Action potential



An action potential is a wave of electrical discharge that travels along the membrane of a cell. Action potentials carry fast internal messages between tissues, and are an essential feature of animal life. They can be created by many types of body cells, but are used most extensively by the nervous system to send messages between nerve cells and from nerve cells to other body tissues such as muscles and glands. Many plants also exhibit action potentials that travel the length of their phloem to coordinate activity. The main difference between plant and animal action potentials is that plants mainly use potassium and calcium currents while animals typically use potassium and sodium.

Action potentials are an essential carrier of the neural code. Their properties may constrain the sizes of evolving anatomies and enable centralized control and coordination of organs and tissues.

Overview
An electrical voltage, or potential, always exists between the inside and outside of a cell. The voltage of an inactive cell stays at a negative value (inside relative to outside the cell) and varies little. When the membrane potential of an excitable cell is depolarized beyond a threshold, the cell will undergo (or "fire") an action potential, (often called a "spike"). (see Threshold and initiation).

An action potential is a rapid swing in the polarity of the membrane potential from negative to positive and back, the entire cycle lasting a few milliseconds. Each cycle has a rising phase, a falling phase, and finally an undershoot (see Action potential phases). In specialized muscle cells of the heart, such as the pacemaker cells, a plateau phase of intermediate voltage may precede the falling phase.

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 or passed it and 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 brain to the tip of the spinal cord. In large animals, such as giraffes and whales, the distance traveled can be many meters.

The speed and simplicity of action potentials vary between different types of cells. However, the amplitudes of the voltage swings tend to be roughly the same. Within any one cell, consecutive action potentials typically are indistinguishable.

Resting membrane potential
The membrane voltage changes during an action potential. This is the result of changes in the permeability of the membrane to specific ions (particularly sodium and potassium), the internal and external concentrations of which cells maintain in an imbalance. This imbalance makes possible not only action potentials but also the resting cell potential arises through the work of pumps (eg, the sodium-potassium exchanger) as well as ion channels (eg, the potassium leak channel). When the cell is at its resting potential the electric forces between the sodium and potassium of the neuron is counterbalanced by the "diffusive forces," creating a state of equilibrium.

Action potential phases
The changes in membrane permeability and the onset and cessation of ionic currents during an action potential reflect the opening and closing of ion channels, which provide portals through the membrane for ions. Residing in and spanning the membrane, some of these proteins sense and respond to changes in membrane potential (see for an illustration).

In a simplified model of the action potential, the resting potential of a patch of membrane is maintained by a potassium leak channel. The rising phase of the action potential occurs when the voltage-dependent sodium channel opens, causing the sodium permeability to greatly exceed the potassium permeability. The membrane potential is then driven toward ENa (see Goldman equation). In other cells, such as cardiac pacemaker cells, the rising phase is governed by the concentration of calcium rather than sodium.

After a short delay, the voltage-dependent (delayed-rectifier) potassium channel opens and the voltage-gated sodium channel inactivates. As a consequence, the membrane potential is driven back toward the resting potential, resulting in the action potential's falling phase.

As more potassium channels are open than sodium channels (at this point the potassium leak channel and voltage-dependent potassium channel are open and the sodium channel is closed), the potassium permeability is now larger than it was before the action potential was generated (at rest only the potassium leak channel is open). As a result, the membrane potential approaches EK more closely than it did at rest, causing the action potential to undershoot (see Action Potential Form and Nomenclature). The delayed-rectifier potassium channel, being voltage-dependent, is closed by the hyperpolarized voltage, and the cell returns to its resting potential.

The rising and falling phases of an action potential are often imprecisely called depolarization and hyperpolarization, respectively. When used in this context, depolarization means any change in membrane potential towards a voltage more positive than the normal resting potential, and hyperpolarization is any change towards a voltage more negative than the normal resting potential.

Threshold and initiation


Action potentials are triggered when an initial depolarization reaches threshold. This threshold potential varies, but generally is about 15 millivolts above 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-voltage-gated 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. ~ 1ms 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:


 * 1) 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.  Note that a stable resting potential will be present at any voltage where the summed I/V (green line) crosses the zero current (x-axis) point with a positive slope, such as at the green arrow.  Consider why: any perturbation of the membrane potential in the negative direction will result in inward current that will depolarize the cell back toward the crossing point, while, any perturbation of the membrane potential in the positive direction will result in an outward current that will hyperpolarize the cell back toward the crossing point.  Thus, any perturbation of the membrane potential around a positive slope crossing will tend to return the voltage to that crossing value.
 * 2) 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 ENa could only be reached if the potassium current were absent.
 * 3) 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.
 * 4) The red arrow indicates the action potential threshold.  This is where Isum 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


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


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. 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 speeding 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.

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.

It 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. The capacity 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 ) 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
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.

Where membrane has undergone an action potential, a refractory period follows. This period arises primarily because of the voltage-dependent inactivation of sodium channels, as described by Hodgkin and Huxley in 1952. In addition to the voltage-dependent opening of sodium channels, these channels are also inactivated in a voltage-dependent manner. 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 and 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.

Why an action potential?
Why has nature evolved this particular method for commicating for long distances? This question is best answered when considering long-distance 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 the 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. 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.

General sources

 * Bear, M.F., B.W. Connors, and M.A. Paradiso. 2001. Neuroscience: Exploring the Brain. Baltimore: Lippincott.
 * Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. McGraw-Hill, New York (2000). ISBN 0838577016
 * Dale Purves, et al. Neuroscience, 2nd ed. 2001. Sinauer Associates, Inc. Ion Channels Underlying Action Potentials.