Action potential

A. A schematic view of an idealized action potential illustrates its various phases as the
action potential passes a point on a cell membrane.
B. Actual recordings of action potentials are often distorted compared to the schematic
view because of variations in electrophysiological techniques used to make the recording
An action potential is a "spike" of positive and negative ionic discharge that travels
along the membrane of a cell. Action potentials are an essential feature of animal life,
rapidly carrying information within and between tissues. They also occur in some plants.
Action potentials can be created by many types of cells, but are used most extensively by
the nervous system for communication between neurons and for transmitting information
from neurons to other body tissues such as muscles and glands. Action potentials are not
the same in all cell types and can even vary in their properties at different locations in the
same cell. For example, cardiac action potentials are significantly different from the
action potentials in most neurons. This article is primarily concerned with the "typical"
action potential of axons.

Overview
There is always a difference in electrostatic potential between the inside and outside of a
cell, i.e. the cell is polarized. This membrane potential is the result of the distribution of
ions across the cell membrane and the permeability of the membrane to these ions. The
voltage of an inactive cell remains close to a resting potential with excess negative charge
inside the cell. When the membrane of an excitable cell becomes depolarized beyond a
threshold, the cell undergoes an action potential (it "fires"), often called a "spike" (see
Threshold and initiation). An action potential is a rapid change of the polarity of the
voltage from negative to positive and then vice versa, the entire cycle lasting on the order
of milliseconds. Each cycle and therefore each action potential has a rising phase, a
falling phase, and finally an undershoot (see Phases). In specialized muscle cells of the

heart, such as cardiac pacemaker cells, a plateau phase of intermediate voltage may
precede the falling phase, extending the action potential duration into hundreds of
milliseconds. Action potentials are measured with the recording techniques of
electrophysiology and more recently with neurochips containing EOSFETs. An
oscilloscope recording the membrane potential from a single point on an axon shows
each stage of the action potential as the wave passes. These phases trace an arc that
resembles a distorted sine wave; its amplitude depends on whether the action potential
wave has reached that point on the membrane or has passed it and if so, how long ago.
The action potential does not dwell in one location of the cell's membrane, but travels
along the membrane (see Propagation). It can travel along an axon for long distances, for
example to carry signals from the spinal cord to the muscles of the foot. After traveling
the whole length of the axon, the action potential reaches a synapse, where it stimulates
the release of neurotransmitters. These neurotransmitters can immediately induce an
action potential in the next neuron to propagate the signal, but the response is usually
more complex. Both the speed and complexity of action potentials vary between different
types of cells, but their amplitudes tend to be roughly the same. Within any one cell,
consecutive action potentials are typically indistinguishable. Neurons are thought to
transmit information by generating sequences of action potentials called "spike trains".
By varying both the rate as well as the precise timing of the action potentials they
generate, neurons can change the information that they transmit.

Underlying mechanism

The hydrophobic cell membrane prevents charged molecules from easily diffusing
through it, permitting a potential difference to exist across the membrane.

Resting potential
The resting potential is what would be maintained were there no action potentials,
synaptic potentials, or other changes to the membrane potential. In neurons the resting
potential is approximately -70 mV (the negative sign signifies excess negative charge
inside the cell relative to the outside). The resting potential is mostly determined by the
ion concentrations in the fluids on both sides of the cell membrane and the ion transport
proteins in the cell membrane. The term resting is somewhat misleading, for the cell must
constantly do work to maintain the resting potential. It takes a cell more energy to
maintain the resting potential as compared to transmission of nerve impulses. The
establishment of this potential difference involves several factors, the most important of
which are the transport of ions across the cell membrane and the selective permeability of
the membrane to these ions. The active transport of potassium and sodium ions into and
out of the cell, respectively, is accomplished by a number of sodium-potassium pumps
scattered across the cell membrane. Each pump transports two ions of potassium into the
cell for every three ions of sodium pumped out. This establishes a particular distribution
of positively charged ions across the cell membrane, with more sodium present outside

the cell than inside. In some situations, the electrogenic sodium-potassium pumps make a
significant contribution to the resting membrane potential, but in most cells there are
potassium leak channels that dominate the value of the resting potential. Sodium and
potassium ions diffuse through open ion channels under the influence of their
electrochemical gradients. At the resting potential, the net movement of sodium into the
cell equals the net movement of potassium out of the cell. However, the resting cell
membrane is approximately 75 times more permeable to potassium than to sodium
because potassium leak channels are always open. As a result, the cell's resting membrane
potential is closer to the equilibrium potential of potassium (=EK=80 mV) than the
equilibrium potential of sodium (=ENa=+60 mV).
Like the resting potential, action potentials depend upon the permeability of the cell
membrane to sodium and potassium ions. Transient changes in conductance for different
ions cause the changes in membrane potential necessary to initiate, sustain, and terminate
action potentials.

Phases
The sequence of events that underlie the action potential have been outlined below:

Resting potential
At resting potential some potassium leak channels are open but the voltage-gated sodium
channels are closed. Even though no net current flows, potassium, the major ion species,
moves across the membrane, thus pulling the resting potential close to the K + equilibrium
potential.

Stimulation
A local membrane depolarization caused by an excitatory stimulus causes some voltagegated sodium channels in the neuron cell surface membrane to open, causing net inward
movement of sodium ions through the channels along their electrochemical gradient. This
movement of sodium ions across the membrane is an example of facilitated diffusion[1].
Because they are positively charged, the inward moving sodium ions make the potential
difference across the membrane less negative inside. This initial inward movement of
sodium ions is favored by both the negative-inside membrane potential and the
concentration gradient of sodium ions across the membrane (less sodium inside). The
movement of individual sodium ions involves many random molecular collisions and at
any particular moment a sodium ion might be moving outward, but the net movement of
sodium is inward, as determined by the electrochemical gradient.

Depolarization ("Rising phase")

As sodium ions enter and the membrane potential becomes less negative, more sodium
channels open, causing an even greater influx of sodium ions. This is an example of
positive feedback. As more sodium channels open, the sodium current dominates over the
potassium leak current and the membrane potential becomes positive inside. Recent
experiments on cortical neurons suggest that sodium channels open cooperatively,[2]
allowing for a much faster uptake than is possible for Hodgkin-Huxleytype dynamics.

Peak
See also: Goldman-Hodgkin-Katz voltage equation
By the time the membrane potential has reached a peak value of around +50 mV, timedependent inactivation gates on the sodium channels have already started to close,
reducing and finally preventing further influx of sodium ions. While this occurs, the
voltage-sensitive activation gates on the voltage-gated potassium channels begin to open.

It is important to appreciate that very few ions actually cross the membrane at any stage
in the action potential. There is no 'flood' of sodium into the cell; the gross intracellular
and extracellular concentrations of sodium and potassium change so little during the
action potential as to be negligible. Instead, the change in membrane polarity occurs due
to the Permeability for Sodium, PNa, increasing greatly via the positive feedback system
described (depolarization causes voltage-gated Sodium channels to open, so membrane
becomes more depolarized etc). Increasing PNa relative to Potassium Permeability
(PK)affects voltage because it lifts the membrane potential towards that of the equilibrium
potential for Sodium (ENa), which is approximately +55mV.
This can be measured quantitively using the Goldman equation,

Concentrations of Na and K in and out of the cell do not change much, but P Na and PK
values do change markedly, and it is this that changes the value for V.

Repolarization ("Falling phase")

As voltage-gated potassium channels open, there is a large outward movement of
potassium ions driven by the potassium concentration gradient and initially favored by
the positive-inside electrical gradient. As potassium ions diffuse out, this movement of
positive charge causes a reversal of the membrane potential to negative-inside and
repolarization of the neuron back towards the large negative-inside resting potential.
Again, it is not the movement of potassium ions that changes membrane voltage. It is the
value for PK rising above that for PNa, dragging membrane voltage back towards the
equilibrium constant for Potassium (around -70mV) (see Goldman Constant Field
Equation).

Hyperpolarization ("Undershoot")
Closing of voltage-gated potassium channels is both voltage- and time-dependent. As
potassium exits the cell, the resulting membrane repolarization initiates the closing of
voltage-gated potassium channels. These channels do not close immediately in response
to a change in membrane potential; rather, voltage-gated potassium channels (also called
delayed rectifier potassium channels) have a delayed response, such that potassium
continues to flow out of the cell even after the membrane has fully repolarized. Thus the
membrane potential dips below the normal resting membrane potential of the cell for a
brief moment; this dip of hyperpolarization is known as the undershoot.

Refractory Period
During the next, ~ 1-3 ms, action potential initiation becomes difficult. This is the
'Refractory Period', consisting of an absolute and relative phase. In the absolute refractory
period, the Na+ Channels cannot be opened by a stimulus; they have entered an
inactivated state. This is time-dependent, and during this phase no action potential,
irrespective of applied voltage, will be fired. In the relative refractory period
(immediately after the absolute phase), action potentials can be initiated, but the threshold
is greater. There are two reasons for this: the cell may still be slightly hyperpolarized due
to still higher than resting value for PK, so more voltage is required to reach threshold,
and also the threshold itself is higher than usual because some of the Sodium channels
will still be inactivated. (Note that the sodium channel therefore has at least three states:

closed, open and inactivated - closed and not able to open). The refractory period is
important because it ensures unidirectional (one way) propagation of the action potential.
There is a common misconception that the Na+/K+ pump restores the resting potential
during the action potential falling phase by actively pumping Na+ out of, and K+ into the
neuron. This (along with the misconception that sodium 'floods' the cell to cause the
action potential), is not correct. The Na+/K+/ATPase (another name for the pump) does
ultimately maintain the resting potential by maintaining the concentration gradients for
Na and K, but does so on a much slower time scale; days as opposed to milliseconds.
During the falling phase of the action potential, the resting potential is restored
exclusively by PK rising to once again be far larger than PNa (i.e. membrane permeability
to potassium far exceeds its permeability to sodium, thus bringing the membrane
potential back down towards EK (the potassium equilibrium potential). The time-course
of the role of the Na+/K+/ATPase in maintaining resting potentials can be demonstrated
by the fact that the poison Ouabain inactivates the Na+/K+/ATPase, yet many thousands
of action potentials can still be fired without significantly running down the concentration
gradients.

Threshold and initiation

A plot of current (ion flux) against voltage (transmembrane potential) illustrates the
action potential threshold (red arrow) of an idealized cell. Action potentials are triggered
when an initial depolarization reaches the threshold. This threshold potential varies, but
generally is about 15 millivolts more positive than the cell's resting membrane potential,
occurring when the inward sodium current exceeds the outward potassium current. The
net influx of positive charges carried by sodium ions depolarizes the membrane potential,
leading to the further opening of voltage-gated sodium channels. These channels support
greater inward current causing further depolarization, creating a positive-feedback cycle
that drives the membrane potential to a very depolarized level. The action potential
threshold can be shifted by changing the balance between sodium and potassium currents.
For example, if some of the sodium channels are in an inactivated state, then a given level
of depolarization will open fewer sodium channels and a greater depolarization will be
needed to trigger an action potential. This is the basis for the refractory period (see
Refractory period). Action potentials are largely dictated by the interplay between sodium
and potassium ions (although there are minor contributions from other ions such as
calcium and chloride), and are often modeled using hypothetical cells containing only
two transmembrane ion channels (a voltage-gated sodium channel and a non-voltagegated potassium channel). The origin of the action potential threshold may be studied
using I/V curves (right) that plot currents through ion channels against the cell's

membrane potential. (Note that the illustrated I/V is an "instantaneous" current voltage
relationship. It represents the peak current through channels at a given voltage before any
inactivation has taken place (i.e. ~ 1 ms after stepping to that voltage) for the Na current.
The most positive voltages in this plot are only attainable by the cell through artificial
means - i.e. voltages imposed by the voltage-clamp apparatus). Four significant points in
the I/V curve are indicated by arrows in the figure:
The green arrow indicates the resting potential of the cell and also the value of the
equilibrium potential for potassium (Ek). As the K+ channel is the only one open at
these negative voltages, the cell will rest at Ek.
The yellow arrow indicates the equilibrium potential for Na+ (ENa). In this two-ion
system, ENa is the natural limit of membrane potential beyond which a cell cannot
pass. Current values illustrated in this graph that exceed ENa are measured by
artificially pushing the cell's voltage past its natural limit. Note however, that E Na
could only be reached if the potassium current were absent.
The blue arrow indicates the maximum voltage that the peak of the action
potential can approach. This is the actual natural maximum membrane potential
that this cell can reach. It cannot reach ENa because of the counteracting influence
of the potassium current.
The red arrow indicates the action potential threshold. This is where I sum becomes
net-inward. Note that this is a zero-current crossing, but with a negative slope.
Any such "negative slope crossing" of the zero current level in an I/V plot is an
unstable point. At any voltage negative to this crossing, the current is outward and
so a cell will tend to return to its resting potential. At any voltage positive of this
crossing, the current is inward and will tend to depolarize the cell. This
depolarization leads to more inward current, thus the sodium current become
regenerative. The point at which the green line reaches its most negative value is
the point where all sodium channels are open. Depolarizations beyond that point
thus decrease the sodium current as the driving force decreases as the membrane
potential approaches ENa.
The action potential threshold is often confused with the "threshold" of sodium channel
opening. This is incorrect, because sodium channels have no threshold. Instead, they open
in response to depolarization in a stochastic manner. Depolarization does not so much
open the channel as increases the probability of it being open. Even at hyperpolarized
potentials, a sodium channel will open very occasionally. In addition, the threshold of an
action potential is not the voltage at which sodium current becomes significant; it is the
point where it exceeds the potassium current. Biologically in neurons, depolarization
typically originates in the dendrites at synapses. In principle, however, an action potential
may be initiated anywhere along a nerve fiber. In his discovery of "animal electricity,"
Luigi Galvani made a leg of a dead frog kick as in life by touching a sciatic nerve with
his scalpel, to which he had inadvertently transferred a negative, static-electric charge,
thus initiating an action potential.

Circuit model

A. basic RC circuit superimposed on an image of a membrane bilayer shows the

relationship between the two.
B. More elaborate circuits can be used to model membranes containing ion
channels, such as this one containing at channels for sodium (blue) and potassium
(green).
Cell membranes that contain ion channels can be modeled as RC circuits to better
understand the propagation of action potentials in biological membranes. In such a
circuit, the resistor represents the membrane's ion channels, while the capacitor models
the insulating lipid membrane. Variable resistors are used for voltage-gated ion channels,
as their resistance changes with voltage. A fixed resistor represents the potassium leak
channels that maintain the membrane's resting potential. The sodium and potassium
gradients across the membrane are modeled as voltage sources (batteries).

Propagation

Propagating action potentials can be modeled by joining several RC circuits, each one
representing a patch of membrane. In unmyelinated axons, action potentials propagate as
an interaction between passively spreading membrane depolarization and voltage-gated
sodium channels. When one patch of cell membrane is depolarized enough to open its
voltage-gated sodium channels, sodium ions enter the cell by facilitated diffusion. Once
inside, positively-charged sodium ions "nudge" adjacent ions down the axon by
electrostatic repulsion (analogous to the principle behind Newton's cradle) and attract
negative ions away from the adjacent membrane. As a result, a wave of positivity moves
down the axon without any individual ion moving very far. Once the adjacent patch of
membrane is depolarized, the voltage-gated sodium channels in that patch open,

regenerating the cycle. The process repeats itself down the length of the axon, with an
action potential regenerated at each segment of membrane.

Speed of propagation
Action potentials propagate faster in axons of larger diameter, other things being equal.
They typically travel from 10 100 m/s. The main reason is that the axial resistance of
the axon lumen is lower with larger diameters, because of an increase in the ratio of
cross-sectional area to membrane surface area. As the membrane surface area is the chief
factor impeding action potential propagation in an unmyelinated axon, increasing this
ratio is a particularly effective way of increasing conduction speed. An extreme example
of an animal using axon diameter to speed action potential conduction is found in the
Atlantic squid. The squid giant axon controls the muscle contraction associated with the
squid's predator escape response. This axon can be more than 1 mm in diameter, and is
presumably an adaptation to allow very fast activation of the escape behavior. The
velocity of nerve impulses in these fibers is among the fastest in nature. Squids are
notable examples of organisms with unmyelinated axons; the first tests to try to determine
the mechanism by which impulses travel along axons, involving the detection of a
potential difference between the inside and the surface of a neuron, were undertaken in
the 1940s by Alan Hodgkin and Andrew Huxley using squid giant axons because of their
relatively large axon diameter. Hodgkin and Huxley won their shares of the 1963 Nobel
Prize in Physiology or Medicine for their work on the electrophysiology of nerve action
potentials. In the autonomic nervous system in mammals, postganglionic neurons are
unmyelinated. The small diameter of these axons (about 2 ) results in a propagatory
speed of approximately 1 m/s, as opposed to approximately 18 m/s in myelinated nerve
fibers of comparable diameter, thus highlighting the effect of myelination on the speed of
transmission of impulses.

Saltatory conduction
In myelinated axons, saltatory conduction is the process by which an action potential
appears to jump along the length of an axon, being regenerated only at uninsulated
segments (the nodes of Ranvier). Saltatory conduction increases nerve conduction
velocity without having to dramatically increase axon diameter. Saltatory conduction has
played an important role in the evolution of larger and more complex organisms whose
nervous systems must rapidly transmit action potentials across greater distances. Without
saltatory conduction, conduction velocity would need large increases in axon diameter,
resulting in organisms with nervous systems too large for their bodies.

Detailed mechanism
The main impediment to conduction speed in unmyelinated axons is membrane
capacitance. In an electric circuit, the capacitance of a capacitor can be decreased by
decreasing the cross-sectional area of its plates, or by increasing the distance between
plates. The nervous system uses myelin as its main strategy to decrease membrane
capacitance. Myelin is an insulating sheath wrapped around axons by Schwann cells and
oligodendrocytes, neuroglia that flatten their cytoplasm to form large sheets made up
mostly of plasma membrane. These sheets wrap around the axon, moving the conducting
plates (the intra- and extracellular fluid) farther apart to decrease membrane capacitance.
The resulting insulation allows the rapid (essentially instantaneous) conduction of ions
through a myelinated segment of axon, but prevents the regeneration of action potentials

through those segments. Action potentials are only regenerated at the unmyelinated nodes
of Ranvier which are spaced intermittently between myelinated segments. An abundance
of voltage-gated sodium channels on these bare segments (up to four orders of magnitude
greater than their density in unmyelinated axons[3]) allows action potentials to be
efficiently regenerated at the nodes of Ranvier. As a result of myelination, the insulated
portion of the axon behaves like a passive wire: it conducts action potentials rapidly
because its membrane capacitance is low, and minimizes the degradation of action
potentials because its membrane resistance is high. When this passively propagated signal
reaches a node of Ranvier, it initiates an action potential, which subsequently travels
passively to the next node where the cycle repeats.
Resilience to injury
The length of myelinated segments of axon is important to saltatory conduction. They
should be as long as possible to maximize the length of fast passive conduction, but not
so long that the decay of the passive signal is too great to reach threshold at the next node
of Ranvier. In reality, myelinated segments are long enough for the passively propagated
signal to travel for at least two nodes while retaining enough amplitude to fire an action
potential at the second or third node. Thus, the safety factor of saltatory conduction is
high, allowing transmission to bypass nodes in case of injury.
Role in disease
Some diseases degrade saltatory conduction and reduce the speed of action potential
conductance. The most well-known of these diseases is multiple sclerosis, in which the
breakdown of myelin impairs coordinated movement.

Refractory period
Where membrane has undergone an action potential, a refractory period follows. Thus,
although the passive transmission of action potentials across myelinated segments would
suggest that action potentials propagate in either direction, most action potentials travel
unidirectionally because the node behind the propagating action potential is refractory.
This period arises primarily because of the time-dependent inactivation of sodium
channels, as described by Hodgkin and Huxley in 1952. Immediately after an action
potential, during the absolute refractory period, virtually all sodium channels are
inactivated and thus it is impossible to fire another action potential in that segment of
membrane. With time, sodium channels are reactivated in a stochastic manner. As they
become available, it becomes possible to fire an action potential, albeit one with a much
higher threshold. This is the relative refractory period and together with the absolute
refractory period, lasts approximately five milliseconds.

Termination and consequences

An action potential proceeding along a membrane is prevented from reversing its
direction by the refractory period, and will eventually depolarize the entire cell. When the
action potential reaches an area where all the cell membrane is already depolarized or still
in the refractory period, the action potential can no longer propagate. Because an action
potential propagates only along contiguous membrane, another mechanism is necessary
to transmit action potentials between cells. Neurons communicate with each other at a
chemical synapse. Other cell types, such as cardiac muscle cells, can communicate action
potentials via electrical synapses. The synapse is a very small gap between neurons that
allows one-way communication. As the presynaptic neuron undergoes an action potential,
voltage-sensitive calcium channels open and cause the release of neurotransmitters into

the synapse. These chemical transmitters can initiate an action potential in the
postsynaptic neuron, allowing communication between neurons. Some neurotransmitters
inhibit action potentials, and the interaction of excitatory and inhibitory signals allows
complex modulation of signals in the nervous system.

Evolutionary advantage
The action potential, as a method of long-distance communication, fits a particular
biological need seen most readily when considering the transmission of information
along a nerve axon. To move a signal from one end of an axon to the other, nature must
contend with physics similar to those that govern the movement of electrical signals
along a wire. Due to the resistance and capacitance of a wire, signals tend to degrade as
they travel along that wire over a distance. These properties, known collectively as cable
properties set the physical limits over which signals can travel. Thus, nonspiking neurons
(which carry signals without action potentials) tend to be small. Proper function of the
body requires that signals be delivered from one end of an axon to the other without loss.
An action potential does not so much propagate along an axon, as it is newly regenerated
by the membrane voltage and current at each stretch of membrane along its path. In other
words, the nerve membrane recreates the action potential at its full amplitude as it travels
down the axon, thus overcoming the limitations imposed by cable physics.
Alternative models
The model of electrical signal propagation in neurons employing voltage-gated ion
channels described above is accepted by almost all scientists working in the field.
However there are a few observations not easily reconciled with the model:
A signal traveling along a neuron is accompanied by a slight local thickening of
the membrane and a force acting outwards.[4]
An action potential traveling along a neuron results in a slight increase in
temperature followed by a decrease in temperature; [5] electrical charges traveling
through a resistor however always produce heat.
One recent alternative, the soliton model, attempts to explain signals in neurons as
pressure (or sound) solitons traveling along the membrane, accompanied by electrical
field changes resulting from piezo-electric effects.