Physiology 5th Ed.


The action potential is a phenomenon of excitable cells such as nerve and muscle and consists of a rapid depolarization (upstroke) followed by repolarization of the membrane potential. Action potentials are the basic mechanism for transmission of information in the nervous system and in all types of muscle.


The following terminology will be used for discussion of the action potential, the refractory periods, and the propagation of action potentials:

image Depolarization is the process of making the membrane potential less negative. As noted, the usual resting membrane potential of excitable cells is oriented with the cell interior negative. Depolarization makes the interior of the cell less negative, or it may even cause the cell interior to become positive. A change in membrane potential should not be described as “increasing” or “decreasing” because those terms are ambiguous. (For example, when the membrane potential depolarizes, or becomes less negative, has the membrane potential increased or decreased?)

image Hyperpolarization is the process of making the membrane potential more negative. As with depolarization, the terms “increasing” or “decreasing” should not be used to describe a change that makes the membrane potential more negative.

image Inward current is the flow of positive charge into the cell. Thus, inward currents depolarize the membrane potential. An example of an inward current is the flow of Na+ into the cell during the upstroke of the action potential.

image Outward current is the flow of positive charge out of the cell. Outward currents hyperpolarize the membrane potential. An example of an outward current is the flow of K+ out of the cell during the repolarization phase of the action potential.

image Threshold potential is the membrane potential at which occurrence of the action potential is inevitable. Because the threshold potential is less negative than the resting membrane potential, an inward current is required to depolarize the membrane potential to threshold. At threshold potential, net inward current (e.g., inward Na+ current) becomes larger than net outward current (e.g., outward K+ current), and the resulting depolarization becomes self-sustaining, giving rise to the upstroke of the action potential. If net inward current is less than net outward current, the membrane will not be depolarized to threshold and no action potential will occur (see all-or-none response).

image Overshoot is that portion of the action potential where the membrane potential is positive (cell interior positive).

image Undershoot, or hyperpolarizing afterpotential, is that portion of the action potential, following repolarization, where the membrane potential is actually more negative than it is at rest.

image Refractory period is a period during which another normal action potential cannot be elicited in an excitable cell. Refractory periods can be absolute or relative.

Characteristics of Action Potentials

Action potentials have three basic characteristics: stereotypical size and shape, propagation, and all-or-none response.

image Stereotypical size and shape. Each normal action potential for a given cell type looks identical, depolarizes to the same potential, and repolarizes back to the same resting potential.

image Propagation. An action potential at one site causes depolarization at adjacent sites, bringing those adjacent sites to threshold. Propagation of action potentials from one site to the next is nondecremental.

image All-or-none response. An action potential either occurs or does not occur. If an excitable cell is depolarized to threshold in a normal manner, then the occurrence of an action potential is inevitable. On the other hand, if the membrane is not depolarized to threshold, no action potential can occur. Indeed, if the stimulus is applied during the refractory period, then either no action potential occurs, or the action potential will occur but not have the stereotypical size and shape.

Ionic Basis of the Action Potential

The action potential is a fast depolarization (the upstroke), followed by repolarization back to the resting membrane potential. Figure 1-13 illustrates the events of the action potential in nerve and skeletal muscle, which occur in the following steps:


Figure 1–13 Time course of voltage and conductance changes during the action potential of nerve.

1.     Resting membrane potential. At rest, the membrane potential is approximately −70 mV (cell interior negative). The K+ conductance or permeability is high and K+ channels are almost fully open, allowing K+ ions to diffuse out of the cell down the existing concentration gradient. This diffusion creates a K+ diffusion potential, which drives the membrane potential toward the K+ equilibrium potential. The conductance to Cl (not shown) also is high, and, at rest, Cl also is near electrochemical equilibrium. At rest, the Na+ conductance is low, and, thus, the resting membrane potential is far from the Na+equilibrium potential.

2.     Upstroke of the action potential. An inward current, usually the result of current spread from action potentials at neighboring sites, causes depolarization of the nerve cell membrane to threshold, which occurs at approximately −60 mV. This initial depolarization causes rapid opening of the activation gates of the Na+ channel, and the Na+ conductance promptly increases and becomes even higher than the K+conductance (Fig. 1-14). The increase in Na+ conductance results in an inward Na+ current; the membrane potential is further depolarized toward, but does not quite reach, the Na+ equilibrium potential of +65 mV. Tetrodotoxin (a toxin from the Japanese puffer fish) and the local anesthetic lidocaine block these voltage-sensitive Na+ channels and prevent the occurrence of nerve action potentials.


Figure 1–14 Functions of activation and inactivation gates on the nerve Na+ channel. At rest, the activation gate is closed and the inactivation gate is open. During the upstroke of the action potential, both gates are open and Na+ flows into the cell down its electrochemical potential gradient. During repolarization, the activation gate remains open but the inactivation gate is closed.

Video: Action potential

3.     Repolarization of the action potential. The upstroke is terminated, and the membrane potential repolarizes to the resting level as a result of two events. First, the inactivation gates on the Na+ channels respond to depolarization by closing, but their response is slower than the opening of the activation gates. Thus, after a delay, the inactivation gates close the Na+ channels, terminating the upstroke. Second, depolarization opens K+channels and increases K+ conductance to a value even higher than occurs at rest. The combined effect of closing of the Na+ channels and greater opening of the K+ channels makes the K+ conductance much higher than the Na+ conductance. Thus, an outward K+ current results, and the membrane is repolarized. Tetraethylammonium (TEA) blocks these voltage-gated K+ channels, the outward K+ current, and repolarization.

4.     Hyperpolarizing afterpotential (undershoot). For a brief period following repolarization, the K+ conductance is higher than at rest and the membrane potential is driven even closer to the K+ equilibrium potential (hyperpolarizing afterpotential). Eventually, the K+ conductance returns to the resting level, and the membrane potential depolarizes slightly, back to the resting membrane potential. The membrane is now ready, if stimulated, to generate another action potential.

The Nerve Na+ Channel

A voltage-gated Na+ channel is responsible for the upstroke of the action potential in nerve and skeletal muscle. This channel is an integral membrane protein, consisting of a large α subunit and two β subunits. The α subunit has four domains, each of which has six transmembrane α-helices. The repeats of transmembrane α-helices surround a central pore, through which Na+ ions can flow (if the channel’s gates are open). A conceptual model of the Na+ channel demonstrating the function of the activation and inactivation gates is shown in Figure 1-14. The basic assumption of this model is that in order for Na+to move through the channel, both gates on the channel must be open. Recall how these gates respond to depolarization: The activation gate opens quickly, and the inactivation gate closes after a time delay.

1.     At rest, the activation gate is closed. Although the inactivation gate is open (because the membrane potential is hyperpolarized), Na+ cannot move through the channel.

2.     During the upstroke of the action potential, depolarization to threshold causes the activation gate to open quickly. The inactivation gate is still open because it responds to depolarization more slowly than the activation gate. Thus, both gates are open briefly, and Na+ can flow through the channel into the cell, causing further depolarization (the upstroke).

3.     At the peak of the action potential, the slow inactivation gate finally responds and closes, and the channel itself is closed. Repolarization begins. When the membrane potential has repolarized back to its resting level, the activation gate will be closed and the inactivation gate will be open, both in their original positions.

Refractory Periods

During the refractory periods, excitable cells are incapable of producing normal action potentials (see Fig. 1-13). The refractory period includes an absolute refractory period and a relative refractory period (Box 1-2).

BOX 1–2 Clinical Physiology: Hyperkalemia with Muscle Weakness

DESCRIPTION OF CASE. A 48-year-old woman with insulin-dependent diabetes mellitus reports to her physician that she is experiencing severe muscle weakness. She is being treated for hypertension with propranolol, a β-adrenergic blocking agent. Her physician immediately orders blood studies, which reveal a serum [K+] of 6.5 mEq/L (normal, 4.5 mEq/L) and elevated BUN (blood urea nitrogen). The physician tapers off the dosage of propranolol, with eventual discontinuation of the drug. He adjusts her insulin dosage. Within a few days, the patient’s serum [K+] has decreased to 4.7 mEq/L, and she reports that her muscle strength has returned to normal.

EXPLANATION OF CASE. This diabetic patient has severe hyperkalemia caused by several factors: (1) Because her insulin dosage is insufficient, the lack of adequate insulin has caused a shift of K+ out of cells into blood (insulin promotes K+ uptake into cells). (2) Propranolol, the β-blocking agent used to treat the woman’s hypertension, also shifts K+ out of cells into blood. (3) Elevated BUN suggests that the woman is developing renal failure; her failing kidneys are unable to excrete the extra K+ that is accumulating in her blood. These mechanisms involve concepts related to renal physiology and endocrine physiology.

It is important to understand that this woman has a severely elevated blood [K+] (hyperkalemia) and that her muscle weakness results from this hyperkalemia. The basis for this weakness can be explained as follows: The resting membrane potential of muscle cells is determined by the concentration gradient for K+ across the cell membrane (Nernst equation). At rest, the cell membrane is very permeable to K+, and K+ diffuses out of the cell down its concentration gradient, creating a K+ diffusion potential. This K+ diffusion potential is responsible for the resting membrane potential, which is cell interior negative. The larger the K+ concentration gradient, the greater the negativity in the cell. When the blood [K+] is elevated, the concentration gradient across the cell membrane is less than normal; resting membrane potential will therefore be less negative (i.e., depolarized).

It might be expected that this depolarization would make it easier to generate action potentials in the muscle because the resting membrane potential would be closer to threshold. A more important effect of depolarization, however, is that it closes the inactivation gates on Na+ channels. When these inactivation gates are closed, no action potentials can be generated, even if the activation gates are open. Without action potentials in the muscle, there can be no contraction.

TREATMENT. Treatment of this patient is based on shifting K+ back into the cells by increasing the woman’s insulin dosages and by discontinuing propranolol. By reducing the woman’s blood [K+] to normal levels, the resting membrane potential of her skeletal muscle cells will return to normal, the inactivation gates on the Na+ channels will be open at the resting membrane potential (as they should be), and normal action potentials can occur.

Absolute Refractory Period

The absolute refractory period overlaps with almost the entire duration of the action potential. During this period, no matter how great the stimulus, another action potential cannot be elicited. The basis for the absolute refractory period is closure of the inactivation gates of the Na+ channel in response to depolarization. These inactivation gates are in the closed position until the cell is repolarized back to the resting membrane potential (see Fig. 1-14).

Relative Refractory Period

The relative refractory period begins at the end of the absolute refractory period and overlaps primarily with the period of the hyperpolarizing afterpotential. During this period, an action potential can be elicited, but only if a greater than usual depolarizing (inward) current is applied. The basis for the relative refractory period is the higher K+ conductance than is present at rest. Because the membrane potential is closer to the K+ equilibrium potential, more inward current is needed to bring the membrane to threshold for the next action potential to be initiated.


When a nerve or muscle cell is depolarized slowly or is held at a depolarized level, the usual threshold potential may pass without an action potential having been fired. This process, called accommodation, occurs because depolarization closes inactivation gates on the Na+ channels. If depolarization occurs slowly enough, the Na+ channels close and remain closed. The upstroke of the action potential cannot occur because there are not enough Na+channels available to carry inward current. An example of accommodation is seen in persons who have an elevated serum K+ concentration, or hyperkalemia. At rest, nerve and muscle cell membranes are very permeable to K+; an increase in extracellular K+ concentration causes depolarization of the resting membrane (as dictated by the Nernst equation). This depolarization brings the cell membrane closer to threshold and would seem to make it more likely to fire an action potential. However, the cell is actually less likely to fire an action potential because this sustained depolarization closes the inactivation gates on the Na+ channels.

Propagation of Action Potentials

Propagation of action potentials down a nerve or muscle fiber occurs by the spread of local currents from active regions to adjacent inactive regions. Figure 1-15 shows a nerve cell body with its dendritic tree and an axon. At rest, the entire nerve axon is at the resting membrane potential, with the cell interior negative. Action potentials are initiated in the initial segment of the axon, nearest the nerve cell body. They propagate down the axon by spread of local currents, as illustrated in the figure.

In Figure 1-15A the initial segment of the nerve axon is depolarized to threshold and fires an action potential (the active region). As the result of an inward Na+ current, at the peak of the action potential, the polarity of the membrane potential is reversed and the cell interior becomes positive. The adjacent region of the axon remains inactive, with its cell interior negative.

Figure 1-15B illustrates the spread of local current from the depolarized active region to the adjacent inactive region. At the active site, positive charges inside the cell flow toward negative charges at the adjacent inactive site. This current flow causes the adjacent region to depolarize to threshold.

In Figure 1-15C the adjacent region of the nerve axon, having been depolarized to threshold, now fires an action potential. The polarity of its membrane potential is reversed, and the cell interior becomes positive. At this time, the original active region has been repolarized back to the resting membrane potential and restored to its inside-negative polarity. The process continues, transmitting the action potential sequentially down the axon.


Figure 1–15 Spread of depolarization down a nerve fiber by local currents. A, The initial segment of the axon has fired an action potential, and the potential difference across the cell membrane has reversed to become inside positive. The adjacent area is inactive and remains at the resting membrane potential, inside negative. B, At the active site, positive charges inside the nerve flow to the adjacent inactive area. C, Local current flow causes the adjacent area to be depolarized to threshold and to fire action potentials; the original active region has repolarized back to the resting membrane potential.

Conduction Velocity

The speed at which action potentials are conducted along a nerve or muscle fiber is the conduction velocity. This property is of great physiologic importance because it determines the speed at which information can be transmitted in the nervous system. To understand conduction velocity in excitable tissues, two major concepts must be explained: the time constant and the length constant. These concepts, called cable properties, explain how nerves and muscles act as cables to conduct electrical activity.

The time constant (τ) is the amount of time it takes following the injection of current for the potential to change to 63% of its final value. In other words, the time constant indicates how quickly a cell membrane depolarizes in response to an inward current or how quickly it hyperpolarizes in response to an outward current. Thus,

τ = RmCm



= Time constant


= Membrane resistance


= Membrane capacitance

Two factors affect the time constant. The first factor is membrane resistance (Rm). When Rm is high, current does not readily flow across the cell membrane, which makes it difficult to change the membrane potential, thus increasing the time constant. The second factor, membrane capacitance (Cm), is the ability of the cell membrane to store charge. When Cm is high, the time constant is increased because injected current first must discharge the membrane capacitor before it can depolarize the membrane. Thus, the time constant is greatest (i.e., takes longest) when Rm and Cm are high.

The length constant (λ) is the distance from the site of current injection where the potential has fallen by 63% of its original value. The length constant indicates how far a depolarizing current will spread along a nerve. In other words, the longer the length constant, the farther the current spreads down the nerve fiber. Thus,




= Length constant


= Membrane resistance


= Internal resistance

Again, Rm represents membrane resistance. Internal resistance, Ri, is inversely related to the ease of current flow in the cytoplasm of the nerve fiber. Therefore, the length constant will be greatest (i.e., current will travel the farthest) when the diameter of the nerve is large, when membrane resistance is high, and when internal resistance is low. In other words, current flows along the path of least resistance.

Changes in Conduction Velocity

There are two mechanisms that increase conduction velocity along a nerve: increasing the size of the nerve fiber and myelinating the nerve fiber. These mechanisms can best be understood in terms of the cable properties of time constant and length constant.

image Increasing nerve diameter. Increasing the size of a nerve fiber increases conduction velocity, a relationship that can be explained as follows: Internal resistance, Ri, is inversely proportional to the cross-sectional area (A = πr2). Therefore, the larger the fiber, the lower the internal resistance. The length constant is inversely proportional to the square root of Ri (refer to the equation for length constant). Thus, the length constant (λ) will be large when internal resistance (Ri) is small (i.e., fiber size is large). The largest nerves have the longest length constants, and current spreads farthest from the active region to propagate action potentials. Increasing nerve fiber size is certainly an important mechanism for increasing conduction velocity in the nervous system, but anatomic constraints limit how large nerves can become. Therefore, a second mechanism, myelination, is invoked to increase conduction velocity.

image Myelination. Myelin is a lipid insulator of nerve axons that increases membrane resistance and decreases membrane capacitance. The increased membrane resistance forces current to flow along the path of least resistance of the axon interior rather than across the high resistance path of the axonal membrane. The decreased membrane capacitance produces a decrease in time constant; thus, at breaks in the myelin sheath (see following), the axonal membrane depolarizes faster in response to inward current. Together, the effects of increased membrane resistance and decreased membrane capacitance result in increased conduction velocity (Box 1-3).

BOX 1–3 Clinical Physiology: Multiple Sclerosis

DESCRIPTION OF CASE. A 32-year-old woman had her first episode of blurred vision 5 years ago. She had trouble reading the newspaper and the fine print on labels. Her vision returned to normal on its own, but 10 months later, the blurred vision recurred, this time with other symptoms including double vision, and a “pins and needles” feeling and severe weakness in her legs. She was too weak to walk even a single flight of stairs. She was referred to a neurologist, who ordered a series of tests. Magnetic resonance testing (MRI) of the brain showed lesions typical of multiple sclerosis. Visual evoked potentials had a prolonged latency that was consistent with decreased nerve conduction velocity. Since the diagnosis, she has had two relapses and she is currently being treated with interferon beta.

EXPLANATION OF CASE. Action potentials are propagated along nerve fibers by spread of local currents as follows: When an action potential occurs, the inward current of the upstroke of the action potential depolarizes the membrane at that site and reverses the polarity (i.e., that site briefly becomes inside positive). The depolarization then spreads to adjacent sites along the nerve fiber by local current flow. Importantly, if these local currents depolarize an adjacent region to threshold, it will fire an action potential (i.e., the action potential will be propagated). The speed of propagation of the action potential is called conduction velocity. The further local currents can spread without decay (expressed as the length constant), the faster the conduction velocity. There are two main factors that increase length constant and, therefore, increase conduction velocity in nerves: increased nerve diameter and myelination.

Myelin is an insulator of axons that increases membrane resistance and decreases membrane capacitance. By increasing membrane resistance, current is forced to flow down the axon interior and less current is lost across the cell membrane (increasing length constant); because more current flows down the axon, conduction velocity is increased. By decreasing membrane capacitance, local currents depolarize the membrane more rapidly, which also increases conduction velocity. In order for action potentials to be conducted in myelinated nerves, there must be periodic breaks in the myelin sheath (at the nodes of Ranvier), where there is a concentration of Na+ and K+channels. Thus, at the nodes, the ionic currents necessary for the action potential can flow across the membrane (e.g., the inward Na+ current necessary for the upstroke of the action potential). Between nodes, membrane resistance is very high and current is forced to flow rapidly down the nerve axon to the next node, where the next action potential can be generated. Thus, the action potential appears to “jump” from one node of Ranvier to the next. This is called saltatory conduction.

Multiple sclerosis is the most common demyelinating disease of the central nervous system. Loss of the myelin sheath around nerves causes a decrease in membrane resistance, which means that current “leaks out” across the membrane during conduction of local currents. For this reason, local currents decay more rapidly as they flow down the axon (decreased length constant) and, because of this decay, may be insufficient to generate an action potential when they reach the next node of Ranvier.

If the entire nerve were coated with the lipid myelin sheath, however, no action potentials could occur because there would be no low resistance breaks in the membrane across which depolarizing current could flow. Therefore, it is important to note that at intervals of 1 to 2 mm, there are breaks in the myelin sheath, at the nodes of Ranvier. At the nodes, membrane resistance is low, current can flow across the membrane, and action potentials can occur. Thus, conduction of action potentials is faster in myelinated nerves than in unmyelinated nerves because action potentials “jump” long distances from one node to the next, a process called saltatory conduction.