Membrane Potential and Action
Potential to diffuse outward
Chapter 7 – Human Anatomy and
Physiology
Introduction
Electrical potentials exist across the
membranes of all cells of the body.
In addition, some cells, such as
nerve and muscle cells, are “excitable”
– that is, capable of self-generation of
electrochemical impulses at their
membranes.
In still other types of cells, such as
glandular cells, macrophages, and
ciliated cells, other types of changes in
membrane potentials probably play
significant roles in controlling many of
the cell’s functions.
This chapter is concerned with
membrane potentials that are generated
both at rest and during action by nerve
and muscle cells.
Basic Physics of Membrane Potentials
Section 7-1
Membrane Potentials Caused by
Diffusion
In a neuron (or nerve fiber) where there
is no active transport of sodium and
potassium ions:
o The potassium concentration is
greater inside the membrane,
whereas that outside is very low
o The sodium concentration is greater
outside the membrane, whereas
that inside is very low
Assuming that this membrane is
permeable to the potassium ions but not
to any other ions:
1. There is large potassium
concentration gradient from the
inside toward the outside, thus a
strong tendency for potassium ions
2. As they diffuse outside, they carry
positive charges to the outside, thus
creating a state of electropositivity
outside the membrane and
electronegativity on the inside
3. Therefore, a new potential
difference is created
4. Within a millisecond or so, the
potential change becomes great
enough to block further net
diffusion to the exterior despite the
high potassium ion gradient
5. In the normal large mammalian
nerve fiber, the potential difference
is about -94 millivolts with
negativity inside the fiber
membrane
Let us assume this time that the
membrane is permeable only to sodium
ions but not to any other ions
1. There is large sodium concentration
gradient
from the outside toward the inside,
thus a strong tendency of sodium to
diffuse inward
2. Diffusion of sodium ions
to the inside creates a membrane
potential now
of opposite polarity, with negativity
outside and positivity inside
3. Again, the membrane potential
rises high enough within
milliseconds to block further net
diffusion of sodium ions to the
inside
4. For the large mammalian fiber, this
potential is about +61 millivolts and
with positivity inside the fiber
o Thus, we are able to observe that a
concentration difference of ions
 across a selectively permeable
membrane can, under appropriate
conditions, cause the creation of a
membrane potential
o Many of the rapid changes in
membrane potentials observed
during the course of nerve and
muscle impulse transmission result
from the occurrence of rapidly
changing diffusion potentials of this
nature
The Nernst Equation
o The potential level across the
membrane that prevents net
diffusion of an ion in either
direction through the membrane is
called the Nernst potential for that
ion
o The magnitude of this potential is
determined by the ratio of the ion
concentrations on the two sides of
the membrane
o The greater this ratio, the greater the
tendency for the ions to diffuse in one
direction, and therefore the greater is the
Nernst potential
o The Nernst equation can be used to
calculate the Nernst potential for
any univalent ion at normal body
temperature of 98.6oF (37oC)
o When using this formula, it is
usually assumed that the potential
outside the membrane always
remains at exactly zero potential,
and the Nernst potential that is
calculated is the potential INSIDE
the membrane
o Usually, the sign of the potential is
positive (+) if the ion under
consideration is a negative ion and
negative (-) if it is a positive ion
Goldman-Hodgkin-Katz Equation
When a membrane is permeable to
several different ions, the diffusion
potential that develops depends on
three factors:
1. The polarity of the electrical charge
of each ion
2. The permeability of the membrane
(P) to each ion
3. The concentrations (C) of the
respective ions on the inside (i) and
outside (o) of the membrane
Thus, the formula, called the Goldman
equation or Goldman-Hodgkin-Katz
equation, gives the calculated membrane
potential on the INSIDE of the membrane
when two univalent positive ions (Na+ and
K+), and one univalent negative ion (Cl-)
are involved
Importance and Meaning of the
Equation
First, sodium, potassium, and chloride
ions are the ions most importantly
involved in the development of
membrane potentials in nerve and
muscle fibers
o The concentration gradient of each
of these ions across the membrane
helps determine the voltage of the
membrane potential
Goldman-Hodgkin-Katz
Equation
Second, the degree of importance of
each of the ions in determining the
voltage is proportional to the
membrane permeability for that
particular ion
o If the membrane is impermeable
to both potassium and chloride
ions, the membrane potential
becomes entirely dominated by
the concentration gradient of
sodium alone
o The resulting potential will be
equal to the Nernst potential for
sodium
o The same principle holds for
each of the other two ions if the
membrane should become
selectively permeable for either
one of them alone
Third, a positive ion concentration
gradient from inside the membrane to
the outside causes electronegativity
inside the membrane
o The reason for this is that positive
ions diffuse to the outside when
their concentration is higher inside
than outside
o This carries positive charges to the
outside but leaves the non-diffusible
negative anions on the inside
o The opposite effect occurs when
there is a negative ion gradient, i.e.,
a chloride ion gradient from the
outside to the inside causes
negativity inside the cell because
negatively charged chloride ions
diffuse to the inside, while leaving
the non-diffusible positive ions on
the outside
Fourth, the permeability of sodium and
potassium channels undergo rapid
changes during conduction of the nerve
impulse, whereas the permeability of
the chloride channels does not change
greatly during this process
o Therefore, the changes in sodium
and potassium permeability are
primarily responsible for signal
transmission in the nerves
Measuring the Membrane Potential
Resting Membrane Potential
Section 7-2
Resting Membrane Potential of
Nerves
o The membrane potential of large
nerve fibers when they are not
conducting nerve signals is about -
90 millivolts
o That is, the potential inside the fiber
is 90 millivolts more negative than
the potential in the extracellular
fluid on the outside of the fiber
o
Sodium-Potassium Pump
o Active transport of sodium and
potassium ions through the
membrane is mainly carried by
the Na+/K+ ATPase pump
o This pump continuously pumps
sodium to the outside of the
fiber (against the concentration
gradient) and potassium to the
inside (against the concentration
gradient)
o Electrogenic pump – because
more positive charges are
 pumped to the outside than to
the inside (three Na+ to the
outside for each two K+ to the
inside)
o This leaves a net deficit of
positive ions on the inside,
which causes a negative charge
inside the cell
o The sodium-potassium pump
also causes large concentration o To the right is shown a channel
gradients for sodium and protein in the cell membrane
potassium across the resting through which sodium ions can
nerve membrane leak, called sodium leak
Leakage of Sodium and Potassium channels
Ions
Origin of the Normal Resting
Potential
o Contribution of the potassium
diffusion potential
o Contribution of sodium
diffusion through the nerve
membrane
o Contribution of sodium-
potassium pump or Na+/K+
o To the right is shown a channel ATPase pump
protein in the cell membrane
through which potassium ions can Contribution of the Potassium
leak, called potassium leak channels Diffusion Potential
o The emphasis is on potassium
leakage because, on the average, the
membrane of nerve fibers is
normally about 100 times more
permeable for potassium than
sodium during the resting state
o This difference in permeability is
exceedingly important in
determining the level of the normal
resting membrane potential

o In the figure, an assumption is made

that the only movement of ions
through the membrane is the
 diffusion of potassium ions as
demonstrated by the open channels
between potassium inside the
membrane and the outside
o There is a high ratio of potassium
ions inside to the outside, 35 to 1
o Substituting these values to the
Nernst equation, the Nernst
potential corresponding to this ratio
is -94 millivolts
o Therefore, if potassium ions were
the only factor causing the resting
potential, this resting potential
inside the fiber would also be equal
to -94 millivolts
Contribution of Sodium Diffusion
through the Nerve Membrane
o Figure B shows the addition of
slight permeability of the nerve
membrane to sodium ions, caused
by the minute diffusion of sodium
ions through the sodium leak
channels
o The ratio of sodium ions from
inside to outside the membrane is
0.1
o This gives a calculated Nernst
potential for the inside of the
membrane of +61 millivolts
o Also shown in the figure the Nernst
potential for potassium diffusion of
-94 millivolts
o Using the Goldman equation, a
summated potential can be
obtained between potentials created
by sodium diffusion and potassium
diffusion
o Since the membrane of a resting
nerve fiber is highly permeable to
potassium but only slightly
permeable to sodium, it is logical
that the diffusion of potassium will
contribute far more to the
membrane potential than will the
diffusion of sodium
o In the normal nerve fiber, the
permeability of the membrane to
potassium is about 100 times as
great as to sodium
o Using this value in the Goldman
equation gives an internal resting
membrane potential of -86
millivolts
Contribution of Na+/K+ Pump
o In figure C, there is continuous
pumping of three sodium ions to the
outside for each two potassium ions
pumped to the inside of the
membrane
o The continuous loss of positive
charges from inside the membrane
 creates an additional degree of positive membrane potential, and
negativity on the inside then ends with an almost equally
o It was determined that this rapid change back to the negative
additional potential is around -4 potential
millivolts o To conduct a nerve signal, the
action potential moves along the
• In summary, the diffusion nerve fiber until it comes to the
potentials alone caused by fiber’s end
potassium and sodium diffusion
would give a membrane potential of
about -86 millivolts, almost all of
this being determined by potassium
diffusion
• An additional -4 millivolts are
contributed to the membrane
potential by the electrogenic
Na+/K+ pump
• Therefore, the overall net resting
membrane potential is -90
millivolts
• The resting membrane potential of
large skeletal muscle fibers is about o The upper panel of the figure on the
the same as that in large nerve right shows the disturbances that
occur at the membrane during an
fibers, also -90 millivolts
action potential
• However, in both small nerve fibers
o There is transfer of positive charges
and small muscle fibers (e.g.
to the interior of the fiber at its onset
smooth muscle) as well as in many
and return of positive charges to the
of the neurons of the central
exterior at its end
nervous system, the resting
o The lower panel shows the
membrane potential is often as little
successive changes in the
as -40 to -60 millivolts instead of -
membrane potential over a few
90 millivolts
10,000ths of a second
o This illustrates the explosive onset
Nerve Action Potential
of the action potential and the
Section 7-3
almost equally rapid recovery
o Nerve signals are transmitted by
action potentials (AP), which are
Stages of Action Potential
rapid changes in the membrane
• Resting stage
potential
• Depolarization stage
o Each action potential begins with a
sudden change from the normal • Repolarization stage
resting membrane potential to a
Resting Stage
 o This is the resting membrane
potential before the action
potential occurs
o The membrane is said to be
“polarized” during this stage
because of the large negative
membrane potential that is
present
Depolarization Stage
o At this time, the membrane
suddenly becomes permeable to
sodium ions, allowing
tremendous numbers
positively charged sodium ions
to flow to the interior of the
axon
o The normal “polarized” state of
-90 millivolts is lost, with the
potential rising rapidly in the
positive direction
o This is called depolarization
o In large nerve fibers, the
membrane potential
“overshoots” beyond the zero
level and becomes somewhat
positive
o In some smaller fibers as well as
many CNS neurons, the
potential merely approaches the
zero level and does not
overshoot to the positive state
Repolarization Stage
o Within a few 10,000ths of a
second after the membrane
becomes highly permeable to
sodium ions, sodium channels
begin to close and potassium
channels open more than they
normally do
o Then, rapid diffusion of
potassium ions to the exterior
re-establishes the normal
negative resting membrane
potential
o This is called repolarization of
the membrane
Voltage-Gated Sodium & Potassium
Channels
o A necessary component in causing
both depolarization and
repolarization of the nerve
membrane during action potential
is the voltage-gated sodium channel
of o The voltage-gated potassium channel
also plays an important role in
increasing the rapidity of
repolarization of the membrane
o These two voltage-gated channels
are in addition to the sodium-
potassium pump and the sodium
and potassium leak channels
The figure on the right shows the
voltage-gated sodium channel in three
separates
states:
o Resting state
o Activated state
o Inactivated state
Resting State
o This channel has two gates, one
near the outside of the channel
called the activation gate and
 another near the inside called
the inactivation gate
o In a normal resting membrane,
the activation gate is closed,
preventing any entry of sodium
ions to the interior of the fiber
Activated State
o When the membrane potential
becomes less negative than
during the resting state, rising
from -90 mV towards zero, it
finally reaches a voltage
somewhere between -70 mV and
-50 mV
o This causes a sudden
conformational change in the
activation gate, flipping to the
open position
o This is called the activated state
o Sodium ions can pour inward
through the channel, increasing
sodium permeability as much as
500- to 5000-fold
Inactivated State
o The same increase in voltage
that opens the activation gate
also closes the inactivation gate
o This, however, closes a few
10,000ths of a second after the
activation gate opens
o The conformational change that
flips the inactivation gate to the
closed state is a slow process
o The conformational change that
opens the activation gate,
however, is a rapid process
o After the sodium channel has
remained open for a few
10,000ths of a second, it closes
and sodium ions can no longer
pour to the inside of the
membrane
o The membrane potential begins
to recover back to toward the
resting membrane state, which
is the repolarization process
o An important characteristic of
the sodium channel inactivation
process is that the inactivation
gate will not re-open until the
membrane potential returns
either to or nearly to the
original resting membrane
potential
o Therefore, it is not possible for
the sodium channels to open
again without the nerve fiber
first repolarizing
Voltage-Gated Potassium Channel
The figure on the right shows the
voltage-gated potassium channel in two
states:
• Resting state
• Toward the end of the action
potential
o During the resting state, the gate of
potassium channel is closed, and
potassium ions are prevented from
passing through this channel to the
exterior
o When the membrane potential rises
from -90 mV toward zero, this
 causes a slow conformational
opening of the gate which allows
increased potassium diffusion
outward through the channel
o Because of the slow opening of
these potassium channels, they
mainly open just at the same time
that the sodium channels are
beginning to close because of
inactivation
o Thus, the decrease in sodium entry
to the cell and simultaneous
increase in potassium exit from the
cell, greatly speed repolarization
o This leads to full recovery of the
resting membrane potential within
a few 10,000ths of a second
Voltage-Gated Sodium & Potassium
Channels
Summary of Events
o Figure shows in summary the
sequential events that occur during
and shortly after the action potential
o At the bottom of the figure are
shown the changes in membrane
conductance for sodium and
potassium ions
o During the resting state, before the
action potential begins, the
conductance for potassium ions is
shown to be 50 to 100 times as great
as the conductance for sodium ions
o This is due to greater leakage of
potassium ions than sodium ions
through the leak channels
o At the onset of action potential, the
sodium channels instantaneously
become activated and allow up to a
5,000-fold increase in sodium
conductance
o Then, the inactivation process
closes the sodium channels within
another few fractions of a
millisecond
o The onset of AP also causes voltage
gating of the potassium channels,
causing them to begin opening
more slowly, a fraction of a
millisecond after the sodium
channels open
o At the end of AP, the return of the
membrane potential to the negative
state causes the potassium channels
to close back to their original status,
but again only after a delay
o The middle portion of the figure on
shows the ratio of sodium
conductance to potassium
conductance at each instant during
the action potential
o Above this shows the action
potential (AP) itself
o During the early stages of AP, the
ratio of sodium to potassium
conductance increases more than a
thousand-fold
o Therefore, far more sodium ions
now flow to the interior of the fiber
than do potassium ions to the
exterior
o This is what causes the membrane
potential to become positive
o Then, the sodium channels begin to
close and, at the same time, the
potassium channels open
o At this point, the ratio of
conductance now shifts far in favor
of high potassium conductance but
low sodium conductance
o This allows extremely rapid loss of
potassium ions to the exterior,
whereas no sodium ions flow to the
interior
o The membrane potential quickly
returns to its baseline level
“Positive” Afterpotential
o The figure also shows that the
membrane potential becomes even
more negative than the original
resting membrane potential for a
few milliseconds after the AP is
over
o This is called the “positive”
afterpotential
o Positive afterpotential is mainly due
to the many potassium channels
that remain open for several
milliseconds after repolarization of
the membrane is complete
o This allows excess potassium ions
to diffuse out of the nerve fiber,
leaving an extra deficit of positive
ions on the inside
ROLES OF OTHER IONS DURING
ACTION POTENTIAL
Impermeable Negatively Charged
Ions (Anions) Inside the Axon
o Inside the axon are many negatively
charged ions that cannot go through
the membrane channels
• Anions of protein molecules
• Many organic phosphate
compounds
• Sulfate compounds
o Because these cannot leave the
interior of the axon, any deficit of
positive ions inside the membrane
leaves an excess of these
impermeable negative anions
o Therefore, these impermeable
anions are responsible for the
negative charge inside the fiber
when there is a deficit of positively
charged potassium ions and other
positive ions
ROLES OF OTHER IONS DURING
ACTION POTENTIAL
Calcium Ions
o The cell membranes of almost
all, if not all, cells of the body
have a calcium pump similar to
 the sodium pump, and calcium
serves along with (or instead of)
sodium in some cells to cause
the action potential
o Calcium pump pumps calcium
ions from the interior to the
exterior of the cell membrane
(or into the endoplasmic
reticulum), creating a calcium
ion gradient of about 10,000-
fold
o This leaves an internal
concentration of calcium ions of
about 10-7 molar in contrast to
an external concentration of
about 10-3 molar
o In addition, there are voltage-
gated calcium channels which
are slightly permeable to sodium
ions as well as to calcium ions
o When they open, both calcium
and sodium ions flow to the
interior of the fiber, therefore,
these channels are called
Na+/Ca2+ channels
o Na+/Ca2+ channels are slow to
become activated, requiring 10
to 20 times as long for activation
as the sodium channels
o Therefore, they are called slow
channels, in contrast to the
sodium channels that are called
fast channels
o Calcium channels are
numerous in both cardiac
muscle and smooth muscle
o In fact, in some types of smooth
muscle, the fast sodium
channels are hardly present, so
the action potentials then are
caused almost entirely by
activation of the slow calcium
channels
ROLES OF OTHER IONS DURING
ACTION POTENTIAL
Increased Permeability of Sodium
Channels When There is Deficit of
Calcium Ions
o The concentration of calcium ions
in the extracellular fluid also has a
profound effect on the voltage level
at which the sodium channels
become activated
o Calcium ions appear to bind to
exterior surfaces of voltage-gated
sodium channels and alter the
electrical state of these channels,
in this way increasing the voltage
level required to open the gate
o When there is deficit of calcium
ions (hypocalcemia), the voltage-
gated sodium channels become
activated (opened) by very little
change of membrane potential
from its normal very negative
resting level to a less negative level
o Therefore, the nerve fiber becomes
highly excitable, sometimes
discharging repetitively without
provocation rather than remaining
in the resting state
o When calcium ion concentration
falls below 50 percent normal,
spontaneous discharge occurs in
many peripheral nerves, often
causing muscle “tetany” that can be
lethal because of tetanic contraction
of the respiratory muscles
INITIATION OF ACTION
POTENTIAL
Positive-Feedback Vicious Circle
Opens the Sodium Channels
o As long as the membrane of the
nerve fiber remains undisturbed, no
action potential occurs in the
normal nerve
o If any event causes enough initial
rise in the membrane potential from
-90 millivolts up toward the zero
level, the rising voltage itself will
cause many voltage-gated sodium
channels to begin opening
o This allows rapid inflow of sodium
channels, which causes still further
rise of the membrane potential, thus
opening still more voltage-gated
sodium channels and allowing
more inflow of sodium ions to the
interior of the fiber
o This process is a positive-feedback
vicious circle that, once the
feedback is strong enough, will
continue until all the voltage-gated
sodium channels have become
activated (or opened)
o Then, within another fraction of a
millisecond, the rising membrane
potential causes beginning closure
of sodium channels as well as
opening of potassium channels, and
the action potential soon terminates
INITIATION OF ACTION
POTENTIAL
Threshold for Initiation of Action
Potential
o An action potential will not occur
until the initial rise in membrane
potential is great enough to create
the vicious circle described
previously
o This occurs when the number of
Na+ ions entering the fiber becomes
greater than the number of K+ ions
leaving the fiber
o A sudden rise in membrane
potential of 15 to 30 millivolts
usually is required
o Therefore, a sudden increase in the
membrane potential in a large nerve
fiber from -90 millivolts up to about
-65 millivolts usually cause the
explosive development of the action
potential
o This level of -65 millivolts is said to
be the threshold for stimulation
INITIATION OF ACTION
POTENTIAL
Accommodation of the Membrane -
Failure to Fire Despite Rising Voltage
o If the membrane potential rises
slowly (over milliseconds instead of
a fraction of a millisecond), the slow
inactivating gates of the sodium
channels will have time to close at
the same time that the activating
gate are opening
o Consequently, the opening of the
activating gates will not be as
effective in increasing the flow of
sodium ions as it is normally
o Therefore, a slow increase in the
internal voltage of a nerve fiber
either requires a higher threshold
voltage than normal to cause firing
or at times prevents firing entirely,
even with a voltage rise all the way
to zero or even to a positive voltage
o This phenomenon is called
accommodation of the membrane to
the stimulus
PROPAGATION OF THE ACTION
POTENTIAL
o An action potential elicited at any
one point on an excitable
membrane usually excites adjacent
 portions of the membrane, resulting
in propagation of the action
potential
o The transmission of the
depolarization process along a
nerve or muscle fiber is called a
nerve or muscle impulse
o An excitable membrane has no
single direction of propagation, but
the action potential will travel in
both directions away from the
stimulus and move along all
branches of a nerve fiber until the
entire membrane has become
depolarized
PROPAGATION OF THE ACTION
POTENTIAL
All-or-Nothing Principle
o Once an action potential has been
elicited at any point on the
membrane of a normal fiber, the
depolarization process will travel
over the entire membrane if
conditions are right, OR it might
not travel at all if conditions are not
right
o This is called the all-or-nothing
principle, and it applies to all normal
excitable tissues
o Occasionally, the action potential
will reach a point on the membrane
at which it does not generate
sufficient voltage to stimulate the
next area of the membrane
o When this occurs, the spread of
depolarization stops
o Therefore, for continuous
propagation of the impulse to occur,
the ratio of action potential to
threshold for excitation must at all
times be greater than 1
o This is called the safety factor for
propagation
RE-ESTABLISHING IONIC
GRADIENTS AFTER AP
o The transmission of each impulse
along the nerve fiber reduces
infinitesimally the concentration
differences of sodium and
potassium between the inside and
outside of the membrane because
of:
➢ Diffusion of sodium ions to the
inside during depolarization; and
➢ Diffusion of potassium ions to the
outside during repolarization
o For a single action potential, this
effect is so minute that it cannot be
measured
o Indeed, 100,000 to 50 million
impulses can be transmitted by
nerve fibers, depending on the size
of the fiber and other factors, before
the concentration differences have
run down to the point that AP
conduction ceases
o With time, it becomes necessary to
re-establish sodium and potassium
membrane concentration
differences, which is achieved by
the action of the Na+/K+ ATPase
pump
o The sodium ions that have diffused
to the interior of the cell during AP
and the potassium ions that have
diffused to the exterior are returned
to their original state by the Na+/K+
ATPase pump
o Because the pump requires energy,
the process of “recharging” the
nerve fiber is an active metabolic
one, using energy derived from
ATP
o A special feature of the Na+/K+
pump is that its degree of activity is
strongly stimulated when excess
sodium ions accumulate inside the
cell membrane
o Therefore, it can easily be
understood how the “recharging”
process of the nerve fiber can
rapidly be set into motion whenever
the concentration differences of
sodium and potassium ions across
the membrane begin to “run down”