Action potential

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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.

Contents 1 Overview 2 Underlying mechanism 2.1 Resting potential 2.2 The action potential 3 Threshold and initiation 4 Circuit model 5 Propagation 5.1 Speed of propagation 5.2 Saltatory conduction 5.2.1 Detailed mechanism 5.2.2 Resilience to injury 5.2.3 Role in disease 6 Refractory period 7 Evolutionary purpose 8 See also 9 References 9.1 General sources 9.2 Primary sources 10 External links

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. Neurons are thought to transmit neural 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 type of information that they transmit.

Underlying mechanism

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Resting potential

The potential difference (a charge) which exists across the cell surface membrane of all cells is usually, as in the case of nerve cells, negative inside the cell with respect to the outside. The membrane is said to be polarised. The potential difference across the membrane at rest is called the resting potential and this is about -70mV (the negative sign indicates that the inside of the cell is negative with respect to the outside). The establishment of this potential difference is due to the following events:

1. Negatively charged organic ions do not pass across the membrane and so remain trapped inside the neuron.
2. Sodium ions are actively transported out of the neurone by sodium-potassium pumps (specialised carrier proteins).
3. Potassium ions are actively transported into the neurone by sodium-potassium pumps (specialised carrier proteins).
4. The active transport of sodium is faster than that of potassium, so that three sodium ions move out for every two potassium ions that are pumped in.
5. Although both sodium and potassium ions are positive, the increased movement outward of the sodium compared with the potassium inward leads to more positive ions in the tissue fluid outside the neurone than in the cytoplasm of the axon.
6. Both ions naturally begin to diffuse back in the opposite way from which they came, because there is a large concentration gradient of each between the inside and the outside of the neurone. However, most of the gates in the channels that allow potassium ions through are open, while most of the gates in the channels allowing sodium ions through are closed. The result is that the membrabe is 100 times more permeable to potassium ions, which therefore diffuse back out of the neurone faster than the sodium ones diffuse back in. This further increases the potential difference between the negative inside and the positive outside of the neurone.
7. Apart from the chemical gradient that causes the movement of the potassium and sodium ions, there is also an electrical gradient. As more and more potassium ions diffuse out of the neurone, so the outside becomes more and more positive. further outward movement of potassium ions is therefore made difficult because, being positively charged, they are attracted back into the neuron by its overall negative state and repelled from moving outwards by the overall positive state of the tissue fluid.
8. An equilibrium is established whereby there is no net movement of ions and which is a balance between the chemical and electrical gradients.

The action potential

When a stimulus arrives at a receptor or nerve ending, its energy causes a temporary reversal of the charges on the neurone cell surface membrane. As a result, the negative charge of 70mV inside the membrane becomes a positive charge of around +40mV. This is known as the action potential, and in this condition the membrane is said to be depolarised. (See depolarization) This depolarisation occurs because channels in the axon membrane change shape, and hence open or close, depending on the voltage across the membrane. They are therefore called voltage-gated ion channels. The sequence of events is described below.

1. At resting potential some potassium voltage-gated channels are open but the sodium voltage-gated channels are closed.
2. The energy of the stimulus causes the sodium voltage-gated channels in the neurone cell surface membrane to open and therefore sodium ions diffuse in through the channels along their electrochemical gradient. Being positively charged, they begin a reversal in the potential difference across the membrane.
3. As sodium ions enter, so more sodium channels open, causing an even greater influx of sodium ions. This is an example of positive feedback.
4. Once the action potential of around +40mV has been established, the voltage gates on sodium channels close (so further influx of sodium is prevented) and the voltage gates on the potassium channels begin to open.
5. With some potassium voltage-gated channels now open, the electrical gradient that was preventing further outward movement of potassium ions is now reversed, causing more potassium channels to open. This means that yet more potassium ions diffuse out, causing repolarisation of the neurone.
6. The outward movement of these potassium ions causes the temporary overshoot of the electrical gradient, with the inside of the neuron being more negative (relative to the outside) than usual. This is called hyperpolarisation (hyperpolarization). The gates on the potassium channels now close and the activities of the sodium-potassium pumps cause sodium ions to be pumped out and potassium ions in, once again. The resting potential of -70mV is re-established and the neurone is said to be repolarised.

Threshold and initiation

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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. ~ 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:

1. The green arrow indicates the resting potential of the cell and also the value of the equilibrium potential for potassium (E_k). As the K⁺ channel is the only one open at these negative voltages, the cell will rest at E_k. 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⁺ (E_Na). In this two-ion system, E_Na is the natural limit of membrane potential beyond which a cell cannot pass. Current values illustrated in this graph that exceed E_Na 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.
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 E_Na because of the counteracting influence of the potassium current.
4. 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 E_Na.

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

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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

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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 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 [1]) 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 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. 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.

Evolutionary purpose

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 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.

See also

• Cardiac action potential
• Ventricular action potential
• Membrane potential
• Depolarization
• Hyperpolarization
• Signals (biology)
• Time constant
• Length constant
• Bursting

References

General sources

• Bear, M.F., B.W. Connors, and M.A. Paradiso. 2001. Neuroscience: Exploring the Brain. Baltimore: Lippincott.[2]
• 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. [3]
• Kent, M., Advanced Biology. 2000. United Kingdom: Oxford University Press.
• Taylor, D.J., Green, N.P.O., & Stout, G.W. 2003. Biological Sciences, 3rd ed. United Kingdom : Cambridge University Press.

Primary sources

• Hodgkin AL, Huxley AF. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J Physiol. 1952 Apr;116(4):449-72. PMID 14946713
• Hodgkin AL, Huxley AF. The components of membrane conductance in the giant axon of Loligo. J Physiol. 1952 Apr;116(4):473-96. PMID 14946714
• Hodgkin AL, Huxley AF. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol. 1952 Apr;116(4):497-506. PMID 14946715
• Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500-44. PMID 12991237
• Clay JR. Axonal excitability revisited. Prog Biophys Mol Biol. 2005 May;88(1):59-90. PMID 15561301

External links

Template:Spoken Wikipedia

• Electrochemistry of plant life, from Case Western Reserve University
• Demonstration of ion flow during action potential
• Nernst/Goldman Equation Simulator
• The Nernst Equation and Action Potentials in the Nervous System from www.medicalcomputing.net

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