Electrical Signals in Neurons

Nerve and muscle cells are described as excitable tissues because of their ability to propagate electrical signals rapidly in response to a stimulus. We now know that many other cell types generate electrical signals to initiate intracellular processes [see insulin secretion], but the ability of nerve and muscle cells to send a constant electrical signal over long distance is characteristic of electrical signaling in these tissues.

The Nernst Equation Predicts Membrane Potential for a Single Ion

Recall that all living cells have a resting membrane potential difference (Vm) [here] that represents the separation of electrical charge across the cell membrane. Two factors influence the membrane potential:

  1. The uneven distribution of ions across the cell membrane. Normally, sodium (Na+), chloride (Cl-), and calcium (Ca2+) are more concentrated in the extracellular fluid than in the cytosol. Potassium (K+) is more concentrated in the cytosol than in the extracellular fluid.

  2. Differing membrane permeability to those ions. The resting cell membrane is much more permeable to K+ than to Na+ or Ca2+. This makes K+ the major ion contributing to the resting membrane potential.

The Nernst equation describes the membrane potential that would result if the membrane were permeable to only one ion [here]. For any given ion concentration gradient, this membrane potential is called the equilibrium potential of the ion ( E ion )

E ion ( in mV ) = 61 Z log [ ion ] out [ ion ] in

where:

(R is the ideal gas constant, T is absolute temperature, and F is the Faraday constant. For additional information on these values, see Appendix B.)

When we use the estimated intracellular and extracellular concentrations for K+ (TBL. 8.2) in the Nernst equation, the equation predicts a potassium equilibrium potential, or EK of −90 mV. However, an average value for the resting membrane potential of neurons is −70 mV (inside the cell relative to outside), more positive than predicted by the potassium equilibrium potential. This means that other ions must be contributing to the membrane potential. Neurons at rest are slightly permeable to Na+, and the leak of positive Na+ into the cell makes the resting membrane potential slightly more positive than it would be if the cell were permeable only to K+.

Table 8.2 Ion Concentrations and Equilibrium Potentials

Ion Extracellular Fluid (mM) Intracellular Fluid (mM) Eion at 37 °C
K+ 5 mM (normal: 3.5–5) 150 mM −90 mV
Na+ 145 mM (normal: 135–145) 15 mM +60 mV
Cl- 108 mM (normal: 100–108) 10 mM (normal: 5–15) −63 mV
Ca2+ 1 mM 0.0001 mM See Concept Check question 7.

Concept Check

  1. Given the values in Table 8.2, use the Nernst equation to calculate the equilibrium potential for Ca2+. Express the concentrations as powers of 10 and use your knowledge of logarithms to try the calculations without a calculator.

The GHK Equation Predicts Membrane Potential Using Multiple Ions

In living systems, several different ions contribute to the membrane potential of cells. The Goldman-Hodgkin-Katz (GHK) equation calculates the membrane potential that results from the contribution of all ions that can cross the membrane. The GHK equation includes membrane permeability values because the permeability of an ion influences its contribution to the membrane potential. If the membrane is not permeable to a particular ion, that ion does not affect the membrane potential.

For mammalian cells, we assume that Na+, K+, and Cl- are the three ions that influence membrane potential in resting cells. Each ion’s contribution to the membrane potential is proportional to its ability to cross the membrane. The GHK equation for cells that are permeable to Na+, K+, and Cl- is

V m = 61 log P k [ k + ] out + P Na [ Na + ] out + P Cl [ Cl - ] in P k [ k + ] in + P Na [ Na + ] in + P Cl [ Cl - ] out

where:

Although this equation looks quite intimidating, it can be simplified into words to say: Resting membrane potential (Vm) is determined by the combined contributions of the (concentration gradient × membrane permeability) for each ion.

If the membrane is not permeable to an ion, the permeability value for that ion is zero, and the ion drops out of the equation. For example, cells at rest normally are not permeable to Ca2+ and, therefore, Ca2+ is not part of the GHK equation.

The GHK equation predicts resting membrane potentials based on given ion concentrations and membrane permeabilities. Notice that if permeabilities for Na+ and Cl- are zero, the equation reverts back to the Nernst equation for K+. The GHK equation explains how the cell’s slight permeability to Na+ makes the resting membrane potential more positive than the EK determined with the Nernst equation. The GHK equation can also be used to predict what happens to membrane potential when ion concentrations or membrane permeabilities change.

Ion Movement Creates Electrical Signals

The resting membrane potential of living cells is determined primarily by the K+ concentration gradient and the cell’s resting permeability to K+, Na+, and Cl-. A change in either the K+ concentration gradient or ion permeabilities changes the membrane potential. If you know numerical values for ion concentrations and permeabilities, you can use the GHK equation to calculate the new membrane potential.

In medicine, you usually will not have numerical values, however, so it is important to be able to think conceptually about the relationship between ion concentrations, permeabilities, and membrane potential. For example, at rest, the cell membrane of a neuron is only slightly permeable to Na+. If the membrane suddenly increases its Na+ permeability, Na+ enters the cell, moving down its electrochemical gradient [here]. The addition of positive Na+ to the intracellular fluid depolarizes the cell membrane and creates an electrical signal.

The movement of ions across the membrane can also hyperpolarize a cell. If the cell membrane suddenly becomes more permeable to K+, positive charge is lost from inside the cell, and the cell becomes more negative (hyperpolarizes). A cell may also hyperpolarize if negatively charged ions, such as Cl-, enter the cell from the extracellular fluid.

Concept Check

  1. Would a cell with a resting membrane potential of −70 mV depolarize or hyperpolarize in the following cases? (You must consider both the concentration gradient and the electrical gradient of the ion to determine net ion movement.)

    1. (a) Cell becomes more permeable to Ca2+.

    2. (b) Cell becomes less permeable to K+.

  2. Would the cell membrane depolarize or hyperpolarize if a small amount of Na+ leaked into the cell?

It is important to understand that a change in membrane potential from −70 mV to a positive value, such as +30 mV does not mean that the ion concentration gradients have reversed! A significant change in membrane potential occurs with the movement of very few ions. For example, to change the membrane potential by 100 mV, only 1 of every 100,000 K+ must enter or leave the cell. This is such a tiny fraction of the total number of K+ in the cell that the intracellular concentration of K+ remains essentially unchanged even though the membrane potential has changed by 100 mV.

To appreciate how a tiny change can have a large effect, think of getting one grain of beach sand into your eye. There are so many grains of sand on the beach that the loss of one grain is not significant, just as the movement of one K+ across the cell membrane does not significantly alter the concentration of K+. However, the electrical signal created by moving a few K+ across the membrane has a significant effect on the cell’s membrane potential, just as getting that one grain of sand in your eye creates significant discomfort.

Gated Channels Control the Ion Permeability of the Neuron

How does a cell change its ion permeability? The simplest way is to open or close existing channels in the membrane. Neurons contain a variety of gated ion channels that alternate between open and closed states, depending on the intracellular and extracellular conditions [here]. A slower method for changing membrane permeability is for the cell to insert new channels into the membrane or remove some existing channels.

Ion channels are usually named according to the primary ion(s) they allow to pass through them. There are four major types of selective ion channels in the neuron: (1) Na+ channels, (2) K+ channels, (3) Ca2+ channels, and (4) Cl- channels. Other channels are less selective, such as the monovalent cation channels that allow both Na+ and K+ to pass.

The ease with which ions flow through a channel is called the channel’s conductance (G) {conductus, escort}. Channel conductance varies with the gating state of the channel and with the channel protein isoform. Some ion channels, such as the K+ leak channels that are the major determinant of resting membrane potential, spend most of their time in an open state. Other channels have gates that open or close in response to particular stimuli. Most gated channels fall into one of three categories [here]:

  1. Mechanically gated ion channels are found in sensory neurons and open in response to physical forces such as pressure or stretch.

  2. Chemically gated ion channels in most neurons respond to a variety of ligands, such as extracellular neurotransmitters and neuromodulators or intracellular signal molecules.

  3. Voltage-gated ion channels respond to changes in the cell’s membrane potential. Voltage-gated Na+ and K+ channels play an important role in the initiation and conduction of electrical signals along the axon.

Not all voltage-gated channels behave in exactly the same way. The voltage for channel opening varies from one channel type to another. For example, some channels we think of as leak channels are actually voltage-gated channels that remain open in the voltage range of the resting membrane potential.

The speed with which a gated channel opens and closes also differs among different types of channels. Channel opening to allow ion flow is called channel activation. For example, Na+ channels and K+ channels of axons are both activated by cell depolarization. The Na+ channels open very rapidly, but the K+ channels are slower to open. The result is an initial flow of Na+ across the membrane, followed later by K+ flow.

Many channels that open in response to depolarization close only when the cell repolarizes. The gating portion of the channel protein has an electrical charge that moves the gate between open and closed positions as membrane potential changes. This is like a spring-loaded door: It opens when you push on it, then closes when you release it.

Some channels also spontaneously inactivate. Even though the activating stimulus that opened them continues, the channel “times out” and closes. This is similar to doors with an automatic timed open-close mechanism. The door opens when you hit the button, then after a certain period of time, it closes itself, whether you are still standing in the doorway or not. An inactivated channel returns to its normal closed state shortly after the membrane repolarizes. The specific mechanisms underlying channel inactivation vary with different channel types.

Each major channel type has several to many subtypes with varying properties, and the list of subtypes gets longer each year. Within each subtype there may be multiple isoforms that express different opening and closing kinetics {kinetikos, moving} as well as associated proteins that modify channel properties. In addition, channel activity can be modulated by chemical factors that bind to the channel protein, such as phosphate groups.

Current Flow Obeys Ohm’s Law

When ion channels open, ions may move into or out of the cell. The flow of electrical charge carried by an ion is called the ion’s current, abbreviated Iion. The direction of ion movement depends on the electrochemical (combined electrical and concentration) gradient of the ion. Potassium ions usually move out of the cell. Na+, Cl-, and Ca2+ usually flow into the cell. The net flow of ions across the membrane depolarizes or hyperpolarizes the cell, creating an electrical signal.

Current flow, whether across a membrane or inside a cell, obeys a rule known as Ohm’s Law. Ohm’s Law says that current flow (I) is directly proportional to the electrical potential difference (in volts, V) between two points and inversely proportional to the resistance (R) of the system to current flow: I = V × 1 / R or I = V / R . In other words, as resistance R increases, current flow I decreases. (You will encounter a variant of Ohm’s Law when you study fluid flow in the cardiovascular and respiratory systems.)

Resistance in biological flow is the same as resistance in everyday life: It is a force that opposes flow. Electricity is a form of energy and, like other forms of energy it dissipates as it encounters resistance. As an analogy, think of rolling a ball along the floor. A ball rolled across a smooth wood floor encounters less resistance than a ball rolled across a carpeted floor. If you throw both balls with the same amount of energy, the ball that encounters less resistance retains energy longer and travels farther along the floor.

In biological electricity, resistance to current flow comes from two sources: the resistance of the cell membrane (Rm) and the internal resistance of the cytoplasm (Ri). The phospholipid bilayer of the cell membrane is normally an excellent insulator, and a membrane with no open ion channels has very high resistance and low conductance. If ion channels open, ions (current) flow across the membrane if there is an electrochemical gradient for them. Opening ion channels therefore decreases the membrane resistance.

The internal resistance of most neurons is determined by the composition of the cytoplasm and the diameter of the cell. Cytoplasmic composition is relatively constant. Internal resistance decreases as cell diameter increases. The membrane resistance and internal resistance together determine how far current will flow through a cell before the energy is dissipated and the current dies. The combination of the two resistances is called the length constant for a given neuron.

Voltage changes across the membrane can be classified into two basic types of electrical signals: graded potentials and action potentials (TBL. 8.3). Graded potentials are variable-strength signals that travel over short distances and lose strength as they travel through the cell. They are used for short-distance communication. If a depolarizing graded potential is strong enough when it reaches an integrating region within a neuron, the graded potential initiates an action potential. Action potentials are very brief, large depolarizations that travel for long distances through a neuron without losing strength. Their function is rapid signaling over long distances, such as from your toe to your brain.

Table 8.3 Comparison of Graded Potential and Action Potential in Neurons

Graded Potential Action Potential
Type of Signal Input signal Regenerating conduction signal
Occurs Where? Usually dendrites and cell body Trigger zone through axon
Types of Gated Ion Channels Involved Mechanically, chemically, or voltage-gated channels Voltage-gated channels
Ions Involved Usually Na+, K+, Ca2+ Na+ and K+
Type of Signal Depolarizing (e.g., Na+) or hyperpolarizing (e.g., Cl-) Depolarizing
Strength of Signal Depends on initial stimulus; can be summed All-or-none phenomenon; cannot be summed
What Initiates the Signal? Entry of ions through gated channels Above-threshold graded potential at the trigger zone opens ion channels

Unique Characteristics

No minimum level required to initiate Threshold stimulus required to initiate
Two signals coming close together in time will sum Refractory period: two signals too close together in time cannot sum
Initial stimulus strength is indicated by frequency of a series of action potentials

Graded Potentials Reflect Stimulus Strength

Graded potentials in neurons are depolarizations or hyperpolarizations that occur in the dendrites and cell body or, less frequently, near the axon terminals. These changes in membrane potential are called “graded” because their size, or amplitude {amplitudo, large}, is directly proportional to the strength of the triggering event. A large stimulus causes a strong graded potential, and a small stimulus results in a weak graded potential.

In neurons of the CNS and the efferent division, graded potentials occur when chemical signals from other neurons open chemically gated ion channels, allowing ions to enter or leave the neuron. Mechanical stimuli (such as stretch) or chemical stimuli open ion channels in some sensory neurons. Graded potentials may also occur when an open channel closes, decreasing the movement of ions through the cell membrane. For example, if K+ leak channels close, fewer K+ leave the cell. The retention of K+ depolarizes the cell.

Concept Check

  1. Match each ion’s movement with the type of graded potential it creates.

    1. (a) Na+ entry

    2. (b) Cl- entry

    3. (c) K+ exit

    4. (d) Ca2+ entry

    1. depolarizing

    2. hyperpolarizing

Figure 8.7a shows a graded potential that begins when a stimulus opens monovalent cation channels on the cell body of a neuron. Sodium ions move into the neuron, bringing in electrical energy. The positive charge carried in by the Na+ spreads as a wave of depolarization through the cytoplasm, just as a stone thrown into water creates ripples or waves that spread outward from the point of entry. The wave of depolarization that moves through the cell is known as local current flow. By convention, current in biological systems is the net movement of positive electrical charge.

The strength of the initial depolarization in a graded potential is determined by how much charge enters the cell, just as the size of waves caused by a stone tossed in water is determined by the size of the stone. If more Na+ channels open, more Na+ enters, and the graded potential has higher initial amplitude. The stronger the initial amplitude, the farther the graded potential can spread through the neuron before it dies out.

Why do graded potentials lose strength as they move through the cytoplasm? Two factors play a role:

  1. Current leak. The membrane of the neuron cell body has open leak channels that allow positive charge to leak out into the extracellular fluid. Some positive ions leak out of the cell across the membrane as the depolarization wave moves through the cytoplasm, decreasing the strength of the signal moving down the cell.

  2. Cytoplasmic resistance. The cytoplasm provides resistance to the flow of electricity, just as water creates resistance that diminishes the waves from the stone. The combination of current leak and cytoplasmic resistance means that the strength of the signal inside the cell decreases over distance.

Graded potentials that are strong enough eventually reach the region of the neuron known as the trigger zone. In efferent neurons and interneurons, the trigger zone is the axon hillock and the very first part of the axon, a region known as the initial segment. In sensory neurons, the trigger zone is immediately adjacent to the receptor, where the dendrites join the axon (see Fig.  8.2).

Concept Check

  1. Identify the trigger zones of the neurons illustrated in Figure 8.2, if possible.

The trigger zone is the integrating center of the neuron and contains a high concentration of voltage-gated Na+ channels in its membrane. If graded potentials reaching the trigger zone depolarize the membrane to the threshold voltage, voltage-gated Na+ channels open, and an action potential begins. If the depolarization does not reach threshold, the graded potential simply dies out as it moves into the axon.

Because depolarization makes a neuron more likely to fire an action potential, depolarizing graded potentials are considered to be excitatory. A hyperpolarizing graded potential moves the membrane potential farther from the threshold value and makes the neuron less likely to fire an action potential. Consequently, hyperpolarizing graded potentials are considered to be inhibitory.

Figure 8.7b shows a neuron with three recording electrodes placed at intervals along the cell body and trigger zone. A single stimulus triggers a subthreshold graded potential, one that is below threshold by the time it reaches the trigger zone. Although the cell is depolarized to −40 mV at the site where the graded potential begins, the current decreases as it travels through the cell body. As a result, the graded potential is below threshold by the time it reaches the trigger zone. (For the typical mammalian neuron, threshold is about −55 mV.) The stimulus is not strong enough to depolarize the cell to threshold at the trigger zone, and the graded potential dies out without triggering an action potential.

Figure 8.7c shows suprathreshold graded potential, one that is strong enough to cause an action potential. A stronger initial stimulus on the cell body initiates a stronger depolarization and current flow. Although this graded potential also diminishes with distance as it travels through the neuron, its higher initial strength ensures that it is above threshold at the trigger zone. In this example, the graded potential triggers an action potential. The ability of a neuron to respond to a stimulus and fire an action potential is called the cell’s excitability.

Action Potentials Travel Long Distances

Action potentials, also known as spikes, are electrical signals of uniform strength that travel from a neuron’s trigger zone to the end of its axon. In action potentials, voltage-gated ion channels in the axon membrane open sequentially as electrical current passes down the axon. As a result, additional Na+ entering the cell reinforce the depolarization, which is why an action potential does not lose strength over distance the way a graded potential does. Instead, the action potential at the end of an axon is identical to the action potential that started at the trigger zone: a depolarization of about 100 mV amplitude. The high-speed movement of an action potential along the axon is called conduction of the action potential.

Action potentials are sometimes called all-or-none phenomena because they either occur as a maximal depolarization (if the stimulus reaches threshold) or do not occur at all (if the stimulus is below threshold). The strength of the graded potential that initiates an action potential has no influence on the amplitude of the action potential.

When we talk about action potentials, it is important to realize that there is no single action potential that moves through the cell. The action potential that occurs at the trigger zone is like the movement in the first domino of a series of dominos standing on end (Fig. 8.8a). As the first domino falls, it strikes the next, passing on its kinetic energy. As the second domino falls, it passes kinetic energy to the third domino, and so on. If you could take a snapshot of the line of falling dominos, you would see that as the first domino is coming to rest in the fallen position, the next one is almost down, the third one most of the way down, and so forth, until you reach the domino that has just been hit and is starting to fall.

FIG. 8.8 Conduction of an action potential

In an action potential, a wave of electrical energy moves down the axon. Instead of getting weaker over distance, action potentials are replenished along the way so that they maintain constant amplitude. As the action potential passes from one part of the axon to the next, the membrane’s energy state is reflected in the membrane potential of each region. If we were to insert a series of recording electrodes along the length of an axon and start an action potential at the trigger zone, we would see a series of overlapping action potentials, each in a different part of the waveform, just like the dominos that are frozen in different positions (Fig. 8.8b).

Concept Check

  1. What is the difference between conductance and conduction in neurons?

Na+ and K+ Move across the Membrane during Action Potentials

What is happening to the axon membrane when an action potential takes place? As you saw in Figure 8.8b, a suprathreshold (above-threshold) stimulus at the trigger zone initiates the action potential. Conduction of the action potential along the axon requires only a few types of ion channels: voltage-gated Na+ channels and voltage-gated K+ channels, plus some leak channels that help set the resting membrane potential. The explanation of action potential generation that follows is typical of an unmyelinated PNS neuron. For their description of this simple but elegant mechanism, A. L. Hodgkin and A. F. Huxley won a Nobel Prize in 1963.

Action potentials begin when voltage-gated ion channels open, altering membrane permeability (P) to Na+ (PNa) and K+ (PK). Figure 8.9 shows the voltage and ion permeability changes that take place in one section of membrane during an action potential. Before and after the action potential, at and , the neuron is at its resting membrane potential of −70 mV. The action potential itself can be divided into three phases: a rising phase, a falling phase, and the after-hyperpolarization phase.

Generation of an Action Potential

Propagation of an Action Potential

Rising Phase of the Action Potential

The rising phase is due to a sudden temporary increase in the cell’s permeability to Na+. An action potential begins when a graded potential reaching the trigger zone depolarizes the membrane to threshold (−55 mV) . As the cell depolarizes, voltage-gated Na+ channels open, making the membrane much more permeable to Na+. Na+ then flows into the cell, down its concentration gradient and attracted by the negative membrane potential inside the cell.

The addition of positive charge to the intracellular fluid further depolarizes the cell (shown by the steep rising phase on the graph ). In the top third of the rising phase, the inside of the cell has become more positive than the outside, and the membrane potential has reversed polarity. This reversal is represented on the graph by the overshoot, that portion of the action potential above 0 mV.

As soon as the cell membrane potential becomes positive, the electrical driving force moving Na+ into the cell disappears. However, the Na+ concentration gradient remains, so Na+ continues to move into the cell. As long as Na+ permeability remains high, the membrane potential moves toward the Na+ equilibrium potential (ENa) of +60 mV. (Recall that ENa is the membrane potential at which the movement of Na+ into the cell down its concentration gradient is exactly opposed by the positive membrane potential.) The action potential peaks at +30 mV when Na+ channels in the axon close and potassium channels open .

Falling Phase of the Action Potential

The falling phase corresponds to an increase in K+ permeability. Voltage-gated K+ channels, like Na+ channels, open in response to depolarization. The K+ channel gates are much slower to open, however, and peak K+ permeability occurs later than peak Na+ permeability (Fig. 8.9, lower graph). By the time the K+ channels finally open, the membrane potential of the cell has reached +30 mV because of Na+ influx through faster-opening Na+ channels.

When the Na+ channels close at the peak of the action potential, the K+ channels have just finished opening, making the membrane very permeable to K+. At a positive membrane potential, the concentration and electrical gradients for K+ favor movement of K+ out of the cell. As K+ moves out of the cell, the membrane potential rapidly becomes more negative, creating the falling phase of the action potential and sending the cell toward its resting potential.

When the falling membrane potential reaches −70 mV, the K+ permeability has not returned to its resting state. Potassium continues to leave the cell through both voltage-gated and K+ leak channels, and the membrane hyperpolarizes, approaching the EK of −90 mV. This after-hyperpolarization is also called the undershoot.

Finally the slow voltage-gated K+ channels close, and some of the outward K+ leak stops . Retention of K+ and leak of Na+ into the axon bring the membrane potential back to −70 mV , the value that reflects the cell’s resting permeability to K+, Cl-, and Na+.

To summarize, the action potential is a change in membrane potential that occurs when voltage-gated ion channels in the membrane open, increasing the cell’s permeability first to Na+ (which enters) and then to K+ (which leaves). The influx (movement into the cell) of Na+ depolarizes the cell. This depolarization is followed by K+ efflux (movement out of the cell), which restores the cell to the resting membrane potential.

One Action Potential Does Not Alter Ion Concentration Gradients

As you just learned, an action potential results from ion movements across the neuron membrane. First, Na+ moves into the cell, and then K+ moves out. However, it is important to understand that very few ions move across the membrane in a single action potential, so that the relative Na+ and K+ concentrations inside and outside the cell remain essentially unchanged. For example, only 1 in every 100,000 K+ must leave the cell to shift the membrane potential from +30 to –70 mV, equivalent to the falling phase of the action potential. The tiny number of ions that cross the membrane during an action potential does not disrupt the Na+ and K+ concentration gradients.

Normally, the ions that do move into or out of the cell during action potentials are rapidly restored to their original compartments by Na+-K+-ATPase (also known as the Na+-K+ pump). The pump uses energy from ATP to exchange Na+ that enters the cell for K+ that leaked out of it [here]. This exchange does not need to happen before the next action potential fires, however, because the ion concentration gradient was not significantly altered by one action potential! A neuron without a functional Na+-K+ pump could fire a thousand or more action potentials before a significant change in the ion gradients occurred.

Axonal Na+ Channels Have Two Gates

One question that puzzled scientists for many years was how the voltage-gated Na+ channels could close at the peak of the action potential, when the cell was depolarized. Why should these channels close when depolarization was the stimulus for Na+ channel opening? After many years of study, they found the answer. These voltage-gated Na+ channels have two gates to regulate ion movement rather than a single gate. The two gates, known as activation and inactivation gates, flip-flop back and forth to open and close the Na+ channel.

When a neuron is at its resting membrane potential, the activation gate of the Na+ channel closes and no Na+ can move through the channel (Fig. 8.10a). The inactivation gate, an amino acid sequence behaving like a ball and chain on the cytoplasmic side of the channel, is open. When the cell membrane near the channel depolarizes, the activation gate swings open (Fig. 8.10b). This opens the channel and allows Na+ to move into the cell down its electrochemical gradient (Fig. 8.10c).

FIG. 8.10 The voltage-gated Na+ channel

The addition of positive charge further depolarizes the inside of the cell and starts a positive feedback loop [here] (Fig. 8.11). More Na+ channels open, and more Na+ enters, further depolarizing the cell. As long as the cell remains depolarized, activation gates in Na+ channels remain open.

FIG. 8.11 Positive feedback

Positive feedback loops require outside intervention to stop them. In axons, the inactivation gates in the Na+ channels are the outside intervention that stops the escalating depolarization of the cell. Both activation and inactivation gates move in response to depolarization, but the inactivation gate delays its movement for 0.5 msec. During that delay, the Na+ channel is open, allowing enough Na+ influx to create the rising phase of the action potential. When the slower inactivation gate finally closes, Na+ influx stops, and the action potential peaks (Fig. 8.10d).

While the neuron repolarizes during K+ efflux, the Na+ channel gates reset to their original positions so they can respond to the next depolarization (Fig. 8.10e). The double-gating mechanism found in axonal voltage-gated Na+ channels allows electrical signals to be conducted in only one direction, as you will see in the next section.

Concept Check

  1. If you put ouabain, an inhibitor of the Na+-K+ pump, on a neuron and then stimulate the neuron repeatedly, what do you expect to happen to action potentials generated by that neuron?

    1. (a) They cease immediately.

    2. (b) There is no immediate effect, but they diminish with repeated stimulation and eventually disappear.

    3. (c) They get smaller immediately, then stabilize with smaller amplitude.

    4. (d) Ouabain has no effect on action potentials.

  2. The pyrethrin insecticides, derived from chrysanthemums, disable inactivation gates of Na+ channels so that the channels remain open. In neurons poisoned with pyrethrins, what happens to the membrane potential? Explain your answer.

  3. When Na+ channel gates are resetting, is the activation gate opening or closing? Is the inactivation gate opening or closing?

Action Potentials Will Not Fire during the Absolute Refractory Period

The double gating of Na+ channels plays a major role in the phenomenon known as the refractory period. The adjective refractory comes from a Latin word meaning “stubborn.” The “stubbornness” of the neuron refers to the fact that once an action potential has begun, a second action potential cannot be triggered for about 1–2 msec, no matter how large the stimulus. This delay, called the absolute refractory period, represents the time required for the Na+ channel gates to reset to their resting positions (Fig. 8.12). Because of the absolute refractory period, a second action potential cannot occur before the first has finished. Consequently, action potentials moving from trigger zone to axon terminal cannot overlap and cannot travel backward.

FIG. 8.12 Refractory periods following an action potential

A relative refractory period follows the absolute refractory period. During the relative refractory period, some but not all Na+ channel gates have reset to their original positions. In addition, during the relative refractory period, K+ channels are still open.

The Na+ channels that have not quite returned to their resting position can be reopened by a stronger-than-normal graded potential. In other words, the threshold value has temporarily moved closer to zero, which requires a stronger depolarization to reach it. Although Na+ enters through newly reopened Na+ channels, depolarization due to Na+ entry is offset by K+ loss through still-open K+ channels. As a result, any action potentials that fire during the relative refractory period will be of smaller amplitude than normal.

The refractory period is a key characteristic that distinguishes action potentials from graded potentials. If two stimuli reach the dendrites of a neuron within a short time, the successive graded potentials created by those stimuli can be added to one another. If, however, two suprathreshold graded potentials reach the action potential trigger zone within the absolute refractory period, the second graded potential has no effect because the Na+ channels are inactivated and cannot open again so soon.

Refractory periods limit the rate at which signals can be transmitted down a neuron. The absolute refractory period also ensures one-way travel of an action potential from cell body to axon terminal by preventing the action potential from traveling backward.

Action Potentials Are Conducted

A distinguishing characteristic of action potentials is that they can travel over long distances of a meter or more without losing energy, a process known as conduction. The action potential that reaches the end of an axon is identical to the action potential that started at the trigger zone. To see how this happens, let’s consider the conduction of action potentials at the cellular level.

The depolarization of a section of axon causes positive current to spread through the cytoplasm in all directions by local current flow (Fig. 8.13). Simultaneously, on the outside of the axon membrane, current flows back toward the depolarized section. The local current flow in the cytoplasm diminishes over distance as energy dissipates. Forward current flow down the axon would eventually die out were it not for voltage-gated channels.

FIG. 8.13 Local current flow

The axon is well supplied with voltage-gated Na+ channels. Whenever a depolarization reaches those channels, they open, allowing more Na+ to enter the cell and reinforcing the depolarization—the positive feedback loop shown in Figure 8.11. Let’s see how this works when an action potential begins at the axon’s trigger zone.

First, a graded potential above threshold enters the trigger zone (Fig. 8.14 ). Its depolarization opens voltage-gated Na+ channels, Na+ enters the axon, and the initial segment of axon depolarizes . Positive charge from the depolarized trigger zone spreads by local current flow to adjacent sections of membrane , repelled by the Na+ that entered the cytoplasm and attracted by the negative charge of the resting membrane potential.

FIG. 8.14 Conduction of action potentials

Figure Question: Match the segments of the neuron in the bottom frame with the corresponding phrase(s):

  1. (a) proximal axon (blue)

  2. (b) absolute refractory period (pink)

    (c) active region (yellow)

    (d) relative refractory period (purple)

    (e) distal inactive region (blue)

    1. rising phase of action potential

    1. falling phase of action potential

    1. after-hyperpolarization

    1. resting potential

The flow of local current toward the axon terminal (to the right in Fig. 8.14) begins conduction of the action potential. When the membrane distal to the trigger zone depolarizes from local current flow, its Na+ channels open, allowing Na+ into the cell . This starts the positive feedback loop: depolarization opens Na+ channels, Na+ enters, causing more depolarization and opening more Na+ channels in the adjacent membrane.

The continuous entry of Na+ as Na+ channels open along the axon means that the strength of the signal does not diminish as the action potential propagates itself. (Contrast this with graded potentials in Fig. 8.7, in which Na+ enters only at the point of stimulus, resulting in a membrane potential change that loses strength over distance.)

As each segment of axon reaches the peak of the action potential, its Na+ channels inactivate. During the action potential’s falling phase, K+ channels are open, allowing K+ to leave the cytoplasm. Finally, the K+ channels close, and the membrane in that segment of axon returns to its resting potential.

Although positive charge from a depolarized segment of membrane may flow backward toward the trigger zone , depolarization in that direction has no effect on the axon. The section of axon that has just completed an action potential is in its absolute refractory period, with its Na+ channels inactivated. For this reason, the action potential cannot move backward.

What happens to current flow backward from the trigger zone into the cell body? Scientists used to believe that there were few voltage-gated ion channels in the cell body, so that retrograde current flow could be ignored. However, they now know that the cell body and dendrites do have voltage-gated ion channels and may respond to local current flow from the trigger zone. These retrograde signals are able to influence and modify the next signal that reaches the cell. For example, depolarization flowing backward from the axon could open voltage-gated channels in the dendrites, making the neuron more excitable.

Concept Check

  1. A stimulating electrode placed halfway down an axon artificially depolarizes the cell above threshold. In which direction will an action potential travel: to the axon terminal, to the cell body, or to both? Explain your answer.

Larger Neurons Conduct Action Potentials Faster

Two key physical parameters influence the speed of action potential conduction in a mammalian neuron: (1) the diameter of the axon and (2) the resistance of the axon membrane to ion leakage out of the cell (the length constant). The larger the diameter of the axon or the more leak-resistant the membrane, the faster an action potential will move.

To understand the relationship between diameter and conduction, think of a water pipe with water flowing through it. The water that touches the walls of the pipe encounters resistance due to friction between the flowing water molecules and the stationary walls. The water in the center of the pipe meets no direct resistance from the walls and, therefore, flows faster. In a large-diameter pipe, a smaller fraction of the water flowing through the pipe is in contact with the walls, making the total resistance lower.

In the same way, charges flowing inside an axon meet resistance from the membrane. Thus, the larger the diameter of the axon, the lower its resistance to ion flow. The connection between axon diameter and speed of conduction is especially evident in the giant axons that certain organisms, such as squid, earthworms, and fish, use for rapid escape responses. These giant axons may be up to 1 mm in diameter. Because of their large diameter, they can easily be punctured with electrodes (Fig. 8.15). For this reason, these species have been very important in research on electrical signaling.

FIG. 8.15 Diameter and resistance

Figure Question: A squid giant axon is 0.8 mm in diameter. A myelinated mammalian axon is 0.002 mm in diameter. What would be the diameter of a mammalian nerve if it contained 100 axons that were each the size of a squid giant axon? (Hint: The area of a circle is π × radius 2 , and π = 3.1459 .)

If you compare a cross section of a squid giant axon with a cross section of a mammalian nerve, you find that the mammalian nerve contains about 200 axons in the same cross-sectional area. Complex nervous systems pack more axons into a small nerve by using smaller-diameter axons wrapped in insulating membranes of myelin instead of large-diameter unmyelinated axons.

Conduction Is Faster in Myelinated Axons

The conduction of action potentials down an axon is faster in axons with high-resistance membranes so that current leak out of the cell is minimized. The unmyelinated axon depicted in ­Figure  8.14 has low resistance to current leak because the entire axon membrane is in contact with the extracellular fluid and it has ion channels through which current can leak.

In contrast, myelinated axons limit the amount of membrane in contact with the extracellular fluid. In these axons, small sections of bare membrane—the nodes of Ranvier—alternate with longer segments wrapped in multiple layers of membrane (the myelin sheath). The myelin sheath creates a high-resistance wall that prevents ion flow out of the cytoplasm. The myelin membranes are analogous to heavy coats of plastic surrounding electrical wires, as they increase the effective thickness of the axon membrane by as much as 100-fold.

As an action potential passes down the axon from trigger zone to axon terminal, it passes through alternating regions of myelinated axon and nodes of Ranvier (Fig. 8.16a). The conduction process is similar to that described previously for the unmyelinated axon, except that it occurs only at the nodes in myelinated axons. Each node has a high concentration of voltage-gated Na+ channels, which open with depolarization and allow Na+ into the axon. Sodium ions entering at a node reinforce the depolarization and restore the amplitude of the action potential as it passes from node to node. The apparent jump of the action potential from node to node is called saltatory conduction, from the Latin word saltare, meaning “to leap.”

FIG. 8.16 Saltatory conduction

What makes conduction more rapid in myelinated axons? Part of the answer lies with the cable properties of neurons (see Biotechnology box on here). Also, channel opening slows conduction slightly. In unmyelinated axons, channels must open sequentially all the way down the axon membrane to maintain the amplitude of the action potential. One clever student compared this process to moving the cursor across a computer screen by repeatedly pressing the space bar.

In myelinated axons, however, only the nodes need Na+ channels because of the insulating properties of the myelin membrane. As the action potential passes along myelinated segments, conduction is not slowed by channel opening. In the student’s analogy, this is like zipping across the screen by using the Tab key.

Saltatory conduction thus is an effective alternative to large-diameter axons and allows rapid action potentials through small axons. A myelinated frog axon 10 μ m in diameter conducts action potentials at the same speed as an unmyelinated 500- μ m squid axon. A myelinated 8.6- μ m mammalian neuron conducts action potentials at 120 m/sec (432 km/hr or 268 miles per hour), while action potentials in a smaller, unmyelinated 1.5- μ m pain fiber travel only 2 m/sec (7.2 km/hr or 4.5 mph). In summary, action potentials travel through different axons at different rates, depending on the two parameters of axon diameter and myelination.

Concept Check

  1. Place the following neurons in order of their speed of conduction, from fastest to slowest:

    1. (a) myelinated axon, diameter 20 μ m

    2. (b)unmyelinated axon, diameter 20 μ m

    3. (c)unmyelinated axon, diameter 200 μ m

In demyelinating diseases, the loss of myelin from vertebrate neurons can have devastating effects on neural signaling. In the central and peripheral nervous systems, the loss of myelin slows the conduction of action potentials. In addition, when current leaks out of now-uninsulated regions of membrane between the channel-rich nodes of Ranvier, the depolarization that reaches a node may no longer be above threshold, and conduction may fail (Fig. 8.16b).

Multiple sclerosis is the most common and best-known demyelinating disease. It is characterized by a variety of neurological complaints, including fatigue, muscle weakness, difficulty walking, and loss of vision. Guillain-Barré syndrome, described in this chapter’s Running Problem, is also characterized by the destruction of myelin. At this time, we can treat some of the symptoms but not the causes of demyelinating diseases, which are mostly either inherited or autoimmune disorders. Currently, researchers are using recombinant DNA technology to study demyelinating disorders in mice.

Chemical Factors Alter Electrical Activity

A large variety of chemicals alter the conduction of action potentials by binding to Na+, K+, or Ca2+ channels in the neuron membrane. For example, some neurotoxins bind to and block Na+ channels. Local anesthetics such as procaine, which block sensation, function the same way. If Na+ channels are not functional, Na+ cannot enter the axon. A depolarization that begins at the trigger zone then cannot be replenished as it travels; it loses strength as it moves down the axon, much like a normal graded potential. If the wave of depolarization manages to reach the axon terminal, it may be too weak to release neurotransmitter. As a result, the message of the presynaptic neuron is not passed on to the postsynaptic cell, and communication fails.

Alterations in the extracellular fluid concentrations of K+ and Ca2+ are also associated with abnormal electrical activity in the nervous system. The relationship between extracellular fluid K+ levels and the conduction of action potentials is the most straightforward and easiest to understand, as well as one of the most clinically significant.

The concentration of K+ in the blood and interstitial fluid is the major determinant of the resting potential of all cells [here]. If K+ concentration in the blood moves out of the normal range of 3.5–5 mmol/L, the result is a change in the resting membrane potential of cells (Fig. 8.17). This change is not important to most cells, but it can have serious consequences to the body as a whole because of the relationship between resting potential and the excitability of nervous and muscle tissue.

FIG. 8.17 Potassium and cell excitability

Figure Question: The EK of -90 mV is based on ECF [K+] = 5 mM and ICF [K+] = 150 mM. Use the Nernst equation to calculate EK when ECF [K+] is (a) 2.5 mM and (b) 6 mM

At normal K+ levels, subthreshold graded potentials do not trigger action potentials, and suprathreshold graded potentials do (Fig. 8.17a, b). An increase in blood K+ concentration— hyperkalemia {hyper-, above + kalium, potassium + -emia, in the blood}—shifts the resting membrane potential of a neuron closer to threshold and causes the cells to fire action potentials in response to smaller graded potentials (Fig. 8.17c).

If blood K+ concentration falls too low—a condition known as hypokalemia—the resting membrane potential of the cells hyperpolarizes, moving farther from threshold. In this case, a stimulus strong enough to trigger an action potential when the resting potential is the normal −70 mV does not reach the threshold value (Fig. 8.17d). This condition shows up as muscle weakness because the neurons that control skeletal muscles are not firing normally.

Hypokalemia and its resultant muscle weakness are one reason that sport drinks supplemented with Na+ and K+ were developed. When people sweat excessively, they lose both salts and water. If they replace this fluid loss with pure water, the K+ remaining in the blood is diluted, causing hypokalemia. By replacing sweat loss with a dilute salt solution, a person can prevent potentially dangerous drops in blood K+ levels. Because of the importance of K+ to normal function of the nervous system, potassium homeostasis mechanisms keep blood K+ concentrations within a narrow range.