Everything about Action Potential totally explained
In
neurophysiology, an
action potential (also known as a
nerve impulse or
spike) is a pulse-like wave of
voltage that travels along several types of
cell membranes. The best-understood example is generated on the membrane of the
axon of a
neuron, but also appears in other types of excitable
cells, such as
cardiac muscle cells, and even
plant cells. The
resting voltage across the axonal membrane is typically −70
millivolts (mV), with the inside being more negative than the outside. As an action potential passes through a point, this voltage rises to roughly +40 mV in one millisecond, then returns to −70 mV. The action potential moves rapidly down the axon, with a
conduction velocity as high as 100 meters/second (225 miles per hour). Because of this high speed, action potentials are used to transmit information, with this being particularly important in neurons, as these cells can be more than a meter long.
An action potential is provoked on a patch of membrane when the membrane is depolarized sufficiently strongly, for example, when the voltage of the cell's interior relative to the cell's exterior is raised above a threshold. Such a depolarization opens voltage-sensitive channels, which allow positive current to flow into the axon, further depolarizing the membrane. This will cause the membrane to "fire", initiating a
positive feedback loop that suddenly and rapidly causes the voltage inside the axon to become more positive. After this rapid rise, the membrane voltage is restored to its resting value by a combination of effects: the channels responsible for the initial inward current are inactivated, while the raised voltage opens other voltage-sensitive channels that allow a compensating outward current. Because of the positive feedback, an action potential is
all-or-none; there are no partial action potentials. In neurons, a typical action potential lasts for just a few thousandths of a second at any given point along their length. The passage of an action potential can leave the
ion channels in a non-equilibrium state, making them more difficult to open, and thus inhibiting another action potential at the same spot: such an axon is said to be
refractory.
The principal ions involved in an action potential are
sodium and
potassium cations; sodium ions enter the cell, and potassium ions leave, restoring equilibrium. Relatively few ions need to cross the membrane for the membrane voltage to change drastically. The ions exchanged during an action potential, therefore, make a negligible change in the interior and exterior ionic concentrations. The few ions that do cross are pumped out again by the continual action of the
sodium–potassium pump, which, with other
ion transporters, maintains the normal ratio of ion concentrations across the membrane.
Calcium cations and
chloride anions are involved in a few types of action potentials, such as the
cardiac action potential and the action potential in the single-celled
alga Acetabularia, respectively.
The action potential "travels" along the axon without fading out because the signal is regenerated at each patch of membrane. This happens because an action potential at one patch raises the voltage at nearby patches, depolarizing them and provoking a new action potential there. In
unmyelinated neurons, the patches are adjacent, but in myelinated neurons, the action potential
"hops" between distant patches, making the process both faster and more efficient. The axons of neurons generally branch, and an action potential often travels along both forks from a
branch point. The action potential stops at the end of these branches, but usually causes the secretion of
neurotransmitters at the
synapses that are found there. These neurotransmitters bind to receptors on adjacent cells. These receptors are themselves ion channels, although—in contrast to the axonal channels—they are generally opened by the presence of a neurotransmitter, rather than by changes in voltage. The opening of these receptor channels can help to depolarize the membrane of the new cell (an
excitatory channel) or work against its depolarization (an
inhibitory channel). If these depolarizations are sufficiently strong, they can provoke another action potential in the new cell.
Biophysical and cellular context
Ions and the forces driving their motion
Electrical signals within biological organisms are generally by
ions, which may be either positively charged
cations or negatively charged
anions. The most important cations for the action potential are
sodium (Na
+) and
potassium (K
+), which are both
monovalent cations that carry a single positive charge. Action potentials can also involve
calcium (Ca
2+), which is a
divalent cation that carries a double positive charge. The
chloride anion (Cl
−) plays a major role in the action potentials of some
algae, but plays a negligible role in the action potentials of most animals.
Ions cross the cell membrane under two influences:
diffusion and
electric fields. Diffusion allows net flow of ions from regions where the ions are highly
concentrated into regions of low concentration. Ions also move in response to an
electric field. By definition, the
integral of the electric field across a patch of membrane equals the
voltage Vm across that patch. Likewise by definition, the flows of different ions through that patch are the
ionic currents at that patch; the total current is the sum of all the individual ionic currents. Using these definitions of voltage and current, such a membrane patch can be modeled by an
equivalent electronic circuit. In particular, for each type of ion the patch will have a
capacitance C and a
conductance g; according to
Ohm's law, the current
I of each ion type is related to the transmembrane voltage
Vm by the equation
I = g
Vm. For a given set of ionic conductances, there's an equilibrium voltage
E at which the total current across the membrane is zero; the natural flow of ions generally causes the membrane voltage
Vm to approach
E.
Cell membrane
Because the
membrane surrounding
cells is nearly impermeable to
ions, cells have evolved systems for transporting ions across the membrane. These systems can be divided into two classes: pores ("channels") that allow
passive transport of ions, and
ion pumps that use
adenosine triphosphate for
active transport of ions. The ion pumps tend to work continuously, as long as there are ions to be pumped. By contrast, the ion channels open and close in response to signals from their environment. The two classes play complementary roles; the ion pumps generate the differences in ion
concentrations across the membrane, which the ion channels exploit to carry out electrical signaling. As an analogy, ion pumps play the role of the battery that allows a radio circuit (the ion channels) to transmit a signal.
Ion channels
Ion channels are
integral membrane proteins through which ions can cross the membrane. Most channels are specific for one ion; whereas that ion passes through relatively quickly, other similar ions pass through very infrequently. For example, although potassium and sodium ions have the same charge and differ only slightly in their radius, potassium channels allow few sodium ions through, and vice versa. The pore through which the ion passes is typically so small that ions must pass through it alone and single-file.
A channel may have several different states (corresponding to different
conformations of the protein), but each such state is either open or closed. In general, closed states correspond either to a contraction of the pore—making it impassable to the ion—or to a separate part of the protein stoppering the pore. For example, the voltage-dependent sodium channel undergoes
inactivation, in which a portion of the protein swings into the pore, sealing it. This inactivation shuts off the sodium current and plays a critical role in the action potential.
Ion channels can be classified by how they respond to their environment. For example, the ion channels involved in the action potential are
voltage-sensitive channels; they open and close in response to the voltage across the membrane.
Ligand-gated channels form another important class; these ion channels open and close in response to the binding of a
ligand molecule, such as a
neurotransmitter. Still other ion channels—such as those of
sensory neurons—open and close in response to other stimuli, such as light, temperature or pressure.
Ion pumps
The ionic currents of the action potential flow in response to
concentration differences of the ions across the
cell membrane. These concentration differences are established by
ion transporters, which are
integral membrane proteins that carry out
active transport, for example, use cellular energy (ATP) to "pump" the ions against their concentration gradient. Such ion pumps take in ions from one side of the membrane (decreasing its concentration there) and release them on the other side (increasing its concentration there). The ion pump most relevant to the action potential is the
sodium–potassium pump, which transports three sodium ions out of the cell and two potassium ions in. Consequently, the concentration of
potassium ions K
+ inside the neuron is roughly 20-fold larger than the outside concentration, whereas the sodium concentration outside is roughly ninefold larger than inside. Similarly, other ions have different concentrations inside and outside the neuron, such as
calcium,
chloride and
magnesium.
However, there's a voltage
Em at which the
net current of all ions across the membrane is zero; this voltage is given by the
Goldman equation
The membrane voltage
Vm need not equal its equilibrium value
Em. However, since
Vm can change drastically when only a few ions cross the membrane,
Vm tracks
Em closely, so that the two are effectively equivalent. In a typical action potential, where
Vm changes by roughly 100 mV, the ionic concentrations inside the axon change only by roughly 1 part in 10 million; hence, hundreds of thousands of action potentials can be fired before the ion pumps are needed to restore the standard ratio of ionic concentrations. (The word "potential" or "potential difference" is sometimes a synonym for
voltage.) Under those conditions, the membrane is much more permeable to potassium than to any other ion; thus, consistent with the Goldman equation, the resting potential is close to the potassium equilibrium potential
EK. which are divided into two main types,
dendrites and
axons. Most neurons have only one axon but numerous dendrites; the beginning of the axon is called the
axon hillock. Action potentials almost always begin at the axon hillock, and travel down the axon; it's very rare for an action potential to occur in the dendrites.
In some animals (mostly vertebrates), segments of the axon are sheathed in
myelin, which generally increases the
conduction velocity at which action potentials travel down the axon. Myelin is composed of
Schwann cells that wrap themselves multiple times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon. Ions can flow into and out of the axon only at the
nodes of Ranvier, which are the gaps between the Schwann cells, the "chinks" in the myelin armor.
Phases
The course of the action potential is determined by two coupled effects. First, voltage-sensitive ion channels open and close in response to changes in the
membrane voltage Vm, thus changing the membrane's permeability to those ions. However, by the
Goldman equation, changes in the ionic permeabilities causes changes in the equilibrium potential
Em, and, thus, the membrane voltage
Vm. A complicating factor is that a single ion channel may have multiple internal "gates" that respond to changes in
Vm in opposite ways, or at different rates. Hence, when
Vm is raised suddenly, the sodium channels open initially, but then close due to the slower inactivation.
The course of the action potential can be divided into four parts: the rising phase, the falling phase, the undershoot phase, and the refractory period. The initial membrane permeability to potassium is low, but much higher than that of other ions, making the resting potential close to
EK. This is the
rising phase. At this point, the sodium channels begin to inactivate, lowering the membrane's permeability to sodium and driving
Vm back down toward the original resting potential. This is the
falling phase. However, their model considers only two types of voltage-sensitive ion channels, and makes several assumptions about them, for example, that their internal gates open and close independently of one another. In reality, there are many types of ion channels,
Stimulation and rising phase
A typical action potential begins at the
axon hillock with a sufficiently strong depolarization, for example, a stimulus that increases
Vm. This depolarization is often caused by the injection of extra sodium
cations into the cell; these cations can come from a wide variety of sources, such as
chemical synapses,
sensory neurons or
pacemaker potentials.
The depolarization opens both the sodium and potassium channels in the membrane, allowing the ions to flow into and out of the axon, respectively. If the depolarization is small (say, increasing
Vm from −70 mV to −60 mV), the outward potassium current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around −70 mV.
Refractory period
The opening and closing of the sodium and potassium channels during an action potential may leave some of them in a "refractory" state, in which they're unable to open again until they've recovered. In the
absolute refractory period, so many ion channels are refractory that no new action potential can be fired. Significant recovery (de-inactivation) requires that the membrane potential remain hyperpolarized for a certain length of time. In the
relative refractory period, enough channels have recovered that an action potential can be provoked, but only with a stimulus much stronger than usual. These
refractory periods ensure that the action potential travels in only one direction along the axon.
Initiation, propagation and termination
A typical action potential is initiated at the axon hillock when the membrane is depolarized sufficiently, for example, when its voltage is increased sufficiently. As the membrane voltage is increased, both the sodium and potassium ion channels begin to open up, increasing both the inward sodium current and the balancing outward potassium current. For small voltage increases, the potassium current triumphs over the sodium current and the voltage returns to its normal resting value, typically −70 mV. However, if the voltage increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates and a runaway condition results; the cell "fires", producing an action potential. the inwards current of an action potential at one patch of membrane depolarizes nearby membrane patches, sparking another action potential there. In effect, the action potential is created afresh at each patch of membrane; its energy derives from the local differences in ionic concentrations, not from the depolarization that triggered it. The axon may branch along its length, and there the inward current may not quite suffice to trigger a new action potential in one or both of its branches; the action potential may stop. Action potentials that do reach the ends of the axon generally cause the release of a
neurotransmitter into the
synapse, which may combine with other inputs to provoke a new action potential in the post-synaptic neuron or muscle cell.
Initiation
Before considering the propagation of action potentials along
axons and their termination at the synaptic knobs, it's helpful to consider the methods by which action potentials can be initiated at the
axon hillock. The basic requirement is that the membrane voltage at the hillock be raised above the threshold for firing; Typically,
neurotransmitter molecules are released by the
presynaptic neuron bound to receptors on the postsynaptic cell. This binding opens various types of
ion channels, changing the local permeability of the
cell membrane and thereby altering the membrane potential. If the binding increases the voltage (depolarizes the membrane), the synapse is excitatory; if the binding decreases the voltage (hyperpolarizes the membrane), it's inhibitory. Whether the voltage is decreased or increased, the change propagates passively to nearby regions of the membrane, as described by the
cable equation and its refinements; typically, the voltage stimulus decays exponentially with the distance from the synapse and with time from the binding of the neurotransmitter. Some fraction of an excitatory voltage may reach the
axon hillock and may (in rare cases) depolarize the membrane enough to provoke a new action potential. More typically, the excitatory potentials from several synapses must
work together at nearly the same time to provoke a new action potential. Their joint efforts can be thwarted, however, by the counter-acting
inhibitory postsynaptic potentials.
Neurotransmission can also occur through
electrical synapses. Due to the direct connection between the excitable cells in such cases, an action potential can well be transmitted directly from one cell to the next. Rectifying channels ensure that action potentials only move in one direction through an electrical synapse.
Sensory neurons
In
sensory neurons, an external signal such as pressure, temperature, light, or sound is coupled with the opening and closing of
ion channels, which in turn alter the ionic permeabilities of the membrane and its voltage. These voltage changes can again be excitatory (depolarizing) or inhibitory (hyperpolarizing) and, in some sensory neurons, their combined effects can depolarize the axon hillock enough to provoke action potentials. Examples in humans include the
olfactory receptor neuron and
Meissner's corpuscle, which are critical for the sense of
smell and
touch, respectively. However, not all sensory neurons convert their external signals into action potentials; some don't even have an axon! Instead, they may convert the signal into the release of a
neurotransmitter, or into continuous
graded potentials, either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration, in the human
ear,
hair cells convert the incoming sound into the opening and closing of
mechanically gated ion channels, which may cause
neurotransmitter molecules to be released. Similarly, in the human
retina, the initial
photoreceptor cells and the next two layers of cells (
bipolar cells and
amacrine cells) don't produce action potentials; only the third layer, the
ganglion cells, produce action potentials, which then travel up the
optic nerve.
Pacemaker potentials
In the cases of neurotransmission and sensory neurons, action potentials result from an external stimulus. However, some excitable cells require no such stimulus to fire: they spontaneously depolarize their axon hillock and fire action potentials at a regular rate, like an internal clock. The voltage traces of such cells are known as
pacemaker potentials. The
cardiac pacemaker cells of the
sinoatrial node in the
heart provide a good example. Although such pacemaker potentials have a natural rhythm, it can be adjusted by external stimuli; for instance,
heart rate can be altered by pharmaceuticals as well as signals from the
sympathetic and
parasympathetic nerves. The external stimuli don't cause the cell's repetitive firing, but merely alter its timing. The currents flowing inwards at a point on the axon during an action potential spread out along the axon, and depolarize the adjacent sections of its membrane. If sufficiently strong, this depolarization provokes a similar action potential at the neighboring membrane patches. This basic mechanism was demonstrated by
Alan Lloyd Hodgkin in 1937. After crushing or cooling nerve segments and thus blocking the action potentials, he showed that an action potential arriving on one side of the block could provoke another action potential on the other, provided that the blocked segment was sufficiently short.
Once an action potential has occurred at a patch of membrane, the membrane patch needs time to recover before it can fire again. At the molecular level, this
absolute refractory period corresponds to the time required for its ion channels to return to their normal open or closed states. Although it limits the frequency of firing, the absolute refractory period ensures that the action potential moves in only one direction along an axon. However, only the unfired part of the axon can respond with an action potential; the part that has just fired is unresponsive until the action potential is safely out of range and can't restimulate that part. In the usual
orthodromic conduction, the action potential propagates from the axon hillock towards the synaptic knobs (the axonal termini); propagation in the opposite direction—known as
antidromic conduction—is very rare. However, if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", for example, unfired; then two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards the synaptic knobs.
Myelin and saltatory conduction
The axons of some neurons are ensheathed in
myelin, a fatty (ie,
lipid-rich) insulating material that increases the speed and energy efficiency of action potential conduction. Axons are myelinated by specialized cells,
Schwann cells and
oligodendrocytes, that wrap themselves multiple times around segments of axon. The gaps between these segments are known as the
nodes of Ranvier.
Myelin prevents ions from entering or leaving the axon along myelinated segments. Myelination is found mainly in
vertebrates, but an analogous system has been discovered in a few invertebrates, such as some species of
shrimp. As a general rule, myelination increases the
conduction velocity of action potentials and makes them more energy-efficient. However, not all neurons in vertebrates are myelinated. Whether saltatory or not, the mean
conduction velocity of an action potential ranges from 1 m/s to over 100 m/s, and generally increases with axonal diameter.
Action potentials can't propagate through the myelinated segments of the axon, since no ions can flow across the membrane there. Instead, the ionic current from an action potential at one
node of Ranvier provokes another action potential at the next node; this "hopping" of the action potential from node to node is known as
saltatory conduction. Although the mechanism of saltatory conduction was suggested in 1925 by Ralph Lillie, the first experimental evidence for saltatory conduction came from
Ichiji Tasaki and Taiji Takeuchi and from
Alan Hodgkin and Robert Stämpfli. By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave.
Myelin has two important advantages: fast conduction speed and energy efficiency. For axons larger than a minimum diameter (roughly 1
micron), myelination increases the
conduction velocity of an action potential, typically tenfold.
The length of axons' myelinated segments is important to the success of saltatory conduction. They should be as long as possible to maximize the speed of conduction, but not so long that the arriving signal is too weak to provoke an action potential at the next node of Ranvier. In nature, myelinated segments are generally 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. However, action potentials may end prematurely in certain places where the safety factor is low, even in unmyelinated neurons; a common example is the branch point of an axon, where it divides into two axons.
Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action potentials. The most well-known of these is
multiple sclerosis, in which the breakdown of myelin impairs coordinated movement.
Cable theory
The flow of currents within an axon can be described quantitatively by
cable theory and its elaborations, such as the compartmental model. Cable theory was developed in 1855 by
Lord Kelvin to model the transatlantic telegraph cable and was shown to be relevant to neurons by
Hodgkin and
Rushton in 1946. In simple cable theory, the neuron is treated as an electrically passive, perfectly cylindrical transmission cable, which can be described by a
partial differential equation
»
These time- and length-scales can be used to understand the dependence of the conduction velocity on the diameter of the neuron in unmyelinated fibers. For example, the time-scale τ increases with both the membrane resistance
rm and capacitance
cm. As the capacitance increases, more charge must be transferred to produce a given transmembrane voltage (by
the equation Q=CV); as the resistance increases, less charge is transferred per unit time, making the equilibration slower. Similarly, if the internal resistance per unit length
ri is lower in one axon than in another (for example, because the radius of the former is larger), the spatial decay length λ becomes longer and the
conduction velocity of an action potential should increase. If the transmembrane resistance
rm is increased, that lowers the average "leakage" current across the membrane, likewise causing λ to become longer, increasing the conduction velocity.
Termination
Chemical synapses
Action potentials that reach the synaptic knobs generally cause a
neurotransmitter to be released into the synaptic cleft. Neurotransmitters are small molecules that may open ion channels in the postsynaptic cell; most axons have the same neurotransmitter at all of their termini. The arrival of the action potential opens voltage-sensitive calcium channels in the pre-synaptic cell; the influx of calcium causes
vesicles filled with neurotransmitter to migrate to the cell's surface and
release their contents into the
synaptic cleft. This complex process is inhibited by the
neurotoxins
tetanospasmin and
botulinum toxin, which are responsible for
tetanus and
botulism, respectively.
Electrical synapses
connexins. Thus, the ionic currents of the presynaptic action potential can directly stimulate the postsynaptic cell. Electrical synapses allow for faster transmission because they don't require the slow diffusion of
neurotransmitters across the synaptic cleft. Hence, electrical synapses are used whenever fast response and coordination of timing are crucial, as in
escape reflexes, the
retina of
vertebrates, and the
heart.
Neuromuscular junctions
A special case of a chemical synapse is the
neuromuscular junction, in which the
axon of a
motor neuron terminates on a
muscle fiber. In such cases, the released neurotransmitter is
acetylcholine, which binds to the acetylcholine receptor, an integral membrane protein in the membrane (the
sarcolemma) of the muscle fiber. However, the acetylcholine doesn't remain bound; rather, it dissociates and is
hydrolyzed by the enzyme,
acetylcholinesterase, located in the synapse. This enzyme quickly reduces the stimulus to the muscle, which allows the degree and timing of muscular contraction to be regulated delicately. Some poisons inactivate acetylcholinesterase to prevent this control, such as the
nerve agents
sarin and
tabun, and the insecticides
diazinon and
malathion.
Other cell types
Cardiac action potentials
sinoatrial node provide the
pacemaker potential that synchronizes the heart. The action potentials of those cells propagate to and through the
atrioventricular node (AV node), which is normally the only conduction pathway between the
atria and the
ventricles. Action potentials from the AV node travel through the
bundle of His and thence to the
Purkinje fibers. Conversely, anomalies in the cardiac action potential—whether due to a congenital mutation or injury—can lead to human pathologies, especially
arrhythmias.
Muscular action potentials
The action potential in a normal skeletal muscle cell is similar to the action potential in neurons. Action potentials result from the depolarization of the cell membrane (the
sarcolemma), which opens voltage-sensitive sodium channels; these becomes inactivated and the membrane is repolarized through the outward current of potassium ions. The resting potential prior to the action potential is typically −90mV, somewhat more negative than typical neurons. The muscle action potential lasts roughly 2–4 ms, the absolute refractory period is roughly 1–3 ms, and the conduction velocity along the muscle is roughly 5 m/s. The action potential releases
calcium ions that free up the
tropomyosin and allow the muscle to contract. Muscle action potentials are provoked by the arrival of a pre-synaptic neuronal action potential at the
neuromuscular junction, which is a common target for
neurotoxins. The main difference between plant and animal action potentials is that plants primarily use
potassium and
calcium currents while animals typically use currents of
potassium and
sodium. These signals are used by plants to rapidly transmit information from environmental signals such as temperature, light, touch or wounding.
Taxonomic distribution and evolutionary advantages
Action potentials are found throughout
multicellular organisms, including
plants,
invertebrates such as
insects, and
vertebrates such as
reptiles and
mammals. The resting potential, as well as the size and duration of the action potential, have not varied much with evolution, although the
conduction velocity does vary dramatically with axonal diameter and myelination.
| Animal |
Cell type |
Resting potential (mV) |
AP increase (mV) |
AP duration (ms) |
Conduction speed (m/s) |
| Squid (Loligo) |
Giant axon |
−60 |
120 |
0.75 |
35 |
| Earthworm (Lumbricus) |
Median giant fiber |
−70 |
100 |
1.0 |
30 |
| Cockroach (Periplaneta) |
Giant fiber |
−70 |
80–104 |
0.4 |
10 |
| Frog (Rana) |
sciatic nerve axon |
−60 to −80 |
110–130 |
1.0 |
7–30 |
| Cat (Felis) |
Spinal motor neuron |
−55 to −80 |
80–110 |
1–1.5 |
30–120 |
Given its conservation throughout evolution, the action potential seems to confer evolutionary advantages. One function of action potentials is rapid, long-range signaling within the organism; the conduction velocity can exceed 110 m/s, which is one-third the
speed of sound. No material object could convey a signal that rapidly throughout the body; for comparison, a hormone molecule carried in the bloodstream moves at roughly 8 m/s in large arteries. Part of this function is the tight coordination of mechanical events, such as the contraction of the heart. A second function is the computation associated with its generation. Being an all-or-none signal that doesn't decay with transmission distance, the action potential has similar advantages to
digital electronics. The integration of various dendritic signals at the axon hillock and its thresholding to form a complex train of action potentials is another form of computation, one that has been exploited biologically to form
central pattern generators and mimicked in
artificial neural networks.
Experimental methods
electrodes enough that the voltage inside a single cell could be recorded.
The first problem was solved by studying the giant axons found in the neurons of the
squid genus
Loligo. These axons are so large in diameter (roughly 1 mm, or 100-fold larger than a typical neuron) that they can be seen with the naked eye, making them easy to extract and manipulate. However, the
Loligo axons are not representative of all excitable cells, and numerous other systems with action potentials have been studied.
The second problem was addressed with the crucial development of the
voltage clamp, which permitted experimenters to study the ionic currents underlying an action potential in isolation, and eliminated a key source of
electronic noise, the current
IC associated with the
capacitance C of the membrane. Since the current equals
C times the rate of change of the transmembrane voltage
Vm, the solution was to design a circuit that kept
Vm fixed (zero rate of change) regardless of the currents flowing across the membrane. Thus, the current required to keep
Vm at a fixed value is a direct reflection of the current flowing through the membrane. Other electronic advances included the use of
Faraday cages and electronics with high
input impedance, so that the measurement itself didn't affect the voltage being measured.
The third problem, that of obtaining electrodes small enough to record voltages within a single axon without perturbing it, was solved in 1949 with the invention of the glass micropipette electrode, which was quickly adopted by other researchers. Refinements of this method are able to produce electrode tips that are as fine as 100
Å (10
nm), which also confers high input impedance. Action potentials may also be recorded with small metal electrodes placed just next to a neuron, with
neurochips containing
EOSFETs, or optically with dyes that are
sensitive to Ca2+ or to voltage.
While glass micropipette electrodes measure the sum of the currents passing through many ion channels, studying the electrical properties of a single ion channel became possible in the 1970s with the development of the
patch clamp by
Erwin Neher and
Bert Sakmann. For this they were awarded the
Nobel Prize in Physiology or Medicine in 1991. Patch-clamping verified that ionic channels have discrete states of conductance, such as open, closed and inactivated.
Neurotoxins
Several
neurotoxins, both natural and synthetic, are designed to block the action potential.
Tetrodotoxin from the
pufferfish and
saxitoxin from the
Gonyaulax (the
dinoflagellate genus responsible for "
red tides") block action potentials by inhibiting the voltage-sensitive sodium channel; similarly,
dendrotoxin from the
black mamba snake inhibits the voltage-sensitive potassium channel. Such inhibitors of ion channels serve an important research purpose, by allowing scientists to "turn off" specific channels at will, thus isolating the other channels' contributions; they can also be useful in purifying ion channels by
affinity chromatography or in assaying their concentration. However, such inhibitors also make effective neurotoxins, and have been considered for use as
chemical weapons. Neurotoxins aimed at the ion channels of insects have been effective
insecticides; one example is the synthetic
permethrin, which prolongs the activation of the sodium channels involved in action potentials. The ion channels of insects are sufficiently different from their human counterparts that there are few side effects in humans. Many other neurotoxins interfere with the transmission of the action potential's effects at the
synapses, especially at the
neuromuscular junction.
History
The role of electricity in the nervous systems of animals was first observed in dissected
frogs by
Luigi Galvani, who studied it from 1791 to 1797. Galvani's results stimulated
Alessandro Volta to develop the
Voltaic pile—the earliest known
electric battery—with which he studied animal electricity (such as
electric eels) and the physiological responses to applied
direct-current voltages.
Scientists of the 19th century studied the propagation of electrical signals in whole
nerves (for example, bundles of
neurons) and demonstrated that nervous tissue was made up of
cells, instead of an interconnected network of tubes (a
reticulum).
Carlo Matteucci followed up Galvani's studies and demonstrated that
cell membranes had a voltage across them and could produce
direct current. Matteucci's work inspired the German physiologist,
Emil du Bois-Reymond, who discovered the action potential in 1848. The
conduction velocity of action potentials was first measured in 1850 by du Bois-Reymond's friend,
Hermann von Helmholtz. To establish that nervous tissue was made up of discrete cells, the Spanish physician
Santiago Ramón y Cajal and his students used a stain developed by
Camillo Golgi to reveal the myriad shapes of neurons, which they rendered painstakingly. For their discoveries, Golgi and Ramón y Cajal were awarded the 1906
Nobel Prize in Physiology. Their work resolved a long-standing controversy in the
neuroanatomy of the 19th century; Golgi himself had argued for the network model of the nervous system.
The 20th century was a golden era for electrophysiology. In 1902 and again in 1912,
Julius Bernstein advanced the hypothesis that the action potential resulted from a change in the
permeability of the axonal membrane to ions. Bernstein's hypothesis was confirmed by
Ken Cole and Howard Curtis, who showed that membrane conductance increases during an action potential. In 1949,
Alan Hodgkin and
Bernard Katz refined Bernstein's hypothesis by considering that the axonal membrane might have different permeabilities to different ions; in particular, they demonstrated the crucial role of the sodium permeability for the action potential. This line of research culminated in the five 1952 papers of Hodgkin, Katz and
Andrew Huxley, in which they applied the
voltage clamp technique to determine the dependence of the axonal membrane's permeabilities to sodium and potassium ions on voltage and time, from which they were able to reconstruct the action potential quantitatively. Hodgkin and Huxley correlated the properties of their mathematical model with discrete
ion channels that could exist in several different states, including "open", "closed", and "inactivated". Their hypotheses were confirmed in the mid-1970s and 1980s by
Erwin Neher and
Bert Sakmann, who developed the technique of
patch clamping to examine the conductance states of individual ion channels. In the 21st century, researchers are beginning to understand the structural basis for these conductance states and for the selectivity of channels for their species of ion, through the atomic-resolution
crystal structures, fluorescence distance measurements and
cryo-electron microscopy studies.
Julius Bernstein was also the first to introduce the
Nernst equation for
resting potential across the membrane; this was generalized by David E. Goldman to the eponymous
Goldman equation in 1943. The
sodium–potassium pump was identified in 1957 and its properties gradually elucidated, culminating in the determination of its atomic-resolution structure by
X-ray crystallography. The crystal structures of related ionic pumps have also been solved, giving a broader view of how these molecular machines work.
Quantitative models
Hodgkin–Huxley model, which describes the action potential by a coupled set of four
ordinary differential equations (ODEs). such as the Morris–Lecar model and the
FitzHugh–Nagumo model, both of which have only two coupled ODEs. The properties of the Hodgkin–Huxley and FitzHugh–Nagumo models and their relatives, such as the Bonhoeffer–van der Pol model, have been well-studied within mathematics, computation and electronics. More modern research has focused on larger and more integrated systems; by joining action-potential models with models of other parts of the nervous system (such as dendrites and synapses), researches can study
neural computation and simple
reflexes, such as
escape reflexes and others controlled by
central pattern generators.
Further Information
Get more info on 'Action Potential'.
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