na⁺ influx. Similarly, if an axon’s membrane is stimulated electrically while the solution surrounding the axon contains TTX (to block sodium channels), a slightly different ion flow due entirely to the efflux of K⁺ is recorded. Figure 4-16 represent ion flow rather than voltage change.

Role of Voltage-Sensitive Ion Channels

What cellular mechanisms underlie the movement of sodium and potassium ions to produce an action potential? The answer is the behavior of a class of gated sodium and potassium channels sensitive to the membrane’s voltage (Figure 4-17). These voltage-sensitive channels are closed when an axon’s membrane is at its resting potential: ions cannot pass through them. When the membrane reaches threshold voltage, the configuration of the voltage-sensitive channels alters: they open briefly, enabling ions to pass through, then close again to restrict ion flow. The sequence of actions:

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Action Potentials and Refractory Periods

There is an upper limit to how frequently action potentials occur, and sodium and potassium channels are responsible for it. Stimulation of the axon membrane during the depolarizing phase of the action potential will not produce another action potential. Nor is the axon able to produce another action potential when it is repolarizing. During these times, the membrane is described as being absolutely refractory.

If on the other hand the axon membrane is stimulated during hyperpolarization, another action potential can be induced, but the second stimulation must be more intense than the first. During this phase, the membrane is relatively refractory.

Refractory periods result from the way gates of the voltage-sensitive sodium and potassium channels open and close. Sodium channels have two gates, and potassium channels have one gate. Figure 4-18 illustrates the position of these gates before, during, and after the phases of the action potential. We describe changes first in the sodium channels and then in the potassium channels.

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During the resting potential, gate 1 of the sodium channel depicted in Figure 4-18 is closed; only gate 2 is open. At the threshold level of stimulation, gate 1 also opens. Gate 2, however, closes very quickly after gate 1 opens. This sequence produces a brief period during which both sodium gates are open. When both gates are open and when gate 2 is closed, the membrane is absolutely refractory.

The opening of the potassium channels repolarizes and eventually hyperpolarizes the cell membrane. The potassium channels open and close more slowly than the sodium channels do. The hyperpolarization produced by a continuing efflux of potassium ions makes it more difficult to depolarize the membrane to the threshold that reopens the gates underlying an action potential. While the membrane is hyperpolarizing, it is relatively refractory.

The action of a lever-activated toilet is analogous to some of the changes in polarity that take place during an action potential. Pushing the lever slightly produces a slight water flow that stops when the lever is released. This activity is analogous to a graded potential. A harder lever press brings the toilet to threshold and initiates flushing, a response that is out of all proportion to the lever press. This activity is analogous to the action potential.

During the flush, the toilet is absolutely refractory: another flush cannot be induced at this time. During the refilling of the bowl, in contrast, the toilet is relatively refractory, meaning that flushing again is possible but harder. Only after the cycle is over and the toilet is once again at rest can a full flush be produced again.

Suppose you place two recording electrodes at a distance from one another on an axon membrane, then electrically stimulate an area adjacent to one electrode. That electrode would immediately record an action potential. A similar recording would register on the second electrode in a flash. An action potential has arisen near this second electrode also, even though it is some distance from the original point of stimulation.

Is this second action potential simply an echo of the first that passes down the axon? No, it cannot be, because the action potential’s size and shape are exactly the same at the two electrodes. The second is not just a faint, degraded version of the first but is equal in magnitude. Somehow the full action potential has moved along the axon. This propagation of an action potential along an axon is called a nerve impulse.

Why does an action potential move? Remember that the total voltage change during an action potential is 100 mV, far beyond the 20-mV change needed to bring the membrane from its resting state of –70 mV to the action potential threshold level of –50 mV. Consequently, the voltage change on the part of the membrane where an action potential first occurs is large enough to bring adjacent parts of the membrane to a threshold of –50 mV.

When the membrane at an adjacent part of the axon reaches –50 mV, the voltage-sensitive channels at that location pop open to produce an action potential there as well. This second occurrence in turn induces a change in the membrane voltage still farther along the axon, and so on and on, down the axon’s length. Figure 4-19 illustrates this process. The nerve impulse occurs because each action potential propagates another action potential on an adjacent part of the axon membrane. The word propagate means to give birth, and that is exactly what happens. Each successive action potential gives birth to another down the length of the axon.

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Because they are propagated by gated ion channels acting on the membrane in their own vicinity, action potentials on a nerve or tract are the same magnitude wherever they occur. An action potential depends on energy expended where it occurs, and the same amount of energy is expended at every site along the membrane as a nerve impulse is propagated.

As a result, action potentials do not dissipate: an action potential is either generated completely or not generated at all. Action potentials are all-or-none events. As the nerve’s impulse, or message, the action potential maintains a constant size and arrives unchanged to every terminal on the nerve that receives it.

Think of the voltage-sensitive channels along the axon as a series of dominoes. When one falls, it knocks over its neighbor, and so on down the line. There is no decrement in the size of the fall. The last domino travels exactly the same distance and falls just as hard as the first one did.

Essentially, the domino effect happens when voltage-sensitive channels open. The opening of one channel produces a voltage change that triggers its neighbor to open, just as one domino knocks over the next. The channel-opening response does not grow any weaker as it moves along the axon, and the last channel opens exactly like the first, just as the domino action stays constant to the end of the line.

Refractory periods are determined by the position of the gates that mediate ion flow in the voltage-sensitive channels. This limits the frequency of action potentials to about 5 ms. The action potential’s refractory phase thus has two practical uses for nerves that are conducting information.

First, the maximum rate at which action potentials can occur is about 200 per second (1 s or 1000 ms/5 ms limit = 200 action potentials in 1 s). The sensitivity of voltage-sensitive channels, which varies among kinds of neurons, likewise affects firing frequency.

Second, although an action potential can travel in either direction on an axon, refractory periods prevent it from reversing direction and returning to its point of origin. Refractory periods thus produce a single, discrete impulse that travels away from the initial point of stimulation. When an action potential begins near the cell body, it usually travels down the axon to the terminals.

To return to our domino analogy, once a domino falls, setting it back up takes time. This is its refractory period. Because each domino falls as it knocks down its neighbor, the sequence cannot reverse until the domino is set upright again: the dominos can fall in only one direction. The same principle determines the action potential’s direction.

Because the giant axons of squid are so large, they can transmit nerve impulses very quickly, much as a large-diameter pipe can rapidly deliver a lot of water. But large axons take up substantial space: a squid cannot accommodate many of them or its body would be too bulky. For us mammals, with our many axons producing repertoires of complex behaviors, giant axons are out of the question. Our axons must be extremely slender because our complex behaviors require a great many of them.

Our largest axons are only about 30 µm wide, so the speed with which they convey information should not be especially fast. And yet, like most vertebrate species, we humans are hardly sluggish creatures. We process information and generate responses with impressive speed. How do we manage to do so if our axons are so thin? The vertebrate nervous system has evolved a solution that has nothing to do with axon size.

Glial cells play a role in speeding nerve impulses in the vertebrate nervous system. Schwann cells in the human peripheral nervous system and oligodendroglia in the central nervous system wrap around each axon, forming the myelin sheath that insulates it (Figure 4-20). Action potentials cannot occur where myelin is wrapped around an axon. For one thing, the myelin is an insulating barrier to ionic current flow. For another, axonal regions that lie under myelin have few channels through which ions can flow, and ion channels are essential to generating an action potential.

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But axons are not totally encased in myelin. Unmyelinated gaps between successive glial cells are richly endowed with voltage-sensitive channels. These tiny gaps in the myelin sheath, the nodes of Ranvier, are sufficiently close to one another that an action potential at one node can open voltage-sensitive gates at an adjacent node. In this way, a relatively slow action potential jumps quickly from node to node, as shown in Figure 4-21. This flow of energy is called saltatory conduction (from the Latin verb saltare, meaning to leap).

Myelin has two important consequences for propagating action potentials. First, propagation becomes energetically cheaper, since action potentials regenerate only at the nodes of Ranvier, not along the axon’s entire length. Action potential conduction in unmyelinated axons, by contrast, has a significant metabolic energy cost (Crotty et al., 2006). The second consequence is that myelin improves the action potential’s conduction speed.

Jumping from node to node speeds the rate at which an action potential can travel along an axon, because the current flowing within the axon beneath the myelin sheath travels very fast. While the current moves speedily, the voltage drops quickly over distance. But the nodes of Ranvier are spaced ideally to ensure sufficient voltage at the next node to regenerate the action potential. On larger, myelinated mammalian axons, nerve impulses can travel at a rate as high as 120 meters per second. On smaller, uninsulated axons they travel only about 30 meters per second.

Spectators at sporting events sometimes initiate a wave that travels around a stadium. Just as one person rises, the next person begins to rise, producing the wave effect. This human wave is like conduction along an unmyelinated axon. Now think of how much faster the wave would complete its circuit around the field if only spectators in the corners rose to produce it. This is analogous to a nerve impulse that travels by jumping from one node of Ranvier to the next. The quick reactions that humans and other mammals are capable of are due in part to this saltatory conduction in their nervous system.

Neurons that send messages over long distances quickly, including sensory and motor neurons, are heavily myelinated. If myelin is damaged, a neuron may be unable to send any messages over its axons. In multiple sclerosis (MS), the myelin formed by oligodendroglia is damaged, which disrupts the functioning of neurons whose axons it encases. Clinical Focus 4-2, Multiple Sclerosis on page 126, describes the course of the disease.

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Electrical Activity of a Membrane

Before you continue, check your understanding.

Question 1

Question 2

Question 3

Question 4

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Question 5

Answers appear in the Self Test section of the book.