CHAPTER 5

Membrane Potentials and

UNIT II
Action Potentials
Electrical potentials exist across the membranes of virtu- creates a membrane potential of opposite polarity to that
ally all cells of the body. Some cells, such as nerve and in Figure 5-­1A, with negativity outside and positivity
muscle cells, generate rapidly changing electrochemical inside. Again, the membrane potential rises high enough
impulses at their membranes, and these impulses are used within milliseconds to block further net diffusion of
to transmit signals along the nerve or muscle membranes. sodium ions to the inside; however, this time, in the mam-
In other types of cells, such as glandular cells, macro- malian nerve fiber, the potential is about 61 millivolts posi-
phages, and ciliated cells, local changes in membrane tive inside the fiber.
potentials also activate many of the cell’s functions. This Thus, in both parts of Figure 5-­1, we see that a con-
chapter reviews the basic mechanisms whereby mem- centration difference of ions across a selectively perme-
brane potentials are generated at rest and during action able membrane can, under appropriate conditions, create
by nerve and muscle cells. See Video 5-­1. a membrane potential. Later in this chapter, we show
that many of the rapid changes in membrane potentials
observed during nerve and muscle impulse transmission
BASIC PHYSICS OF MEMBRANE result from such rapidly changing diffusion potentials.
POTENTIALS
The Nernst Equation Describes the Relationship of
Membrane Potentials Caused by Ion Diffusion Potential to the Ion Concentration Difference
Concentration Differences Across a Across a Membrane. The diffusion potential across a
Selectively Permeable Membrane membrane that exactly opposes the net diffusion of a par-
In Figure 5-­1A, the potassium concentration is great ticular ion through the membrane is called the Nernst po-
inside a nerve fiber membrane but very low outside the tential for that ion, a term that was introduced in Chapter
membrane. Let us assume that the membrane in this case 4. The magnitude of the Nernst potential is determined
is permeable to the potassium ions but not to any other by the ratio of the concentrations of that specific ion on
ions. Because of the large potassium concentration gradi- the two sides of the membrane. The greater this ratio, the
ent from the inside toward the outside, there is a strong greater the tendency for the ion to diffuse in one direction
tendency for potassium ions to diffuse outward through and therefore the greater the Nernst potential required to
the membrane. As they do so, they carry positive electri- prevent additional net diffusion. The following equation,
cal charges to the outside, thus creating electropositivity called the Nernst equation, can be used to calculate the
outside the membrane and electronegativity inside the Nernst potential for any univalent ion at the normal body
membrane because of negative anions that remain behind temperature of 98.6°F (37°C):
and do not diffuse outward with the potassium. Within 61 Concentration inside
about 1 millisecond, the potential difference between the EMF (millivolts ) = ± × log
z Concentration outside
inside and outside, called the diffusion potential, becomes
great enough to block further net potassium diffusion to where EMF is the electromotive force and z is the electri-
the exterior, despite the high potassium ion concentra- cal charge of the ion (e.g., +1 for K+).
tion gradient. In the normal mammalian nerve fiber, the When using this formula, it is usually assumed that
potential difference is about 94 millivolts, with negativity the potential in the extracellular fluid outside the mem-
inside the fiber membrane. brane remains at zero potential, and the Nernst potential
Figure 5-­1B shows the same phenomenon as in Fig- is the potential inside the membrane. Also, the sign of the
ure 5-­1A, but this time with a high concentration of potential is positive (+) if the ion diffusing from inside to
sodium ions outside the membrane and a low concentra- outside is a negative ion, and it is negative (−) if the ion is
tion of sodium ions inside. These ions are also positively positive. Thus, when the concentration of positive potas-
charged. This time, the membrane is highly permeable to sium ions on the inside is 10 times that on the outside, the
the sodium ions but is impermeable to all other ions. Dif- log of 10 is 1, so the Nernst potential calculates to be −61
fusion of the positively charged sodium ions to the inside millivolts inside the membrane.

63
UNIT II Membrane Physiology, Nerve, and Muscle

DIFFUSION POTENTIALS Table 5-­1 Resting Membrane Potential in Different

(Anions)– Nerve fiber (Anions)– Nerve fiber
Cell Types
+ – – – + – + – + –
(Anions) – + (Anions) + Cell Type Resting Potential (mV)
+ – – + –
+ – – + – + + – Neurons −60 to −70
+ + – + – + + – + + + –
K K Na – + Na Skeletal muscle −85 to −95
+ – – + + –
+ – – + – + + – Smooth muscle −50 to −60
+ – – + – + + –
(–94 mV) – + (+61 mV) + – Cardiac muscle −80 to −90
+ – – + – + + – Hair (cochlea) −15 to −40
+ – – + – + + –
Astrocyte −80 to −90
A B
Erythrocyte −8 to −12
Figure 5-­1 A, Establishment of a diffusion potential across a nerve
fiber membrane, caused by diffusion of potassium ions from inside Photoreceptor −40 (dark) to −70 (light)
the cell to outside the cell through a membrane that is selectively per-
meable only to potassium. B, Establishment of a diffusion potential
when the nerve fiber membrane is permeable only to sodium ions. inside the membrane. The reason for this phenomenon
Note that the internal membrane potential is negative when potas-
sium ions diffuse and positive when sodium ions diffuse because of
is that excess positive ions diffuse to the outside when
opposite concentration gradients of these two ions. their concentration is higher inside than outside the
membrane. This diffusion carries positive charges to the
outside but leaves the nondiffusible negative anions on
the inside, thus creating electronegativity on the inside.
The Goldman Equation Is Used to Calculate the Dif-
The opposite effect occurs when there is a gradient for
fusion Potential When the Membrane Is Permeable
a negative ion. That is, a chloride ion gradient from the
to Several Different Ions. When a membrane is per-
outside to the inside causes negativity inside the cell
meable to several different ions, the diffusion potential
because excess negatively charged chloride ions diffuse
that develops depends on three factors: (1) the polarity
to the inside while leaving the nondiffusible positive ions
of the electrical charge of each ion; (2) the permeability
on the outside.
of the membrane (P) to each ion; and (3) the concentra-
Fourth, as explained later, the permeability of the
tion (C) of the respective ions on the inside (i) and out-
sodium and potassium channels undergoes rapid
side (o) of the membrane. Thus, the following formula,
changes during transmission of a nerve impulse,
called the Goldman equation or the Goldman-­Hodgkin-­
whereas the permeability of the chloride channels does
Katz equation, gives the calculated membrane potential
not change greatly during this process. Therefore, rapid
on the inside of the membrane when two univalent pos-
changes in sodium and potassium permeability are pri-
itive ions, sodium (Na+) and potassium (K+), and one
marily responsible for signal transmission in neurons,
univalent negative ion, chloride (Cl−), are involved:
which is the subject of most of the remainder of this
CNa+ PNa+ + CK+ PK+ + CCIo− PCI− chapter.
EMF (millivolts ) = −61 × log i i

CNao+ PNa+ + CKo+ PK+ + CCIi− PCI−

Resting Membrane Potential of Different Cell Types. In
Several key points become evident from the Goldman some cells, such as the cardiac pacemaker cells discussed
in Chapter 10, the membrane potential is continuously
equation. First, sodium, potassium, and chloride ions are
changing, and the cells are never “resting”. In many other
the most important ions involved in the development of
cells, even excitable cells, there is a quiescent period in which
membrane potentials in nerve and muscle fibers, as well a resting membrane potential can be measured. Table 5-­1
as in the neuronal cells. The concentration gradient of shows the approximate resting membrane potentials of some
each of these ions across the membrane helps determine different types of cells. The membrane potential is obviously
the voltage of the membrane potential. very dynamic in excitable cells such as neurons, in which
Second, the quantitative importance of each of the ions action potentials occur. However, even in nonexcitable cells,
in determining the voltage is proportional to the membrane the membrane potential (voltage) also changes in response
permeability for that particular ion. If the membrane has to various stimuli, which alter activities for the various ion
zero permeability to sodium and chloride ions, the mem- transporters, ion channels, and membrane permeability for
brane potential becomes entirely dominated by the concen- sodium, potassium, calcium, and chloride ions. The resting
membrane potential is, therefore, only a brief transient state
tration gradient of potassium ions alone, and the resulting
for many cells.
potential will be equal to the Nernst potential for potassium.
Electrochemical Driving Force. When multiple ions
The same holds true for each of the other two ions if the
contribute to the membrane potential, the equilibrium
membrane should become selectively permeable for either potential for any of the contributing ions will differ from
one of them alone. the membrane potential, and there will be an electrochemi-
Third, a positive ion concentration gradient from inside cal driving force (Vdf) for each ion that tends to cause net
the membrane to the outside causes electronegativity

64
 Chapter 5 Membrane Potentials and Action Potentials

0 Nerve fiber
–+–+–+–+–+–+–+–
— + +–++––+–+––++–+
–+–+–+–+–+–+–+–
+–++––+–+––++–+
–+–+–+–+–+–+–+–
I +–++––+–+––++–+
KC Silver–silver –+–+–+–+–+–+–+–

UNIT II
+++++++++++ +++++ chloride +–++––+–+––++–+
–––––––––– ––––– electrode –+–+–+–+–+–+–+–
+–++––+–+––++–+

Electrical potential
– – – – – – – – – (–70 – – – – – – – 0
+ + + + + + + + + mV) + + + + + + + +

(millivolts)
Figure 5-­2 Measurement of the membrane potential of the nerve
fiber using a microelectrode.

–70

movement of the ion across the membrane. This driving

force is equal to the difference between the membrane po- Figure 5-­3 Distribution of positively and negatively charged ions in
tential (Vm) and the equilibrium potential of the ion (Veq) the extracellular fluid surrounding a nerve fiber and in the fluid inside
the fiber. Note the alignment of negative charges along the inside
Thus, Vdf = Vm – Veq.
surface of the membrane and positive charges along the outside
The arithmetic sign of Vdf (positive or negative) and the
surface. The lower panel displays the abrupt changes in membrane
valence of the ion (cation or anion) can be used to predict potential that occur at the membranes on the two sides of the fiber.
the direction of ion flow across the membrane, into or out
of the cell. For cations such as Na+ and K+, a positive Vdf
predicts ion movement out of the cell down its electro- is zero, which is the potential of the extracellular fluid.
chemical gradient, and a negative Vdf predicts ion move- Then, as the recording electrode passes through the volt-
ment into the cell. For anions, such as Cl−, a positive Vdf age change area at the cell membrane (called the electrical
predicts ion movement into the cell, and a negative Vdf pre- dipole layer), the potential decreases abruptly to −70 mil-
dicts ion movement out of the cell. When Vm = Veq, there livolts. Moving across the center of the fiber, the potential
is no net movement of the ion into or out of the cell. Also, remains at a steady −70-­millivolt level but reverses back
the direction of ion flux through the membrane reverses as to zero the instant it passes through the membrane on the
Vm becomes greater than or less than Veq; hence, the equi- opposite side of the fiber.
librium potential (Veq) is also called the reversal potential. To create a negative potential inside the membrane,
only enough positive ions to develop the electrical
dipole layer at the membrane itself must be trans-
Measuring the Membrane Potential ported outward. The remaining ions inside the nerve
The method for measuring the membrane potential is fiber can be both positive and negative, as shown in
simple in theory but often difficult in practice because of the upper panel of Figure 5-­3. Therefore, transfer of
the small size of most of the cells and fibers. Figure 5-­2 an incredibly small number of ions through the mem-
shows a small micropipette filled with an electrolyte solu- brane can establish the normal resting potential of −70
tion. The micropipette is impaled through the cell mem- millivolts inside the nerve fiber, which means that only
brane to the interior of the fiber. Another electrode, called about 1/3,000,000 to 1/100,000,000 of the total posi-
the indifferent electrode, is then placed in the extracellu- tive charges inside the fiber must be transferred. Also,
lar fluid, and the potential difference between the inside an equally small number of positive ions moving from
and outside of the fiber is measured using an appropriate outside to inside the fiber can reverse the potential
voltmeter. This voltmeter is a highly sophisticated elec- from −70 millivolts to as much as +35 millivolts within
tronic apparatus that is capable of measuring small volt- as little as 1/10,000 of a second. Rapid shifting of ions in
ages despite extremely high resistance to electrical flow this manner causes the nerve signals discussed in sub-
through the tip of the micropipette, which has a lumen sequent sections of this chapter.
diameter usually less than 1 micrometer and a resistance
of more than 1 million ohms. For recording rapid changes
RESTING MEMBRANE POTENTIAL OF
in the membrane potential during transmission of nerve
NEURONS
impulses, the microelectrode is connected to an oscillo-
scope, as explained later in the chapter. The resting membrane potential of large nerve fibers when
The lower part of Figure 5-­3 shows the electrical they are not transmitting nerve signals is about −70 mil-
potential that is measured at each point in or near the livolts. That is, the potential inside the fiber is 70 millivolts
nerve fiber membrane, beginning at the left side of the more negative than the potential in the extracellular fluid
figure and passing to the right. As long as the electrode is on the outside of the fiber. In the next few paragraphs, the
outside the neuronal membrane, the recorded potential transport properties of the resting nerve membrane for

65
UNIT II Membrane Physiology, Nerve, and Muscle

Outside K+
3Na+
2K+ Selectivity K+ 4 mEq/L
filter
K+
140 mEq/L (–94 mV)
(–94 mV)

A
3Na+ Na+ K+ Na+ K+
ATP ADP
2K+ K+ "leak" 142 mEq/L 4 mEq/L
Na+-K+ pump channels
Figure 5-­4 Functional characteristics of the Na+-­K+ pump and the K+ Na+ K+
“leak” channels. The K+ leak channels also leak Na+ ions into the cell 14 mEq/L 140 mEq/L (–86 mV)
slightly but are much more permeable to K+. ADP, Adenosine diphos-
(+61 mV) (–94 mV)
phate; ATP, adenosine triphosphate.
B

sodium and potassium and the factors that determine the + – – +

level of this resting potential are explained. + – – +
Diffusion – +
Active Transport of Sodium and Potassium Ions + – – +
Through the Membrane—the Sodium-­ Potassium Na+ Na+ – +
pump
(Na+-­K+) Pump. Recall from Chapter 4 that all cell mem- + – – +
branes of the body have a powerful Na+-­K+ pump that 142 mEq/L + – 14 mEq/L – +
continually transports sodium ions to the outside of the + – – +
+ – – +
cell and potassium ions to the inside, as illustrated on the – +
left side in Figure 5-­4. Note that this is an electrogenic Diffusion
– +
pump because three Na+ ions are pumped to the outside + – – +
K+ K+
for each two K+ ions to the inside, leaving a net deficit of pump – +
+ – – +
positive ions on the inside and causing a negative poten- 4 mEq/L + – 140 mEq/L – +
tial inside the cell membrane. + – – +
The Na+-­K+ pump also causes large concentration gra- + – (–90 mV) – +
dients for sodium and potassium across the resting nerve + – – +
(Anions)– + – (Anions)–
membrane. These gradients are as follows: C
– +

Na+ (outside): 142 mEq/L Figure 5-­5 Establishment of resting membrane potentials under
three conditions. A, When the membrane potential is caused entirely
by potassium diffusion alone. B, When the membrane potential is
Na+ (inside): 14 mEq/L caused by diffusion of both sodium and potassium ions. C, When
the membrane potential is caused by diffusion of both sodium and
potassium ions plus pumping of both these ions by the Na+-­K+ pump.
K + (outside): 4 mEq/L

channels may also leak sodium ions slightly but are far
K + (inside): 140 mEq/L
more permeable to potassium than to sodium, normally
The ratios of these two respective ions from the inside about 100 times as permeable. As discussed later, this dif-
to the outside are as follows: ferential in permeability is a key factor in determining the
level of the normal resting membrane potential.
Na+ inside /Na+ outside = 0.1
Origin of the Normal Resting Membrane
Potential
K + inside /K + outside = 35.0
Figure 5-­5 shows the important factors in the establish-
ment of the normal resting membrane potential. They are
Leakage of Potassium Through the Nerve Cell Mem- as follows.
brane. The right side of Figure 5-­4 shows a channel pro-
tein (sometimes called a tandem pore domain, potassium Contribution of the Potassium Diffusion Potential.
channel, or potassium [K+] “leak” channel) in the nerve In Figure 5-­5A, we assume that the only movement of
membrane through which potassium ions can leak, even ions through the membrane is diffusion of potassium
in a resting cell. The basic structure of potassium channels ions, as demonstrated by the open channels between
was described in Chapter 4 (Figure 4-­4). These K+ leak the potassium symbol (K+) inside and outside the mem-

66
UNIT II Membrane Physiology, Nerve, and Muscle

Depolarization Stage. At this time, the membrane sud- Activation Selectivity

denly becomes permeable to sodium ions, allowing rapid gate Na+ Na+ filter Na+
diffusion of positively charged sodium ions to the interior
of the axon. The normal polarized state of −70 millivolts
is immediately neutralized by the inflowing, positively
charged sodium ions, with the potential rising rapidly in
the positive direction—a process called depolarization.
In large nerve fibers, the great excess of positive sodium Inactivation
gate
ions moving to the inside causes the membrane poten- Resting Activated Inactivated
tial to actually overshoot beyond the zero level and to be- (−70 mV) (−70 to +35 mV) (+35 to −70 mV,
come somewhat positive. In some smaller fibers, as well delayed)
as in many central nervous system neurons, the potential
merely approaches the zero level and does not overshoot
to the positive state.

Repolarization Stage. Within a few 10,000ths of a sec-

ond after the membrane becomes highly permeable to K+ K+
sodium ions, the sodium channels begin to close, and the Resting Slow activation
(−70 mV) (+35 to −70 mV)
potassium channels open to a greater degree than normal. Inside
Then, rapid diffusion of potassium ions to the exterior re-­ Figure 5-­7 Characteristics of the voltage-­gated sodium (top) and
establishes the normal negative resting membrane poten- potassium (bottom) channels, showing successive activation and in-
tial, which is called repolarization of the membrane. activation of the sodium channels and delayed activation of the po-
To explain more fully the factors that cause both depo- tassium channels when the membrane potential is changed from the
larization and repolarization, we will describe the special normal resting negative value to a positive value.
characteristics of two other types of transport channels
through the nerve membrane, the voltage-­gated sodium change in the activation gate, flipping it all the way to
and potassium channels. the open position. During this activated state, sodium
ions can pour inward through the channel, increasing
the sodium permeability of the membrane as much as
VOLTAGE-­GATED SODIUM AND
500-­ to 5000-­fold.
POTASSIUM CHANNELS
The necessary factor in causing both depolarization and Inactivation of the Sodium Channel. The upper right
repolarization of the nerve membrane during the action panel of Figure 5-­7 shows a third state of the sodium
potential is the voltage-­gated sodium channel. A voltage-­ channel. The same increase in voltage that opens the ac-
gated potassium channel also plays an important role in tivation gate also closes the inactivation gate. The inacti-
increasing the rapidity of repolarization of the membrane. vation gate, however, closes a few 10,000ths of a second
These two voltage-­gated channels are in addition to the after the activation gate opens. That is, the conforma-
Na+-­K+ pump and the K+ leak channels. tional change that flips the inactivation gate to the closed
state is a slower process than the conformational change
Activation and Inactivation of the that opens the activation gate. Therefore, after the sodi-
Voltage-­Gated Sodium Channel um channel has remained open for a few 10,000ths of a
The upper panel of Figure 5-­7 shows the voltage-­gated second, the inactivation gate closes, and sodium ions no
sodium channel in three separate states. This channel has longer can pour to the inside of the membrane. At this
two gates—one near the outside of the channel called the point, the membrane potential begins to return toward
activation gate, and another near the inside called the the resting membrane state, which is the repolarization
inactivation gate. The upper left of the figure depicts the process.
state of these two gates in the normal resting membrane Another important characteristic of the sodium chan-
when the membrane potential is −70 millivolts. In this nel inactivation process is that the inactivation gate will
state, the activation gate is closed, which prevents any not reopen until the membrane potential returns to or
entry of sodium ions to the interior of the fiber through near the original resting membrane potential level. There-
these sodium channels. fore, it is usually not possible for the sodium channels to
open again without first repolarizing the nerve fiber.
Activation of the Sodium Channel. When the mem-
brane potential becomes less negative than during the Voltage-­Gated Potassium Channel and Its
resting state, rising from −70 millivolts toward zero, it Activation
finally reaches a voltage—usually somewhere around The lower panel of Figure 5-­7 shows the voltage-­gated
−55 millivolts—that causes a sudden conformational potassium channel in two states—during the resting state

68
UNIT II Membrane Physiology, Nerve, and Muscle

the sudden opening of the sodium channels (the activa- within another fraction of a millisecond. The onset of
tion stage) within a small fraction of a millisecond after the action potential also initiates voltage gating of the
the membrane potential is increased to the positive value. potassium channels, causing them to begin opening
However, during the next millisecond or so, the sodium more slowly, a fraction of a millisecond after the sodium
channels automatically close (the inactivation stage).
channels open. At the end of the action potential, the
Note the opening (activation) of the potassium chan-
return of the membrane potential to the negative state
nels, which open less rapidly and reach their full open state
only after the sodium channels have almost completely causes the potassium channels to close back to their
closed. Furthermore, once the potassium channels open, original status but, again, only after an additional mil-
they remain open for the entire duration of the positive lisecond or more delay.
membrane potential and do not close again until after the The middle portion of Figure 5-­10 shows the ratio of
membrane potential is decreased back to a negative value. sodium to potassium conductance at each instant dur-
ing the action potential, and above this depiction is the
action potential itself. During the early portion of the
SUMMARY OF EVENTS THAT CAUSE THE
action potential, the ratio of sodium to potassium con-
ACTION POTENTIAL
ductance increases more than 1000-­fold. Therefore, far
Figure 5-­10 summarizes the sequential events that more sodium ions flow to the interior of the fiber than
occur during and shortly after the action potential. The potassium ions to the exterior. This is what causes the
bottom of the figure shows the changes in membrane membrane potential to become positive at the action
conductance for sodium and potassium ions. During potential onset. Then, the sodium channels begin to close,
the resting state, before the action potential begins, the and the potassium channels begin to open; thus, the ratio
conductance for potassium ions is 50 to 100 times as of conductance shifts far in favor of high potassium con-
great as the conductance for sodium ions. This dispar- ductance but low sodium conductance. This shift allows
ity is caused by much greater leakage of potassium ions for a very rapid loss of potassium ions to the exterior but
than sodium ions through the leak channels. However, virtually zero flow of sodium ions to the interior. Conse-
at the onset of the action potential, the sodium chan- quently, the action potential quickly returns to its baseline
nels almost instantaneously become activated and allow level.
up to a 5000-­fold increase in sodium conductance. The
inactivation process then closes the sodium channels Roles of Other Ions During the Action Potential
Thus far, we have considered only the roles of sodium and
potassium ions in generating the action potential. At least
Membrane potential (mV)

Overshoot two other types of ions must be considered, negative anions

+40
and calcium ions.
+20
Action potential Impermeant Negatively Charged Ions (Anions) Inside
100 0
–20 the Nerve Axon. Inside the axon are many negatively
10 –40 charged ions that cannot go through the membrane chan-
Na+ conductance
K+ conductance

–60 nels. They include the anions of protein molecules and

1 of many organic phosphate compounds and sulfate com-
–80
0.1 Positive
pounds, among others. Because these ions cannot leave
afterpotential the interior of the axon, any deficit of positive ions inside
0.01 the membrane leaves an excess of these impermeant nega-
Ratio of conductances tive anions. Therefore, these impermeant negative ions are
0.001
100
responsible for the negative charge inside the fiber when
there is a net deficit of positively charged potassium ions
10 and other positive ions.
Conductance
(mmho/cm2)

Calcium Ions. The membranes of almost all cells of the

1 K+
body have a calcium pump similar to the sodium pump,
0.1 and calcium serves along with (or instead of ) sodium in
Na+ some cells to cause most of the action potential. Like the
0.01 sodium pump, the calcium pump transports calcium ions
0.005
from the interior to the exterior of the cell membrane (or
0 0.5 1.0 1.5
Milliseconds
into the endoplasmic reticulum of the cell), creating a cal-
cium ion gradient of about 10,000-­fold. This process leaves
Figure 5-­10 Changes in sodium and potassium conductance dur- an internal cell concentration of calcium ions of about 10−7
ing the course of the action potential. Sodium conductance increases
molar, in contrast to an external concentration of about
several thousand–fold during the early stages of the action potential,
whereas potassium conductance increases only about 30-­fold during
10−3 molar.
the latter stages of the action potential and for a short period thereaf- In addition, there are voltage-­gated calcium channels.
ter. (These curves were constructed from theory presented in papers Because the calcium ion concentration is more than 10,000
by Hodgkin and Huxley but transposed from a squid axon to apply to times greater in the extracellular fluid than in the intracellular
the membrane potentials of large mammalian nerve fibers.) fluid, there is a tremendous diffusion gradient and elec-

70
 Chapter 5 Membrane Potentials and Action Potentials

trochemical driving force for the passive flow of calcium rise in the membrane potential, thus opening still more
ions into the cells. These channels are slightly permeable
voltage-­gated sodium channels and allowing more stream-
to sodium ions and calcium ions, but their permeability to
ing of sodium ions to the interior of the fiber. This process
calcium is about 1000-­fold greater than to sodium under
normal physiological conditions. When the channels open is a positive feedback cycle that, once the feedback is strong
in response to a stimulus that depolarizes the cell mem- enough, continues until all the voltage-­gated sodium chan-
nels have become activated (opened). Then, within another

UNIT II
brane, calcium ions flow to the interior of the cell.
A major function of the voltage-­gated calcium ion fraction of a millisecond, the rising membrane potential
channels is to contribute to the depolarizing phase on the causes closure of the sodium channels and opening of po-
action potential in some cells. The gating of calcium chan- tassium channels, and the action potential soon terminates.
nels, however, is relatively slow, requiring 10 to 20 times
as long for activation as for the sodium channels. For this Initiation of the Action Potential Occurs Only After
reason, they are often called slow channels, in contrast the Threshold Potential is Reached. An action poten-
to the sodium channels, which are called fast channels.
tial will not occur until the initial rise in membrane po-
Therefore, the opening of calcium channels provides a
tential is great enough to create the positive feedback de-
more sustained depolarization, whereas the sodium chan-
nels play a key role in initiating action potentials. scribed in the preceding paragraph. This occurs when the
Calcium channels are numerous in cardiac muscle and number of sodium ions entering the fiber is greater than
smooth muscle. In fact, in some types of smooth muscle, the number of potassium ions leaving the fiber. A sudden
the fast sodium channels are hardly present; therefore, the rise in membrane potential of 15 to 30 millivolts is usually
action potentials are caused almost entirely by the activa- required. Therefore, a sudden increase in the membrane
tion of slow calcium channels. potential in a large nerve fiber, from −70 millivolts up to
Increased Permeability of the Sodium Channels When about −55 millivolts, usually causes the explosive devel-
There Is a Deficit of Calcium Ions. The concentration of opment of an action potential. This level of −55 millivolts
calcium ions in the extracellular fluid also has a profound is said to be the threshold for stimulation.
effect on the voltage level at which the sodium channels
become activated. When there is a deficit of calcium ions,
the sodium channels become activated (opened) by a small
increase of the membrane potential from its normal, very PROPAGATION OF THE ACTION
negative level. Therefore, the nerve fiber becomes highly
POTENTIAL
excitable, sometimes discharging repetitively without prov-
ocation, rather than remaining in the resting state. In fact, In the preceding paragraphs, we discussed the action
the calcium ion concentration needs to fall only 50% be- potential as though it occurs at one spot on the mem-
low normal before spontaneous discharge occurs in some brane. However, an action potential elicited at any one
peripheral nerves, often causing muscle “tetany.” Muscle point on an excitable membrane usually excites adjacent
tetany is sometimes lethal because of tetanic contraction of
portions of the membrane, resulting in propagation of the
the respiratory muscles.
action potential along the membrane. This mechanism is
The probable way in which calcium ions affect the so-
dium channels is as follows. These ions appear to bind to demonstrated in Figure 5-­11.
the exterior surfaces of the sodium channel protein. The Figure 5-­11A shows a normal resting nerve fiber, and
positive charges of these calcium ions, in turn, alter the Figure 5-­11B shows a nerve fiber that has been excited in
electrical state of the sodium channel protein, thus altering its midportion, which suddenly develops increased perme-
the voltage level required to open the sodium gate. ability to sodium. The arrows show a local circuit of cur-
rent flow from the depolarized areas of the membrane
to the adjacent resting membrane areas. That is, posi-
INITIATION OF THE ACTION POTENTIAL tive electrical charges are carried by the inward-­diffusing
sodium ions through the depolarized membrane and then
Thus far, we have explained the changing sodium and for several millimeters in both directions along the core of
potassium permeability of the membrane, as well as the the axon. These positive charges increase the voltage for a
development of the action potential, but we have not distance of 1 to 3 millimeters inside the large myelinated
explained what initiates the action potential. fiber to above the threshold voltage value for initiating an
action potential. Therefore, the sodium channels in these
A Positive-­Feedback Cycle Opens the Sodium Chan- new areas immediately open, as shown in Figure 5-­11C
nels. As long as the membrane of the nerve fiber remains and D, and the explosive action potential spreads. These
undisturbed, no action potential occurs in the normal newly depolarized areas produce still more local circuits of
nerve. However, if any event causes enough initial rise in current flow farther along the membrane, causing progres-
the membrane potential from −70 millivolts toward the sively more and more depolarization. Thus, the depolariza-
zero level, the rising voltage will cause many voltage-­gated tion process travels along the entire length of the fiber. This
sodium channels to begin opening. This occurrence allows transmission of the depolarization process along a nerve or
for the rapid inflow of sodium ions, which causes a further muscle fiber is called a nerve or muscle impulse.

71
UNIT II Membrane Physiology, Nerve, and Muscle

Direction of Propagation. As demonstrated in Figure 5-­ repolarization. For a single action potential, this effect is
11, an excitable membrane has no single direction of prop- so minute that it cannot be measured. Indeed, 100,000
agation, but the action potential travels in all directions to 50 million impulses can be transmitted by large nerve
away from the stimulus—even along all branches of a nerve fibers before the concentration differences reach the point
fiber—until the entire membrane has become depolarized. that action potential conduction ceases. With time, how-
ever, it becomes necessary to re-­establish the sodium and
All-­or-­Nothing Principle. Once an action potential has potassium membrane concentration differences, which is
been elicited at any point on the membrane of a normal achieved by action of the Na+-­K+ pump in the same way
fiber, the depolarization process travels over the entire as described previously for the original establishment of
membrane if conditions are right, but it does not travel at the resting potential. That is, sodium ions that have dif-
all if conditions are not right. This principle is called the all-­ fused to the interior of the cell during the action poten-
or-­nothing principle, and it applies to all normal excitable tials and potassium ions that have diffused to the exterior
tissues. Occasionally, the action potential reaches a point must be returned to their original state by the Na+-­K+
on the membrane at which it does not generate sufficient pump. Because this pump requires energy for operation,
voltage to stimulate the next area of the membrane. When this “recharging” of the nerve fiber is an active metabolic
this situation occurs, the spread of depolarization stops. process, using energy derived from the adenosine tri-
Therefore, for continued propagation of an impulse to oc- phosphate (ATP) energy system of the cell. Figure 5-­12
cur, the ratio of action potential to threshold for excitation shows that the nerve fiber produces increased heat dur-
must at all times be greater than 1. This “greater than 1” ing recharging, which is a measure of energy expenditure
requirement is called the safety factor for propagation. when the nerve impulse frequency increases.
A special feature of the Na+-­K+ ATP pump is that
its degree of activity is strongly stimulated when excess
RE-­ESTABLISHING SODIUM AND
sodium ions accumulate inside the cell membrane. In fact,
POTASSIUM IONIC GRADIENTS
the pumping activity increases approximately in propor-
AFTER ACTION POTENTIALS ARE
tion to the third power of this intracellular sodium con-
COMPLETED—IMPORTANCE OF
centration. As the internal sodium concentration rises
ENERGY METABOLISM
from 10 to 20 mEq/L, the activity of the pump does not
Transmission of each action potential along a nerve fiber merely double but increases about eightfold. Therefore, it
slightly reduces the concentration differences of sodium is easy to understand how the recharging process of the
and potassium inside and outside the membrane because nerve fiber can be set rapidly into motion whenever the
sodium ions diffuse to the inside during depolariza- concentration differences of sodium and potassium ions
tion, and potassium ions diffuse to the outside during across the membrane begin to run down.

+++++++++++++++++++++++ PLATEAU IN SOME ACTION

–––––––––––––––––––––––
POTENTIALS
––––––––––––––––––––––– In some cases, the excited membrane does not repolarize
A +++++++++++++++++++++++
immediately after depolarization; instead, the potential
remains on a plateau near the peak of the spike potential
++++++++++++––+++++++++ for many milliseconds before repolarization begin. Such a
––––––––––––++––––––––– plateau is shown in Figure 5-­13; one can readily see that
––––––––––––++–––––––––
B ++++++++++++––+++++++++

++++++++++––––++++++++
––––––––––++++––––––––
Heat production

––––––––––++++––––––––
C ++++++++++––––++++++++

++––––––––––––––––––++
––++++++++++++++++++––
At rest
––++++++++++++++++++––
0 100 200 300
++––––––––––––––––––++
D Impulses per second
Figure 5-­11 A–D, Propagation of action potentials in both directions Figure 5-­12 Heat production in a nerve fiber at rest and at progres-
along a conductive fiber. sively increasing rates of stimulation.

72
UNIT II Membrane Physiology, Nerve, and Muscle

nearer to the potassium Nernst potential. This state, called electrical insulator that decreases ion flow through the
hyperpolarization, is also shown in Figure 5-­14. As long membrane about 5000-­fold. At the juncture between each
as this state exists, self–re-­excitation will not occur. How- two successive Schwann cells along the axon, a small unin-
ever, the increased potassium conductance (and the state sulated area only 2 to 3 micrometers in length remains
of hyperpolarization) gradually disappears, as shown after where ions still can flow with ease through the axon mem-
each action potential is completed in the figure, thereby brane between the extracellular fluid and intracellular fluid
again allowing the membrane potential to increase up to inside the axon. This area is called the node of Ranvier.
the threshold for excitation. Then, suddenly, a new action
potential results and the process occurs again and again. Saltatory Conduction in Myelinated Fibers from Node
to Node. Even though almost no ions can flow through
the thick myelin sheaths of myelinated nerves, they can
SPECIAL CHARACTERISTICS OF SIGNAL
flow with ease through the nodes of Ranvier. Therefore,
TRANSMISSION IN NERVE TRUNKS
action potentials occur only at the nodes. Yet, the action
potentials are conducted from node to node by saltatory
Myelinated and Unmyelinated Nerve Fibers. Figure
conduction, as shown in Figure 5-­17. That is, electrical
5-­15 shows a cross section of a typical small nerve, re- current flows through the surrounding extracellular fluid
vealing many large nerve fibers that constitute most of the outside the myelin sheath, as well as through the axoplasm
cross-­sectional area. However, a more careful look reveals inside the axon from node to node, exciting successive
many more small fibers lying between the large ones. The nodes one after another. Thus, the nerve impulse jumps
large fibers are myelinated, and the small ones are unmy- along the fiber, which is the origin of the term saltatory.
elinated. The average nerve trunk contains about twice as Saltatory conduction is of value for two reasons:
many unmyelinated fibers as myelinated fibers. 1. First, by causing the depolarization process to jump
Figure 5-­16 illustrates schematically the features of a long intervals along the axis of the nerve fiber, this
typical myelinated fiber. The central core of the fiber is the mechanism increases the velocity of nerve transmis-
axon, and the membrane of the axon is the membrane that sion in myelinated fibers as much as 5-­to 50-­fold.
actually conducts the action potential. The axon is filled in
its center with axoplasm, which is a viscid intracellular fluid.
Surrounding the axon is a myelin sheath that is often much
thicker than the axon itself. About once every 1 to 3 millime-
ters along the length of the myelin sheath is a node of Ranvier.
The myelin sheath is deposited around the axon by
Schwann cells in the following manner. The membrane of
a Schwann cell first envelops the axon. The Schwann cell
then rotates around the axon many times, laying down mul- Axon
tiple layers of Schwann cell membrane containing the lipid
substance sphingomyelin. This substance is an excellent Myelin
sheath
Schwann cell
cytoplasm
Schwann cell
nucleus

Node of Ranvier
A

Unmyelinated axons

Schwann cell nucleus

Schwann cell cytoplasm

B
Figure 5-­16 Function of the Schwann cell to insulate nerve fibers. A,
Wrapping of a Schwann cell membrane around a large axon to form
the myelin sheath of the myelinated nerve fiber. B, Partial wrapping
of the membrane and cytoplasm of a Schwann cell around multiple
Figure 5-­15 Cross section of a small nerve trunk containing both unmyelinated nerve fibers (shown in cross section). (A, Modified from
myelinated and unmyelinated fibers. Leeson TS, Leeson R: Histology. Philadelphia: WB Saunders, 1979.)

74
 Chapter 5 Membrane Potentials and Action Potentials

2. Second, saltatory conduction conserves energy for action potentials: mechanical pressure to excite sensory
the axon because only the nodes depolarize, allowing nerve endings in the skin, chemical neurotransmitters to
perhaps 100 times less loss of ions than would other- transmit signals from one neuron to the next in the brain,
wise be necessary, and therefore requiring much less and electrical current to transmit signals between succes-
energy expenditure for re-­establishing the sodium sive muscle cells in the heart and intestine.
and potassium concentration differences across the

UNIT II
membrane after a series of nerve impulses. Excitation of a Nerve Fiber by a Negatively Charged
The excellent insulation afforded by the myelin mem- Metal Electrode. The usual means for exciting a nerve or
brane and the 50-­fold decrease in membrane capacitance muscle in the experimental laboratory is to apply electricity
also allow repolarization to occur with little transfer of ions. to the nerve or muscle surface through two small electrodes,
one of which is negatively charged and the other positively
Velocity of Conduction in Nerve Fibers. The velocity charged. When electricity is applied in this manner, the
of action potential conduction in nerve fibers varies from excitable membrane becomes stimulated at the negative
as little as 0.25 m/sec in small unmyelinated fibers to as electrode.
much as 100 m/sec—more than the length of a football Remember that the action potential is initiated by the
field in 1 second—in large myelinated fibers. opening of voltage-­gated sodium channels. Furthermore,
these channels are opened by a decrease in the normal rest-
ing electrical voltage across the membrane—that is, nega-
EXCITATION—THE PROCESS OF tive current from the electrode decreases the voltage on the
ELICITING THE ACTION POTENTIAL outside of the membrane to a negative value nearer to the
voltage of the negative potential inside the fiber. This effect
Basically, any factor that causes sodium ions to begin to decreases the electrical voltage across the membrane and
diffuse inward through the membrane in sufficient num- allows the sodium channels to open, resulting in an action
bers can set off automatic regenerative opening of the potential. Conversely, at the positive electrode, the injec-
sodium channels. This automatic regenerative opening tion of positive charges on the outside of the nerve mem-
can result from mechanical disturbance of the membrane, brane heightens the voltage difference across the mem-
chemical effects on the membrane, or passage of electric- brane, rather than lessening it. This effect causes a state of
ity through the membrane. All these approaches are used hyperpolarization, which actually decreases the excitability
at different points in the body to elicit nerve or muscle of the fiber rather than causing an action potential.

Saltatory conduction

Action potential
starts here

Action potential Action potential

Saltatory conduction

Na+ Na+

– – – + + + + + + + + + + + + + – – –
– – – + + + + + + + + + + + + + – – –

Na+ Na+

Na+ channel Axoplasm Myelin sheath Node of Ranvier

Figure 5-­17 Saltatory conduction along a myelinated axon. The flow of electrical current from node to node is illustrated by the arrows.

75
UNIT II Membrane Physiology, Nerve, and Muscle

Threshold for Excitation and Acute Local Potentials. resting membrane potential level. Then, within another
A weak negative electrical stimulus may not be able to small fraction of a second, the inactivation gates of the
excite a fiber. However, when the voltage of the stimu- channels open, and a new action potential can be initiated.
lus is increased, there comes a point at which excitation The period during which a second action potential can-
does take place. Figure 5-­18 shows the effects of suc- not be elicited, even with a strong stimulus, is called the
cessively applied stimuli of progressing strength. A weak absolute refractory period. This period for large myelin-
stimulus at point A causes the membrane potential to ated nerve fibers is about 1/2500 second. Therefore, one
change from −70 to −65 millivolts, but this change is can readily calculate that such a fiber can transmit a maxi-
not sufficient for the automatic regenerative processes mum of about 2500 impulses per second.
of the action potential to develop. At point B, the stimu-
lus is greater, but the intensity is still not enough. The Inhibition of Excitability—Stabilizers and Local
stimulus does, however, disturb the membrane potential Anesthetics
locally for as long as 1 millisecond or more after both In contrast to the factors that increase nerve excitability,
of these weak stimuli. These local potential changes are membrane-­stabilizing factors can decrease excitability. For
called acute local potentials and, when they fail to elicit example, a high extracellular fluid calcium ion concentration
an action potential, they are called acute subthreshold decreases membrane permeability to sodium ions and
potentials. simultaneously reduces excitability. Therefore, calcium ions
At point C in Figure 5-­18, the stimulus is even stronger. are said to be what is called a stabilizer.
Now, the local potential has barely reached the threshold Local Anesthetics. Among the most important sta-
level required to elicit an action potential, but this occurs bilizers are the many substances used clinically as local
anesthetics, including procaine and tetracaine. Most of
only after a short “latent period.” At point D, the stimulus is
these agents act directly on the activation gates of the so-
still stronger, the acute local potential is also stronger, and dium channels, making it much more difficult for these
the action potential occurs after less of a latent period. gates to open and thereby reducing membrane excitabil-
Thus, this figure shows that even a weak stimulus ity. When excitability has been reduced so low that the
causes a local potential change at the membrane, but the ratio of action potential strength to excitability threshold
intensity of the local potential must rise to a threshold (called the safety factor) is reduced below 1.0, nerve im-
level before the action potential is set off. pulses fail to pass along the anesthetized nerves.

REFRACTORY PERIOD AFTER AN ACTION

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