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| [[File:Action Potential.gif|thumb|300px|As an action potential travels down the [[axon]], there is a change in polarity across the [[cell membrane|membrane]]. The Na<sup>+</sup> and K<sup>+</sup> gated [[Voltage-gated ion channel|ion channels]] open and close as the membrane reaches the [[threshold potential]], in response to a signal from another [[neuron]]. At the beginning of the action potential, the Na<sup>+</sup> channels open and Na<sup>+</sup> moves into the axon, causing [[depolarization]]. [[Repolarization]] occurs when the K<sup>+</sup> channels open and K<sup>+</sup> moves out of the axon. This creates a change in polarity between the outside of the cell and the inside. The impulse travels down the axon in one direction only, to the [[axon terminal]] where it signals other neurons.]]
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| In [[physiology]], an '''action potential''' is a short-lasting event in which the electrical [[membrane potential]] of a [[Cell (biology)|cell]] rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of [[animal cell]]s, called [[Membrane potential|excitable cells]], which include [[neuron]]s, [[myocyte|muscle cells]], and [[endocrine]] cells, as well as in some [[plant cell]]s. In neurons, they play a central role in cell-to-cell communication. In other types of cells, their main function is to activate intracellular processes. In muscle cells, for example, an action potential is the first step in the chain of events leading to contraction. In [[beta cell]]s of the [[pancreas]], they provoke release of [[insulin]].<ref name="pmid16464129">{{cite journal | author = MacDonald PE, Rorsman P | title = Oscillations, intercellular coupling, and insulin secretion in pancreatic beta cells | journal = PLoS Biol. | volume = 4 | issue = 2 | pages = e49 |date=February 2006 | pmid = 16464129 | pmc = 1363709 | doi = 10.1371/journal.pbio.0040049 | url = | issn = }}</ref> Action potentials in neurons are also known as "'''nerve impulse'''s" or "spikes", and the temporal sequence of action potentials generated by a neuron is called its "'''spike train'''". A neuron that emits an action potential is often said to "fire".
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| Action potentials are generated by special types of [[voltage-gated ion channel]]s embedded in a cell's [[plasma membrane]].<ref name="pmid17515599">{{cite journal | author = Barnett MW, Larkman PM | title = The action potential | journal = Pract Neurol | volume = 7 | issue = 3 | pages = 192–7 |date=June 2007 | pmid = 17515599 | doi = | url = http://pn.bmj.com/content/7/3/192.short | issn = }}</ref> These channels are shut when the membrane potential is near the [[resting potential]] of the cell, but they rapidly begin to open if the membrane potential increases to a precisely defined threshold value. When the channels open (by detecting the [[depolarization]] in transmembrane voltage<ref name="pmid17515599" />), they allow an inward flow of [[sodium]] ions, which changes the electrochemical gradient, which in turn produces a further rise in the membrane potential. This then causes more channels to open, producing a greater electric current across the cell membrane, and so on. The process proceeds explosively until all of the available ion channels are open, resulting in a large upswing in the membrane potential. The rapid influx of sodium ions causes the polarity of the plasma membrane to reverse, and the ion channels then rapidly inactivate. As the sodium channels close, sodium ions can no longer enter the neuron, and they are actively transported out of the plasma membrane. [[Potassium]] channels are then activated, and there is an outward current of potassium ions, returning the electrochemical gradient to the resting state. After an action potential has occurred, there is a transient negative shift, called the [[afterhyperpolarization]] or refractory period, due to additional potassium currents. This is the mechanism that prevents an action potential from traveling back the way it just came.
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| In animal cells, there are two primary types of action potentials, one type generated by voltage-gated sodium channels, the other by voltage-gated [[calcium]] channels. Sodium-based action potentials usually last for under one millisecond, whereas calcium-based action potentials may last for 100 milliseconds or longer. In some types of neurons, slow calcium spikes provide the driving force for a long burst of rapidly emitted sodium spikes. In cardiac muscle cells, on the other hand, an initial fast sodium spike provides a "primer" to provoke the rapid onset of a calcium spike, which then produces muscle contraction.
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| ==Overview==
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| ===Function===
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| Nearly all cells from animals, plants and fungi function as batteries, in the sense that they maintain a voltage difference between the interior and the exterior of the cell, with the interior being the negative pole of the battery. The voltage of a cell is usually measured in millivolts (mV), or thousandths of a volt. A typical voltage for an animal cell is –65 mV—approximately one-fifteenth of a volt. Because the cell membrane is very thin, voltages of this magnitude give rise to very strong electric forces across the cell membrane.
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| In the majority of cells, the [[membrane potential|voltage]] stays fairly constant over time. There are some types of cells, however, that are electrically active in the sense that their voltages fluctuate. In some of these, the voltages sometimes show very rapid up-and-down fluctuations that have a stereotyped form: these up-and-down cycles are known as action potentials. The durations of action potentials vary across a wide range, and consequently they are [[analog signal]]s. In brain cells of animals, the entire up-and-down cycle may take place in less than a thousandth of a second. In other types of cells, the cycle may last for several seconds.
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| The electrical properties of an animal cell are determined by the structure of the membrane that surrounds it. A [[cell membrane]] consists of a layer of [[lipid]] molecules with larger protein molecules embedded in it. The lipid layer is highly resistant to movement of electrically charged ions, so it functions mainly as an insulator. The large membrane-embedded molecules, in contrast, provide channels through which ions can pass across the membrane, and some of the large molecules are capable of actively moving specific types of ions from one side of the membrane to the other.
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| ===Process in a typical neuron===
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| [[Image:Action potential vert.png|thumb|300px|Figure 1. '''A.''' view of an idealized action potential shows its various phases as the action potential passes a point on a [[cell membrane]]. '''B.''' Recordings of action potentials are often distorted compared to the schematic view because of variations in [[electrophysiology|electrophysiological]] techniques used to make the recording.|alt=Two plots of the membrane potential (measured in mV) versus time (ms). Top: idealized plot where the membrane potential starts out at -70 mV at time zero. A stimulus is applied at time = 1 ms, which raises the membrane potential above -55 mV (the threshold potential). After the stimulus is applied, the membrane potential rapidly rises to a peak potential of +40 mV at time = 2 ms. Just as quickly, the potential then drops and overshoots to -90 mV at time = 3 ms, and finally the resting potential of -70 mV is reestablished at time = 5 ms. Bottom: a plot of an experimentally determined action potential that is very similar in appearance to the idealized plot, except that the peak is much sharper and the initial drop is to -50 mV increasing to -30 mV before dropping back to the resting potential of -70 mV.]]
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| All cells in animal body tissues are electrically polarized – in other words, they maintain a voltage difference across the cell's [[plasma membrane]], known as the [[membrane potential]]. This electrical polarization results from a complex interplay between protein structures embedded in the membrane called [[Ion transporter|ion pump]]s and [[ion channel]]s. In neurons, the types of ion channels in the membrane usually vary across different parts of the cell, giving the [[dendrite]]s, [[axon]], and [[soma (biology)|cell body]] different electrical properties. As a result, some parts of the membrane of a neuron may be excitable (capable of generating action potentials), whereas others are not. The most excitable part of a neuron is usually the [[axon hillock]] (the point where the axon leaves the cell body), but the axon and cell body are also excitable in most cases.
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| Each excitable patch of membrane has two important levels of membrane potential: the [[resting potential]], which is the value the membrane potential maintains as long as nothing perturbs the cell, and a higher value called the [[threshold potential]]. At the axon hillock of a typical neuron, the resting potential is around –70 millivolts (mV) and the threshold potential is around –55 mV. Synaptic inputs to a neuron cause the membrane to [[depolarization|depolarize]] or [[Hyperpolarization (biology)|hyperpolarize]]; that is, they cause the membrane potential to rise or fall. Action potentials are triggered when enough depolarization accumulates to bring the membrane potential up to threshold. When an action potential is triggered, the membrane potential abruptly shoots upward, often reaching as high as +100 mV, then equally abruptly shoots back downward, often ending below the resting level, where it remains for some period of time. The shape of the action potential is stereotyped; that is, the rise and fall usually have approximately the same amplitude and time course for all action potentials in a given cell. (Exceptions are discussed later in the article.) In most neurons, the entire process takes place in less than a thousandth of a second. Many types of neurons emit action potentials constantly at rates of up to 10–100 per second; some types, however, are much quieter, and may go for minutes or longer without emitting any action potentials.
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| ==Biophysical basis==
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| [[File:Blausen 0011 ActionPotential Nerve.png|thumb|Action potential propagation along an axon]]
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| Action potentials result from the presence in a cell's membrane of special types of [[voltage-gated ion channel]]s. A voltage-gated ion channel is a cluster of proteins embedded in the membrane that has three key properties:
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| #It is capable of assuming more than one conformation.
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| #At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions.
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| #The transition between conformations is influenced by the membrane potential.
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| Thus, a voltage-gated ion channel tends to be open for some values of the membrane potential, and closed for others. In most cases, however, the relationship between membrane potential and channel state is probabilistic and involves a time delay. Ion channels switch between conformations at unpredictable times: The membrane potential determines the rate of transitions and the probability per unit time of each type of transition.
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| Voltage-gated ion channels are capable of producing action potentials because they can give rise to [[positive feedback]] loops: The membrane potential controls the state of the ion channels, but the state of the ion channels controls the membrane potential. Thus, in some situations, a rise in the membrane potential can cause ion channels to open, thereby causing a further rise in the membrane potential. An action potential occurs when this positive feedback cycle proceeds explosively. The time and amplitude trajectory of the action potential are determined by the biophysical properties of the voltage-gated ion channels that produce it. Several types of channels that are capable of producing the positive feedback necessary to generate an action potential exist. Voltage-gated sodium channels are responsible for the fast action potentials involved in nerve conduction. Slower action potentials in muscle cells and some types of neurons are generated by voltage-gated calcium channels. Each of these types comes in multiple variants, with different voltage sensitivity and different temporal dynamics.
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| The most intensively studied type of voltage-dependent ion channels comprises the sodium channels involved in fast nerve conduction. These are sometimes known as Hodgkin-Huxley sodium channels because they were first characterized by [[Alan Lloyd Hodgkin|Alan Hodgkin]] and [[Andrew Huxley]] in their Nobel Prize-winning studies of the biophysics of the action potential, but can more conveniently be referred to as ''Na''<sub>V</sub> channels. (The "V" stands for "voltage".) An ''Na''<sub>V</sub> channel has three possible states, known as ''deactivated'', ''activated'', and ''inactivated''. The channel is permeable only to sodium ions when it is in the ''activated'' state. When the membrane potential is low, the channel spends most of its time in the ''deactivated'' (closed) state. If the membrane potential is raised above a certain level, the channel shows increased probability of transitioning to the ''activated'' (open) state. The higher the membrane potential the greater the probability of activation. Once a channel has activated, it will eventually transition to the ''inactivated'' (closed) state. It tends then to stay inactivated for some time, but, if the membrane potential becomes low again, the channel will eventually transition back to the ''deactivated'' state. During an action potential, most channels of this type go through a cycle ''deactivated''→''activated''→''inactivated''→''deactivated''. This is only the population average behavior, however — an individual channel can in principle make any transition at any time. However, the likelihood of a channel's transitioning from the ''inactivated'' state directly to the ''activated'' state is very low: A channel in the ''inactivated'' state is refractory until it has transitioned back to the ''deactivated'' state.
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| The outcome of all this is that the kinetics of the ''Na''<sub>V</sub> channels are governed by a transition matrix whose rates are voltage-dependent in a complicated way. Since these channels themselves play a major role in determining the voltage, the global dynamics of the system can be quite difficult to work out. Hodgkin and Huxley approached the problem by developing a set of [[differential equation]]s for the parameters that govern the ion channel states, known as the [[Hodgkin–Huxley model|Hodgkin-Huxley equations]]. These equations have been extensively modified by later research, but form the starting point for most theoretical studies of action potential biophysics.
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| As the membrane potential is increased, [[sodium channel|sodium ion channels]] open, allowing the entry of [[sodium]] ions into the cell. This is followed by the opening of [[potassium channel|potassium ion channels]] that permit the exit of [[potassium]] ions from the cell. The inward flow of sodium ions increases the concentration of positively charged [[cation]]s in the cell and causes depolarization, where the potential of the cell is higher than the cell's [[resting potential]]. The sodium channels close at the peak of the action potential, while potassium continues to leave the cell. The efflux of potassium ions decreases the membrane potential or hyperpolarizes the cell. For small voltage increases from rest, the potassium current exceeds the sodium current and the voltage returns to its normal resting value, typically −70 mV.<ref name="failed_initiations">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 150–151; Junge, pp. 89–90; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], p. 484.</ref> However, if the voltage increases past a critical threshold, typically 15 mV higher than the resting value, the sodium current dominates. This results in a runaway condition whereby the [[positive feedback]] from the sodium current activates even more sodium channels. Thus, the cell "fires," producing an action potential.<ref name="positive_feedback" /><ref>In general, while this simple description of action potential initiation is accurate, it does not explain phenomena such as excitation block (the ability to prevent neurons from eliciting action potentials by stimulating them with large current steps) and the ability to elicit action potentials by briefly hyperpolarizing the membrane. By analyzing the dynamics of a system of sodium and potassium channels in a membrane patch using [[computational model]]s, however, these phenomena are readily explained (http://www.scholarpedia.org/article/FitzHugh-Nagumo_model).</ref>
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| Currents produced by the opening of voltage-gated channels in the course of an action potential are typically significantly larger than the initial stimulating current. Thus, the amplitude, duration, and shape of the action potential are determined largely by the properties of the excitable membrane and not the amplitude or duration of the stimulus. This [[All-or-none law|all-or-nothing]] property of the action potential sets it apart from [[graded potential]]s such as [[receptor potential]]s, [[electrotonic potential]]s, and [[synaptic potential]]s, which scale with the magnitude of the stimulus. A variety of action potential types exist in many cell types and cell compartments as determined by the types of voltage-gated channels, [[leak channels]], channel distributions, ionic concentrations, membrane capacitance, temperature, and other factors.
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| 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 continuous action of the [[Na⁺/K⁺-ATPase|sodium–potassium pump]], which, with other [[ion transporter]]s, maintains the normal ratio of ion concentrations across the membrane. [[Calcium]] cations and [[chloride]] [[anion]]s are involved in a few types of action potentials, such as the [[cardiac action potential]] and the action potential in the single-cell [[algae|alga]] ''[[Acetabularia]]'', respectively.
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| Although action potentials are generated locally on patches of excitable membrane, the resulting currents can trigger action potentials on neighboring stretches of membrane, precipitating a domino-like propagation. In contrast to passive spread of electric potentials ([[electrotonic potential]]), action potentials are generated anew along excitable stretches of membrane and propagate without decay.<ref name="no_decrement">[[Knut Schmidt-Nielsen|Schmidt-Nielsen]], p. 484.</ref> Myelinated sections of axons are not excitable and do not produce action potentials and the signal is propagated passively as [[electrotonic potential]]. Regularly spaced unmyelinated patches, called the [[nodes of Ranvier]], generate action potentials to boost the signal. Known as [[saltatory conduction]], this type of signal propagation provides a favorable tradeoff of signal velocity and axon diameter. Depolarization of [[axon terminal]]s, in general, triggers the release of [[neurotransmitter]] into the [[synaptic cleft]]. In addition, backpropagating action potentials have been recorded in the dendrites of [[pyramidal cell|pyramidal neurons]], which are ubiquitous in the neocortex.<ref name="backpropagation_in_pyramidal_cells">{{cite journal | author = Golding NL, Kath WL, Spruston N | title = Dichotomy of action-potential backpropagation in CA1 pyramidal neuron dendrites | journal = J. Neurophysiol. | volume = 86 | issue = 6 | pages = 2998–3010 |date=December 2001 | pmid = 11731556 | doi = | url = http://jn.physiology.org/cgi/content/abstract/86/6/2998 | issn = }}</ref> These are thought to have a role in [[spike-timing-dependent plasticity]].
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| ==Neurotransmission==
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| {{Main|Neurotransmission}}
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| ===Anatomy of a neuron===
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| {{Neuron map|Neuron}}
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| Several types of cells support an action potential, such as plant cells, muscle cells, and the specialized cells of the heart (in which occurs the [[cardiac action potential]]). However, the main excitable cell is the [[neuron]], which also has the simplest mechanism for the action potential.
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| Neurons are electrically excitable cells composed, in general, of one or more dendrites, a single [[soma (biology)|soma]], a single axon and one or more [[axon terminal]]s. Dendrites are cellular projections whose primary function is to receive synaptic signals. Their protrusions, or [[dendritic spine|spines]], are designed to capture the neurotransmitters released by the presynaptic neuron. They have a high concentration of [[ligand-gated ion channel]]s. These spines have a thin neck connecting a bulbous protrusion to the dendrite. This ensures that changes occurring inside the spine are less likely to affect the neighboring spines. The dendritic spine can, with rare exception (see [[Long-term potentiation#Properties|LTP]]), act as an independent unit. The dendrites extend from the soma, which houses the [[Cell nucleus|nucleus]], and many of the "normal" [[eukaryote|eukaryotic]] organelles. Unlike the spines, the surface of the soma is populated by voltage activated ion channels. These channels help transmit the signals generated by the dendrites. Emerging out from the soma is the [[axon hillock]]. This region is characterized by having a very high concentration of voltage-activated sodium channels. In general, it is considered to be the spike initiation zone for action potentials.<ref name="bullock_p11">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, p. 11.</ref> Multiple signals generated at the spines, and transmitted by the soma all converge here. Immediately after the axon hillock is the axon. This is a thin tubular protrusion traveling away from the soma. The axon is insulated by a [[myelin]] sheath. Myelin is composed of either [[Schwann cells]] (in the peripheral nervous system) or [[oligodendrocytes]] (in the central nervous system), both of which are types of [[glial cells]]. Although glial cells are not involved with the transmission of electrical signals, they communicate and provide important biochemical support to neurons.<ref>{{cite book|last=Silverthorn|first=Dee Unglaub|title=Human Physiology: An Integrated Approach|year=2010|publisher=Pearson|isbn=978-0-321-55980-7|pages=253}}</ref> To be specific, myelin wraps multiple times around the axonal segment, forming a thick fatty layer that prevents ions from entering or escaping the axon. This insulation prevents significant signal decay as well as ensuring faster signal speed. This insulation, however, has the restriction that no channels can be present on the surface of the axon. There are, therefore, regularly spaced patches of membrane, which have no insulation. These [[nodes of Ranvier]] can be considered to be "mini axon hillocks", as their purpose is to boost the signal in order to prevent significant signal decay. At the furthest end, the axon loses its insulation and begins to branch into several [[axon terminal]]s. These presynaptic terminals, or synaptic boutons, are a specialized area within the axon of the presynaptic cell that contains [[neurotransmitters]] enclosed in small membrane-bound spheres called [[synaptic vesicle]]s.
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| ===Initiation===
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| Before considering the propagation of action potentials along [[axon]]s and their termination at the synaptic knobs, it is 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.<ref name="rising_phase" /> There are several ways in which this depolarization can occur.
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| {{clear}}
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| [[Image:Synapse Illustration2 tweaked.svg|thumb|left|300px|When an action potential arrives at the end of the pre-synaptic axon (yellow), it causes the release of [[neurotransmitter]] molecules that open ion channels in the post-synaptic neuron (green). The combined [[excitatory postsynaptic potential|excitatory]] and [[inhibitory postsynaptic potential]]s of such inputs can begin a new action potential in the post-synaptic neuron.|alt=The pre- and post-synaptic axons are separated by a short distance known as the synaptic cleft. Neurotransmitter released by pre-synaptic axons diffuse through the synaptic clef to bind to and open ion channels in post-synaptic axons.]]
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| ===Dynamics===
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| Action potentials are most commonly initiated by [[excitatory postsynaptic potential]]s from a presynaptic neuron.<ref name="neurotransmission">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 177–240; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 490–499; Stevens, pp. 47–68.</ref> Typically, [[neurotransmitter]] molecules are released by the [[synapse|presynaptic]] [[neuron]]. These neurotransmitters then bind to receptors on the postsynaptic cell. This binding opens various types of [[ion channel]]s. This opening has the further effect of changing the local permeability of the [[cell membrane]] and, thus, the membrane potential. If the binding increases the voltage (depolarizes the membrane), the synapse is excitatory. If, however, the binding decreases the voltage (hyperpolarizes the membrane), it is inhibitory. Whether the voltage is increased or decreased, 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 [[spatial summation|work together]] at [[temporal summation|nearly the same time]] to provoke a new action potential. Their joint efforts can be thwarted, however, by the counteracting [[inhibitory postsynaptic potential]]s.
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| Neurotransmission can also occur through [[electrical synapse]]s.<ref name="electrical_synapses">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 178–180; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 490–491.</ref> Due to the direct connection between excitable cells in the form of [[gap junction]]s, an action potential can be transmitted directly from one cell to the next in either direction. The free flow of ions between cells enables rapid non-chemical-mediated transmission. Rectifying channels ensure that action potentials move only in one direction through an electrical synapse.{{Citation needed|date=May 2011}} Electrical synapses are found in all nervous systems, including the human brain, although they are a distinct minority.<ref name=Neuroscience>{{cite book|title=Neuroscience|url=http://www.ncbi.nlm.nih.gov/books/NBK11164/|edition=2|year=2001|isbn=0-87893-742-0}}</ref>
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| ==="All-or-none" principle===
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| The [[amplitude]] of an action potential is independent of the amount of current that produced it. In other words, larger currents do not create larger action potentials. Therefore, action potentials are said to be [[All-or-none law|all-or-none]] signals, since either they occur fully or they do not occur at all.<ref name=" Sasaki ">Sasaki, T., Matsuki, N., Ikegaya, Y. 2011 Action-potential modulation during axonal conduction Science 331 (6017), pp. 599-601</ref><ref name="Aur">Aur D., Connolly C.I., Jog M.S., (2005) Computing spike directivity with tetrodes, Journal of Neuroscience Methods, 149 (1), pp. 57-63</ref><ref name="Aur,Jog">Aur D., Jog, MS., 2010 Neuroelectrodynamics: Understanding the brain language, IOS Press, 2010. http://dx.doi.org/10.3233/978-1-60750-473-3-i</ref> The [[frequency]] of action potentials is correlated with the intensity of a stimulus. This is in contrast to [[receptor potential]]s, whose amplitudes are dependent on the intensity of a stimulus.<ref name="Purves" >{{cite book | author = Dale Purves ''et al.'' | title = Neuroscience (4th Ed.) | publisher = Sinauer | pages = 26–28 | year = 2008 | isbn = 978-0-87893-697-7 | author-separator = , | display-authors = 1}}</ref>
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| ===Sensory neurons===
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| {{Main|Sensory neuron}}
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| 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.<ref name="sensory_neurons">[[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 535–580; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 49–56, 76–93, 247–255; Stevens, 69–79</ref> 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 [[olfaction|smell]] and [[somatosensory system|touch]], respectively. However, not all sensory neurons convert their external signals into action potentials; some do not even have an axon!<ref name="amacrine_cells">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 53, 122–124.</ref> Instead, they may convert the signal into the release of a [[neurotransmitter]], or into continuous [[receptor potential|graded potentials]], either of which may stimulate subsequent neuron(s) into firing an action potential. For illustration, in the human [[ear]], [[hair cell]]s convert the incoming sound into the opening and closing of [[stretch-activated ion channel|mechanically gated ion channels]], which may cause [[neurotransmitter]] molecules to be released. In similar manner, in the human [[retina]], the initial [[photoreceptor cell]]s and the next layer of cells (comprising [[bipolar cell]]s and [[horizontal cell]]s) do not produce action potentials; only some [[amacrine cell]]s and the third layer, the [[ganglion cell]]s, produce action potentials, which then travel up the [[optic nerve]].
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| ===Pacemaker potentials===
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| {{Main|Pacemaker potential}}
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| [[Image:Pacemaker potential.svg|thumb|right|In [[pacemaker potential]]s, the cell spontaneously depolarizes (straight line with upward slope) until it fires an action potential.|alt=A plot of action potential (mV) vs time. The membrane potential is initially -60 mV, rise relatively slowly to the threshold potential of -40 mV and then quickly spikes at a potential of +10 mV, after which it rapidly returns to the starting -60 mV potential. The cycle is then repeated.]]
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| In 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.<ref name="pacemakers">Junge, pp. 115–132</ref> The voltage traces of such cells are known as [[pacemaker potential]]s.<ref name="pacemaker_potentials">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 152–153.</ref> The [[cardiac pacemaker]] cells of the [[sinoatrial node]] in the [[heart]] provide a good example.<ref name="noble_1960">{{cite journal | author = Noble D | year=1960 | title = Cardiac action and pacemaker potentials based on the Hodgkin-Huxley equations | journal = Nature | volume = 188 | pages = 495–497 | doi = 10.1038/188495b0 | pmid = 13729365|bibcode = 1960Natur.188..495N | issue=4749}}</ref> Although such pacemaker potentials have a [[neural oscillation|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 nervous system|sympathetic]] and [[parasympathetic nervous system|parasympathetic]] nerves.<ref name="parasympathetic">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 444–445.</ref> The external stimuli do not cause the cell's repetitive firing, but merely alter its timing.<ref name="pacemaker_potentials" /> In some cases, the regulation of frequency can be more complex, leading to patterns of action potentials, such as [[bursting]].
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| ==Phases==
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| The course of the action potential can be divided into five parts: the rising phase, the peak phase, the falling phase, the undershoot phase, and the refractory period. During the rising phase the membrane potential depolarizes (becomes more positive). The point at which depolarization stops is called the peak phase. At this stage, the membrane potential reaches a maximum. Subsequent to this, there is a falling phase. During this stage the membrane potential hyperpolarizes (becomes more negative). The undershoot phase is the point during which the membrane potential becomes temporarily more negatively charged than when at rest. Finally, the time during which a subsequent action potential is impossible or difficult to fire is called the [[refractory period (physiology)|refractory period]], which may overlap with the other phases.<ref name="phase_nomenclature" >Purves ''et al.'', p. 38.</ref>
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| The course of the action potential is determined by two coupled effects.<ref name="coupling">Stevens, pp. 127–128.</ref> First, voltage-sensitive ion channels open and close in response to changes in the [[membrane potential|membrane voltage]] ''V<sub>m</sub>''. This changes the membrane's permeability to those ions.<ref name="permeability_channels" >Purves ''et al.'', pp. 61–65.</ref> Second, according to the [[Goldman equation]], this change in permeability changes in the equilibrium potential ''E<sub>m</sub>'', and, thus, the membrane voltage ''V<sub>m</sub>''.<ref name="goldman_1943" /> Thus, the membrane potential affects the permeability, which then further affects the membrane potential. This sets up the possibility for [[positive feedback]], which is a key part of the rising phase of the action potential.<ref name="positive_feedback">Purves ''et al.'', pp. 48–49; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 141, 150–151; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], p. 483; Junge, p. 89; Stevens, p. 127</ref> A complicating factor is that a single ion channel may have multiple internal "gates" that respond to changes in ''V<sub>m</sub>'' in opposite ways, or at different rates.<ref name="multiple_gates">Purves ''et al.'', pp. 64–74; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 149–150; Junge, pp. 84–85; Stevens, pp. 152–158.</ref><ref name="hodgkin_1952" /> For example, although raising ''V<sub>m</sub>'' ''opens'' most gates in the voltage-sensitive sodium channel, it also ''closes'' the channel's "inactivation gate", albeit more slowly.<ref name="sodium inactivation">''Purves ''et al.'', pp. 47, 65; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 147–148; Stevens, p. 128.</ref> Hence, when ''V<sub>m</sub>'' is raised suddenly, the sodium channels open initially, but then close due to the slower inactivation.
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| The voltages and currents of the action potential in all of its phases were modeled accurately by [[Alan Lloyd Hodgkin]] and [[Andrew Huxley]] in 1952,<ref name="hodgkin_1952" /> for which they were awarded the [[Nobel Prize in Physiology or Medicine]] in 1963.<ref name = "Nobel_1963">{{cite press release | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1963/index.html | title = The Nobel Prize in Physiology or Medicine 1963 | publisher = The Royal Swedish Academy of Science | year = 1963 | accessdate = 2010-02-21 }}</ref> However, [[Hodgkin–Huxley model|their model]] considers only two types of voltage-sensitive ion channels, and makes several assumptions about them, e.g., that their internal gates open and close independently of one another. In reality, there are many types of ion channels,<ref name="goldin_2007">{{cite book | author = Goldin AL | year = 2007 | chapter = Neuronal Channels and Receptors | title = Molecular Neurology | editor = Waxman SG | publisher = Elsevier Academic Press | location = Burlington, MA | isbn = 978-0-12-369509-3 | pages = 43–58}}</ref> and they do not always open and close independently.<ref>{{cite journal|author = Naundorf B, Wolf F, Volgushev M | url=http://www.nature.com/nature/journal/v440/n7087/abs/nature04610.html|title=Unique features of action potential initiation in cortical neurons|journal=Nature |volume=440|pages=1060–1063 |date=April 2006 | format = Letter | accessdate=2008-03-27| doi= 10.1038/nature04610|pmid = 16625198|issue = 7087|bibcode = 2006Natur.440.1060N }}</ref>
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| ===Stimulation and rising phase===
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| A typical action potential begins at the [[axon hillock]]<ref name="axon_hillock_origin">Stevens, p. 49.</ref> with a sufficiently strong depolarization, e.g., a stimulus that increases ''V<sub>m</sub>''. This depolarization is often caused by the injection of extra sodium [[cation]]s into the cell; these cations can come from a wide variety of sources, such as [[chemical synapse]]s, [[sensory neuron]]s or [[pacemaker potential]]s.
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| For a neuron at rest, there is a high concentration of sodium and chlorine ions in the [[extracellular fluid]] compared to the [[intracellular fluid]] while there is a high concentration of potassium ions in the intracellular fluid compared to the extracellular fluid. This concentration gradient along with [[potassium leak channel]]s present on the membrane of the neuron causes an [[wikt:Special:Search/efflux|efflux]] of potassium ions making the resting potential close to ''E''<sub>K</sub>≈ –75 mV.<ref name="resting_potential">Purves ''et al.'', p. 34; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, p. 134; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 478–480.</ref> 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 ''V<sub>m</sub>'' 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.<ref name="failed_initiations" /> However, if the depolarization is large enough, the inward sodium current increases more than the outward potassium current and a runaway condition ([[positive feedback]]) results: the more inward current there is, the more ''V<sub>m</sub>'' increases, which in turn further increases the inward current.<ref name="positive_feedback" /> A sufficiently strong depolarization (increase in ''V<sub>m</sub>'') causes the voltage-sensitive sodium channels to open; the increasing permeability to sodium drives ''V<sub>m</sub>'' closer to the sodium equilibrium voltage ''E''<sub>Na</sub>≈ +55 mV. The increasing voltage in turn causes even more sodium channels to open, which pushes ''V<sub>m</sub>'' still further towards ''E''<sub>Na</sub>. This positive feedback continues until the sodium channels are fully open and ''V<sub>m</sub>'' is close to ''E''<sub>Na</sub>.<ref name="rising phase">Purves ''et al.'', pp. 49–50; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 140–141, 150–151; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 480–481, 483–484; Junge, pp. 89–90.</ref> The sharp rise in ''V<sub>m</sub>'' and sodium permeability correspond to the ''rising phase'' of the action potential.<ref name="rising_phase" />
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| The critical threshold voltage for this runaway condition is usually around −45 mV, but it depends on the recent activity of the axon. A membrane that has just fired an action potential cannot fire another one immediately, since the ion channels have not returned to the deactivated state. The period during which no new action potential can be fired is called the ''absolute refractory period''.<ref name="refractory" /> At longer times, after some but not all of the ion channels have recovered, the axon can be stimulated to produce another action potential, but with a higher threshold, requiring a much stronger depolarization, e.g., to −30 mV. The period during which action potentials are unusually difficult to evoke is called the ''relative refractory period''.<ref name="refractory" />
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| ===Peak and falling phase===
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| The positive feedback of the rising phase slows and comes to a halt as the sodium ion channels become maximally open. At the peak of the action potential, the sodium permeability is maximized and the membrane voltage ''V<sub>m</sub>'' is nearly equal to the sodium equilibrium voltage ''E''<sub>Na</sub>. However, the same raised voltage that opened the sodium channels initially also slowly shuts them off, by closing their pores; the sodium channels become ''inactivated''.<ref name="sodium inactivation" /> This lowers the membrane's permeability to sodium relative to potassium, driving the membrane voltage back towards the resting value. At the same time, the raised voltage opens voltage-sensitive potassium channels; the increase in the membrane's potassium permeability drives ''V<sub>m</sub>'' towards ''E''<sub>K</sub>.<ref name="sodium inactivation" /> Combined, these changes in sodium and potassium permeability cause ''V<sub>m</sub>'' to drop quickly, repolarizing the membrane and producing the "falling phase" of the action potential.<ref name="repolarization" /><ref name="repolarization">Purves ''et al.'', p. 49; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 147–149, 152; [[Knut Schmidt-Nielsen|Schmidt-Nielsen]], pp. 483–484; Stevens, pp. 126–127.</ref>
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| ===<!--"Afterhyperolarization" is a single word; please do not divide it into two words!-->Afterhyperpolarization===
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| The raised voltage opened many more potassium channels than usual, and some of these do not close right away when the membrane returns to its normal resting voltage. In addition, [[SK channel|further potassium channels]] open in response to the influx of calcium ions during the action potential. The potassium permeability of the membrane is transiently unusually high, driving the membrane voltage ''V<sub>m</sub>'' even closer to the potassium equilibrium voltage ''E''<sub>K</sub>. Hence, there is an undershoot or [[hyperpolarization (biology)|hyperpolarization]], termed an [[afterhyperpolarization]] in technical language, that persists until the membrane potassium permeability returns to its usual value.<ref name="hyperpolarization">Purves ''et al.'', p. 37; [[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, p. 152.</ref>
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| ===Refractory period===
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| Each action potential is followed by a [[refractory period (physiology)|refractory period]], which can be divided into an ''absolute refractory period'', during which it is impossible to evoke another action potential, and then a ''relative refractory period'', during which a stronger-than-usual stimulus is required.<ref name="refractory">Purves ''et al.'', p. 49; [[Theodore Holmes Bullock|Bullock]], Orkand, Grinell, p. 151; Stevens, pp. 19–20; Junge, pp. 4–5.</ref> These two refractory periods are caused by changes in the state of sodium and potassium channel molecules. When closing after an action potential, sodium channels enter an [[Sodium channel#Gating|"inactivated" state]], in which they cannot be made to open regardless of the membrane potential—this gives rise to the absolute refractory period. Even after a sufficient number of sodium channels have transitioned back to their resting state, it frequently happens that a fraction of potassium channels remains open, making it difficult for the membrane potential to depolarize, and thereby giving rise to the relative refractory period. Because the density and subtypes of potassium channels may differ greatly between different types of neurons, the duration of the relative refractory period is highly variable.
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| The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons.<ref name="unidirectional" >Purves ''et al.'', p. 56.</ref> At any given moment, the patch of axon behind the actively spiking part is refractory, but the patch in front, not having been activated recently, is capable of being stimulated by the depolarization from the action potential.
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| ==Propagation==
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| {{Main|Conduction velocity}} <!-- note: factually not a main article, but a stub in need of expansion; perhaps the material below should simply be moved there and a summary left in its place -->
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| The action potential generated at the axon hillock propagates as a wave along the axon.<ref>Bullock, Orkland, and Grinnell, pp. 160–64.</ref> 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.<ref>{{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]] | year = 1937 | title = Evidence for electrical transmission in nerve, Part I | journal = Journal of Physiology | volume = 90 | pages = 183–210 | pmid = 16994885 | issue = 2 | pmc = 1395060}}<br />* {{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]] | year = 1937 | title = Evidence for electrical transmission in nerve, Part II | journal = Journal of Physiology | volume = 90 | pages = 211–32 | pmid = 16994886 | issue = 2 | pmc = 1395062}}</ref>
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| 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 the voltage-activated sodium channels to recover from inactivation, i.e., to return to their closed state.<ref>Stevens, pp. 19–20.</ref> There are many types of voltage-activated potassium channels in neurons, some of them inactivate fast (A-type currents) and some of them inactivate slowly or not inactivate at all; this variability guarantees that there will be always an available source of current for repolarization, even if some of the potassium channels are inactivated because of preceding depolarization. On the other hand, all neuronal voltage-activated sodium channels inactivate within several millisecond during strong depolarization, thus making following depolarization impossible until a substantial fraction of sodium channels have returned to their closed state. Although it limits the frequency of firing,<ref>Stevens, pp. 21–23.</ref> the absolute refractory period ensures that the action potential moves in only one direction along an axon.<ref name="unidirectional" /> The currents flowing in due to an action potential spread out in both directions along the axon.<ref name="internal_currents">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, pp. 161–164.</ref> 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 cannot 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.<ref name="orthodromic">[[Theodore Holmes Bullock|Bullock]], Orkand, and Grinnell, p. 509.</ref> However, if a laboratory axon is stimulated in its middle, both halves of the axon are "fresh", i.e., unfired; then two action potentials will be generated, one traveling towards the axon hillock and the other traveling towards the synaptic knobs.
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| [[Image:Neuron1.jpg|thumb|left|In [[saltatory conduction]], an action potential at one [[node of Ranvier]] causes inwards currents that depolarize the membrane at the next node, provoking a new action potential there; the action potential appears to "hop" from node to node.|alt=Axons of neurons are wrapped by several myelin sheaths, which shield the axon from extracellular fluid. There are short gaps between the myelin sheaths known as nodes of Ranvier where the axon is directly exposed to the surrounding extracellular fluid.]]
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| ===Myelin and saltatory conduction===
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| {{Main|Myelination|Saltatory conduction}}
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| In order to enable fast and efficient transduction of electrical signals in the nervous system, certain neuronal axons are covered with [[myelin]] sheaths. Myelin is a multilamellar membrane that enwraps the axon in segments separated by intervals known as [[nodes of Ranvier]]. It is produced by specialized cells: [[Schwann cell]]s exclusively in the [[peripheral nervous system]], and [[oligodendrocyte]]s exclusively in the [[central nervous system]]. Myelin sheath reduces membrane capacitance and increases membrane resistance in the inter-node intervals, thus allowing a fast, saltatory movement of action potentials from node to node.<ref name=Zalc>{{cite journal |author=Zalc B |title=The acquisition of myelin: a success story |journal=Novartis Found. Symp. |volume=276 |issue= |pages=15–21; discussion 21–5, 54–7, 275–81 |year=2006 |pmid=16805421 |doi=10.1002/9780470032244.ch3 |series=Novartis Foundation Symposia |isbn=978-0-470-03224-4}}</ref><ref name="S. Poliak & E. Peles">{{cite journal |author=S. Poliak & E. Peles |title=The local differentiation of myelinated axons at nodes of Ranvier|journal=Nature Reviews Neuroscience |volume=12 |issue=4 |pages=968–80 |year=2006 |pmid=14682359 |doi=10.1038/nrn1253}}</ref><ref>{{cite journal |author=Simons M, Trotter J |title=Wrapping it up: the cell biology of myelination |journal=Curr. Opin. Neurobiol. |volume=17 |issue=5 |pages=533–40 |date=October 2007 |pmid=17923405 |doi=10.1016/j.conb.2007.08.003}}</ref> Myelination is found mainly in [[vertebrate]]s, but an analogous system has been discovered in a few invertebrates, such as some species of [[shrimp]].<ref>{{cite journal |author=Xu K, Terakawa S |title=Fenestration nodes and the wide submyelinic space form the basis for the unusually fast impulse conduction of shrimp myelinated axons |journal=J. Exp. Biol. |volume=202 |issue=Pt 15 |pages=1979–89 |date=1 August 1999 |pmid=10395528 |url=http://jeb.biologists.org/cgi/pmidlookup?view=long&pmid=10395528 }}</ref> Not all neurons in vertebrates are myelinated; for example, axons of the neurons comprising the autonomous nervous system are not, in general, myelinated.
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| Myelin prevents ions from entering or leaving the axon along myelinated segments. As a general rule, myelination increases the [[conduction velocity]] of action potentials and makes them more energy-efficient. Whether saltatory or not, the mean conduction velocity of an action potential ranges from 1 [[Metre per second|meter per second]] (m/s) to over 100 m/s, and, in general, increases with axonal diameter.<ref name="hursh_1939">{{cite journal | author = Hursh JB | year = 1939 | title = Conduction velocity and diameter of nerve fibers | journal = American Journal of Physiology | volume = 127 | pages = 131–39}}</ref>
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| Action potentials cannot propagate through the membrane in myelinated segments of the axon. However, the current is carried by the cytoplasm, which is sufficient to depolarize the first or second subsequent [[node of Ranvier]]. Instead, the ionic current from an action potential at one [[node of Ranvier]] provokes another action potential at the next node; this apparent "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,<ref>{{cite journal | author = Lillie RS | year = 1925 | title = Factors affecting transmission and recovery in passive iron nerve model | journal = J. Gen. Physiol. | volume = 7 | pages = 473–507 | doi = 10.1085/jgp.7.4.473 | pmid = 19872151 | issue = 4 | pmc = 2140733}} See also Keynes and Aidley, p. 78.</ref> the first experimental evidence for saltatory conduction came from [[Ichiji Tasaki]]<ref name="tasaki_1939">{{cite journal | author = Tasaki I | year = 1939 | title = Electro-saltatory transmission of nerve impulse and effect of narcosis upon nerve fiber | journal = Amer. J. Physiol. | volume = 127 | pages = 211–27}}</ref> and Taiji Takeuchi<ref name="tasaki_1941_1942_1959">{{cite journal | author = Tasaki I, Takeuchi T | year = 1941 | title = Der am Ranvierschen Knoten entstehende Aktionsstrom und seine Bedeutung für die Erregungsleitung | journal = Pflüger's Arch. Ges. Physiol. | volume = 244 | pages = 696–711 | doi = 10.1007/BF01755414 | issue = 6}}<br />* {{cite journal | author = Tasaki I, Takeuchi T | year = 1942 | title = Weitere Studien über den Aktionsstrom der markhaltigen Nervenfaser und über die elektrosaltatorische Übertragung des nervenimpulses | journal = Pflüger's Arch. Ges. Physiol. | volume = 245 | pages = 764–82 | doi = 10.1007/BF01755237 | issue = 5}}<br />* {{cite book | author = Tasaki I | year = 1959 | title = Handbook of Physiology: Neurophysiology | edition = (sect. 1, vol. 1) | editor = J Field, HW Magoun, VC Hall | publisher = American Physiological Society | location = Washington, D.C. | pages = 75–121}}</ref> and from [[Andrew Huxley]] and Robert Stämpfli.<ref name="huxley_staempfli_1949_1951">{{cite journal | author = [[Andrew Huxley|Huxley A]], Stämpfli R | year = 1949 | title = Evidence for saltatory conduction in peripheral myelinated nerve-fibers | journal = Journal of Physiology | volume = 108 | pages = 315–39}}<br />* {{cite journal | author = [[Andrew Huxley|Huxley A]], Stämpfli R | year = 1949 | title = Direct determination of membrane resting potential and action potential in single myelinated nerve fibers | journal = Journal of Physiology | volume = 112 | pages = 476–95 | pmid = 14825228 | issue = 3–4 | pmc = 1393015}}</ref> By contrast, in unmyelinated axons, the action potential provokes another in the membrane immediately adjacent, and moves continuously down the axon like a wave.
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| [[Image:Conduction velocity and myelination.png|thumb|right|300px|Comparison of the [[conduction velocity|conduction velocities]] of myelinated and unmyelinated [[axon]]s in the [[cat]].<ref>Schmidt-Nielsen, Figure 12.13.</ref> The conduction velocity ''v'' of myelinated neurons varies roughly linearly with axon diameter ''d'' (that is, ''v'' ∝ ''d''),<ref name="hursh_1939" /> whereas the speed of unmyelinated neurons varies roughly as the square root (''v'' ∝√ ''d'').<ref name="rushton_1951">{{cite journal | author = [[W. A. H. Rushton|Rushton WAH]] | year = 1951 | title = A theory of the effects of fibre size in the medullated nerve | journal = Journal of Physiology | volume = 115 | pages = 101–22 | pmid = 14889433 | issue = 1 | pmc = 1392008}}</ref> The red and blue curves are fits of experimental data, whereas the dotted lines are their theoretical extrapolations.|alt=A log-log plot of conduction velocity (m/s) vs axon diameter (μm).]]
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| Myelin has two important advantages: fast conduction speed and energy efficiency. For axons larger than a minimum diameter (roughly 1 [[micrometre]]), myelination increases the [[conduction velocity]] of an action potential, typically tenfold.<ref name="hartline_2007" /> Conversely, for a given conduction velocity, myelinated fibers are smaller than their unmyelinated counterparts. For example, action potentials move at roughly the same speed (25 m/s) in a myelinated frog axon and an unmyelinated squid giant axon, but the frog axon has a roughly 30-fold smaller diameter and 1000-fold smaller cross-sectional area. Also, since the ionic currents are confined to the nodes of Ranvier, far fewer ions "leak" across the membrane, saving metabolic energy. This saving is a significant [[natural selection|selective advantage]], since the human nervous system uses approximately 20% of the body's metabolic energy.<ref name="hartline_2007">{{cite journal |author=Hartline DK, Colman DR |title=Rapid conduction and the evolution of giant axons and myelinated fibers |journal=Curr. Biol. |volume=17 |issue=1 |pages=R29–R35 |year=2007 |pmid=17208176 |doi=10.1016/j.cub.2006.11.042}}</ref>
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| 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.<ref>Bullock, Orkland, and Grinnell, p. 163.</ref>
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| Some diseases degrade myelin and impair saltatory conduction, reducing the conduction velocity of action potentials.<ref>{{cite journal |author=Miller RH, Mi S |title=Dissecting demyelination |journal=Nat. Neurosci. |volume=10 |issue=11 |pages=1351–54 |year=2007 |pmid=17965654 |doi=10.1038/nn1995}}</ref> The most well-known of these is [[multiple sclerosis]], in which the breakdown of myelin impairs coordinated movement.<ref>{{cite book | author = Waxman SG | year = 2007 | chapter = Multiple Sclerosis as a Neurodegenerative Disease | title=Molecular Neurology |editor = Waxman SG | publisher = Elsevier Academic Press | location = Burlington, MA | isbn = 978-0-12-369509-3 | pages = 333–46}}</ref>
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| ===Cable theory===
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| {{Main|Cable theory}}
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| [[Image:NeuronResistanceCapacitanceRev.jpg|thumb|300px|right|Figure.1: Cable theory's simplified view of a neuronal fiber. The connected [[RC circuit]]s correspond to adjacent segments of a passive [[neurite]]. The extracellular resistances ''r<sub>e</sub>'' (the counterparts of the intracellular resistances ''r<sub>i</sub>'') are not shown, since they are usually negligibly small; the extracellular medium may be assumed to have the same voltage everywhere.|alt=A diagram showing the resistance and capacitance across the cell membrane of an axon. The cell membrane is divided into adjacent regions, each having its own resistance and capacitance between the cytosol and extracellular fluid across the membrane. Each of these regions is in turn connected by an intracellular circuit with a resistance.]]
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| The flow of currents within an axon can be described quantitatively by [[cable theory]]<ref name="rall_1989">{{cite book | author = [[Wilfrid Rall|Rall W]] | year = 1989 | title = Methods in Neuronal Modeling: From Synapses to Networks | chapter = Cable Theory for Dendritic Neurons | editor = [[Christof Koch|C. Koch]] and I. Segev | publisher = Bradford Books, MIT Press | location = Cambridge MA | isbn = 0-262-11133-0 | pages = 9–62}}</ref> and its elaborations, such as the compartmental model.<ref name="segev_1989">{{cite book | author = Segev I, Fleshman JW, Burke RE | year = 1989 | title = Methods in Neuronal Modeling: From Synapses to Networks | chapter = Compartmental Models of Complex Neurons | editor = [[Christof Koch|C. Koch]] and I. Segev | publisher = Bradford Books, MIT Press | location = Cambridge MA | isbn = 0-262-11133-0 | pages = 63–96}}</ref> Cable theory was developed in 1855 by [[William Thomson, 1st Baron Kelvin|Lord Kelvin]] to model the transatlantic telegraph cable<ref name="kelvin_1855">{{cite journal | author = [[William Thomson, 1st Baron Kelvin|Kelvin WT]] | year = 1855 | title = On the theory of the electric telegraph | journal = Proceedings of the Royal Society | volume = 7 | pages = 382–99 | doi = 10.1098/rspl.1854.0093}}</ref> and was shown to be relevant to neurons by [[Alan Lloyd Hodgkin|Hodgkin]] and [[W. A. H. Rushton|Rushton]] in 1946.<ref name="hodgkin_1946">{{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[W. A. H. Rushton|Rushton WAH]] | year = 1946 | title = The electrical constants of a crustacean nerve fibre | journal = Proceedings of the Royal Society B | volume = 133 | pages = 444–79 | doi = 10.1098/rspb.1946.0024 | pmid=20281590 |bibcode = 1946RSPSB.133..444H | issue=873}}</ref> 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]]<ref name="rall_1989" />
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| :<math>
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| \tau \frac{\partial V}{\partial t} = \lambda^{2} \frac{\partial^{2} V}{\partial x^{2}} - V
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| </math>
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| where ''V(x, t)'' is the voltage across the membrane at a time ''t'' and a position ''x'' along the length of the neuron, and where λ and τ are the characteristic length and time scales on which those voltages decay in response to a stimulus. Referring to the circuit diagram above, these scales can be determined from the resistances and capacitances per unit length<ref name="space_time_constants" >Purves ''et al.'', pp. 52–53.</ref>
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| :<math>
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| \tau =\ r_{m} c_{m} \,
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| </math>
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| :<math>
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| \lambda = \sqrt \frac{r_m}{r_l}
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| </math>
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| 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 ''r<sub>m</sub>'' and capacitance ''c<sub>m</sub>''. As the capacitance increases, more charge must be transferred to produce a given transmembrane voltage (by [[capacitance|the equation ''Q''=''CV'']]); as the resistance increases, less charge is transferred per unit time, making the equilibration slower. In similar manner, if the internal resistance per unit length ''r<sub>i</sub>'' is lower in one axon than in another (e.g., 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 ''r<sub>m</sub>'' is increased, that lowers the average "leakage" current across the membrane, likewise causing ''λ'' to become longer, increasing the conduction velocity.
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| ==Termination==
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| ===Chemical synapses===
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| {{Main|Chemical synapse|Neurotransmitter|Excitatory postsynaptic potential|Inhibitory postsynaptic potential}}
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| In general, action potentials that reach the synaptic knobs cause a [[neurotransmitter]] to be released into the synaptic cleft.<ref>{{cite journal |author=Süudhof TC |title=Neurotransmitter release |journal=Handb Exp Pharmacol |volume= 184|issue= 184|pages=1–21 |year=2008 |pmid=18064409 |doi=10.1007/978-3-540-74805-2_1 |series=Handbook of Experimental Pharmacology |isbn=978-3-540-74804-5}}</ref> 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 presynaptic membrane; the influx of calcium causes [[synaptic vesicle|vesicles]] filled with neurotransmitter to migrate to the cell's surface and [[exocytosis|release their contents]] into the [[synaptic cleft]].<ref>{{cite journal |author=Rusakov DA |title=Ca2+-dependent mechanisms of presynaptic control at central synapses |journal=Neuroscientist |volume=12 |issue=4 |pages=317–26 |date=August 2006 |pmid=16840708 |doi=10.1177/1073858405284672 |pmc=2684670}}</ref> This complex process is inhibited by the [[neurotoxin]]s [[tetanospasmin]] and [[botulinum toxin]], which are responsible for [[tetanus]] and [[botulism]], respectively.<ref>{{cite journal |author=Humeau Y, Doussau F, Grant NJ, Poulain B |title=How botulinum and tetanus neurotoxins block neurotransmitter release |journal=Biochimie |volume=82 |issue=5 |pages=427–46 |date=May 2000 |pmid=10865130 |doi=10.1016/S0300-9084(00)00216-9}}</ref>
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| [[Image:Gap cell junction-en.svg|thumb|left|[[Electrical synapse]]s between excitable cells allow ions to pass directly from one cell to another, and are much faster than [[chemical synapse]]s.|alt=Electrical synapases are composed of protein complexes that are imbedded in both membranes of adjacent neurons and thereby provide a direct channel for ions to flow from the cytoplasm of one cell into an adjacent cell.]]
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| ===Electrical synapses===
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| {{Main|Electrical synapse|Gap junction|Connexin}}
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| Some synapses dispense with the "middleman" of the neurotransmitter, and connect the presynaptic and postsynaptic cells together.<ref>{{cite journal |author=Zoidl G, Dermietzel R |title=On the search for the electrical synapse: a glimpse at the future |journal=Cell Tissue Res. |volume=310 |issue=2 |pages=137–42 |year=2002 |pmid=12397368 |doi=10.1007/s00441-002-0632-x}}</ref> When an action potential reaches such a synapse, the ionic currents flowing into the presynaptic cell can cross the barrier of the two cell membranes and enter the postsynaptic cell through pores known as [[connexon]]s.<ref>{{cite journal |author=Brink PR, Cronin K, Ramanan SV |title=Gap junctions in excitable cells |journal=J. Bioenerg. Biomembr. |volume=28 |issue=4 |pages=351–8 |year=1996 |pmid=8844332 |doi=10.1007/BF02110111}}</ref> Thus, the ionic currents of the presynaptic action potential can directly stimulate the postsynaptic cell. Electrical synapses allow for faster transmission because they do not require the slow diffusion of [[neurotransmitter]]s across the synaptic cleft. Hence, electrical synapses are used whenever fast response and coordination of timing are crucial, as in [[escape reflex]]es, the [[retina]] of [[vertebrate]]s, and the [[heart]].
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| ===Neuromuscular junctions===
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| {{Main|Neuromuscular junction|Acetylcholine receptor|Cholinesterase enzyme}}
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| A special case of a chemical synapse is the [[neuromuscular junction]], in which the [[axon]] of a [[motor neuron]] terminates on a [[muscle fiber]].<ref>{{cite journal |author=Hirsch NP |title=Neuromuscular junction in health and disease |journal=Br J Anaesth |volume=99 |issue=1 |pages=132–8 |date=July 2007 |pmid=17573397 |doi=10.1093/bja/aem144 |url=http://bja.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=17573397}}</ref> 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.<ref>{{cite journal |author=Hughes BW, Kusner LL, Kaminski HJ |title=Molecular architecture of the neuromuscular junction |journal=Muscle Nerve |volume=33 |issue=4 |pages=445–61 |date=April 2006 |pmid=16228970 |doi=10.1002/mus.20440}}</ref> However, the acetylcholine does not remain bound; rather, it dissociates and is [[hydrolysis|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 agent]]s [[sarin]] and [[tabun (nerve agent)|tabun]],<ref name=Newmark>{{cite journal |author=Newmark J |title=Nerve agents |journal=Neurologist |volume=13 |issue=1 |pages=20–32 |year=2007 |pmid=17215724 |doi=10.1097/01.nrl.0000252923.04894.53}}</ref> and the insecticides [[diazinon]] and [[malathion]].<ref>{{cite journal |author=Costa LG |title=Current issues in organophosphate toxicology |journal=Clin. Chim. Acta |volume=366 |issue=1–2 |pages=1–13 |year=2006 |pmid=16337171 |doi=10.1016/j.cca.2005.10.008}}</ref>
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| ==Other cell types==
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| ===Cardiac action potentials===
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| {{Main|Cardiac action potential|Electrical conduction system of the heart|Cardiac pacemaker|Arrhythmia}}
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| [[Image:Action potential2.svg|thumb|right|220px|Phases of a cardiac action potential. The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing eflux of potassium ions. The characteristic plateau ("2") results from the opening of voltage-sensitive [[calcium]] channels.|alt=Plot of membrane potential versus time. The initial resting phase (region 4) is negative and constant flowed by sharp rise (0) to a peak (1). The plateau phase (2) is slightly below the peak. The plateau phase is followed by a fairly rapid return (3) back to the resting potential (4).]]
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| The cardiac action potential differs from the neuronal action potential by having an extended plateau, in which the membrane is held at a high voltage for a few hundred milliseconds prior to being repolarized by the potassium current as usual.<ref name=Kleber /> This plateau is due to the action of slower [[calcium]] channels opening and holding the membrane voltage near their equilibrium potential even after the sodium channels have inactivated.
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| The cardiac action potential plays an important role in coordinating the contraction of the heart.<ref name=Kleber>{{cite journal |author=Kléber AG, Rudy Y |title=Basic mechanisms of cardiac impulse propagation and associated arrhythmias |journal=Physiol. Rev. |volume=84 |issue=2 |pages=431–88 |date=April 2004 |pmid=15044680 |doi=10.1152/physrev.00025.2003 |url=http://physrev.physiology.org/cgi/pmidlookup?view=long&pmid=15044680}}</ref> The cardiac cells of the [[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 [[atrium (heart)|atria]] and the [[ventricle (heart)|ventricles]]. Action potentials from the AV node travel through the [[bundle of His]] and thence to the [[Purkinje fiber]]s.<ref group=note>Note that these [[Purkinje fiber]]s are muscle fibers and not related to the [[Purkinje cell]]s, which are [[neuron]]s found in the [[cerebellum]].</ref> Conversely, anomalies in the cardiac action potential—whether due to a congenital mutation or injury—can lead to human pathologies, especially [[arrhythmia]]s.<ref name=Kleber/> Several anti-arrhythmia drugs act on the cardiac action potential, such as [[quinidine]], [[lidocaine]], [[beta blocker]]s, and [[verapamil]].<ref>{{cite journal |author=Tamargo J, Caballero R, Delpón E |title=Pharmacological approaches in the treatment of atrial fibrillation |journal=Curr. Med. Chem. |volume=11 |issue=1 |pages=13–28 |date=January 2004 |pmid=14754423 |doi=10.2174/0929867043456241}}</ref>
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| ===Muscular action potentials===
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| {{Main|Neuromuscular junction|Muscle contraction}}
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| The action potential in a normal skeletal muscle cell is similar to the action potential in neurons.<ref name="ganong_1991">{{cite book | author = Ganong W | year = 1991 | title = Review of Medical Physiology | edition = 15th | publisher = Appleton and Lange | location = Norwalk CT | isbn = 0-8385-8418-7 | pages = 59–60}}</ref> Action potentials result from the depolarization of the cell membrane (the [[sarcolemma]]), which opens voltage-sensitive sodium channels; these become 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 [[neurotoxin]]s.<ref name=Newmark/>
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| ===Plant action potentials===
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| [[Plant cells|Plant]] and [[fungi|fungal cells]] <ref name="Slayman_1976">{{cite journal | author = Slayman CL, Long WS, Gradmann D | year = 1976 | title = Action potentials in ''[[Neurospora crassa]]'' , a mycelial fungus | journal = Biochimica et Biophysica Acta | volume = 426 | pages = 737–744 | pmid = 130926 | doi = 10.1016/0005-2736(76)90138-3 | issue = 4}}</ref> are also electrically excitable. The fundamental difference to animal action potentials is, that the depolarization in plant cells is not accomplished by an uptake of positive sodium ions, but by release of negative ''chloride'' ions.<ref name = "Mummert_1991">{{cite journal | author = Mummert H, Gradmann D | year = 1991 | title = Action potentials in ''[[Acetabularia]]'': measurement and simulation of voltage-gated fluxes | journal = Journal of Membrane Biology | volume = 124 | pages = 265–273 | pmid = 1664861 | doi = 10.1007/BF01994359 | issue = 3}}</ref><ref name = "Gradmann_2001">{{cite journal | author = Gradmann D | year = 2001 | title = Models for oscillations in plants | journal = Austr. J. Plant Physiol. | volume = 28 | pages = 577–590}}</ref><ref name = "Beilby_2007">{{cite journal | author = Beilby MJ | year = 2007 | title = Action potentials in charophytes | journal = Int. Rev. Cytol. | volume = 257 | pages = 43–82 | doi = 10.1016/S0074-7696(07)57002-6 | pmid = 17280895 | series = International Review of Cytology | isbn = 978-0-12-373701-4}}</ref> Together with the following release of positive potassium ions, which is common to plant and animal action potentials, the action potential in plants infers, therefore, an [[osmotic]] loss of salt (KCl), whereas the animal action potential is osmotically neutral, when equal amounts of entering sodium and leaving potassium cancel each other osmotically. The interaction of electrical and osmotic relations in plant cells <ref name = "Gradmann_1998">{{cite journal | author = Gradmann D, Hoffstadt J | year = 1998 | title = Electrocoupling of ion transporters in plants: Interaction with internal ion concentrations | journal = Journal of Membrane Biology | volume = 166 | pages = 51–59 | pmid = 9784585 | doi = 10.1007/s002329900446 | issue = 1}}</ref> indicates an osmotic function of electrical excitability in the common, unicellular ancestors of plants and animals under changing salinity conditions, whereas the present function of rapid signal transmission is seen as a younger accomplishment of [[metazoan]] cells in a more stable osmotic environment.<ref name = "Gradmann_1980">{{cite book | author = Gradmann D, Mummert H | year = 1980 | chapter = Plant action potentials | title = Plant Membrane Transport: Current Conceptual Issues | editor = Spanswick RM, Lucas WJ, Dainty J | publisher = Elsevier Biomedical Press | location = Amsterdam | pages = 333–344 | isbn = 0-444-80192-8}}</ref> It must be assumed that the familiar signalling function of action potentials in some vascular plants (e.g. ''[[Mimosa pudica]]''), arose independently from that in metazoan excitable cells.
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| ==Taxonomic distribution and evolutionary advantages==
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| Action potentials are found throughout [[multicellular organism]]s, including [[plant]]s, [[invertebrate]]s such as [[insect]]s, and [[vertebrate]]s such as [[reptile]]s and [[mammal]]s.<ref name=Fromm>{{cite journal |author=Fromm J, Lautner S |title=Electrical signals and their physiological significance in plants |journal=Plant Cell Environ. |volume=30 |issue=3 |pages=249–257 |year=2007 |pmid=17263772 |doi=10.1111/j.1365-3040.2006.01614.x}}</ref> [[Sponge]]s seem to be the main [[phylum]] of multicellular [[eukaryote]]s that does not transmit action potentials, although some studies have suggested that these organisms have a form of electrical signaling, too.<ref>{{cite journal |author=Leys SP, Mackie GO, Meech RW |title=Impulse conduction in a sponge |journal=J. Exp. Biol. |volume=202 |issue= 9|pages=1139–50 |date=1 May 1999|pmid=10101111 |url=http://jeb.biologists.org/cgi/pmidlookup?view=long&pmid=10101111 }}</ref> 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.
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| <center>
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| {| class="wikitable" id="action_potential_texonomic_comparison" border="2" cellpadding="5" cellspacing="1" align="center"
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| |+ Comparison of action potentials (APs) from a representative cross-section of animals<ref name="bullock_1965">{{cite book | author = [[Theodore Holmes Bullock|Bullock TH]], Horridge GA | year = 1965 | title = Structure and Function in the Nervous Systems of Invertebrates | publisher = W. H. Freeman | location = San Francisco}}</ref>
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| ! Animal !! Cell type !! Resting potential (mV) !! AP increase (mV) !! AP duration (ms) !! Conduction speed (m/s)
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| | Squid (''Loligo'') || Giant axon || −60 || 120 || 0.75 || 35
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| | Earthworm (''Lumbricus'') || Median giant fiber || −70 || 100 || 1.0 || 30
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| | Cockroach (''Periplaneta'') || Giant fiber || −70 || 80–104 || 0.4 || 10
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| | Frog (''Rana'') || Sciatic nerve axon || −60 to −80 || 110–130 || 1.0 || 7–30
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| | Cat (''Felis'') || Spinal motor neuron || −55 to −80 || 80–110 || 1–1.5 || 30–120
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| |}
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| </center>
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| 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]]. 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 does not 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 generator]]s and mimicked in [[artificial neural network]]s.
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| ==Experimental methods==
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| {{See also|Electrophysiology}}
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| [[Image:Loligo vulgaris.jpg|thumb|right|250px|The giant axons of the European squid (''[[Loligo vulgaris]]'') were crucial for scientists to understand the action potential.|alt=Photograph of a giant squid.]]
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| The study of action potentials has required the development of new experimental methods. The initial work, prior to 1955, focused on three goals: isolating signals from single neurons or axons, developing fast, sensitive electronics, and shrinking [[electrode]]s enough that the voltage inside a single cell could be recorded.
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| The first problem was solved by studying the giant axons found in the neurons of the [[squid]] genus ''[[Loligo]]''.<ref name="keynes_1989">{{cite journal | author = Keynes RD | year = 1989 | title = The role of giant axons in studies of the nerve impulse | journal = BioEssays | volume = 10 | pages = 90–93|pmid=2541698 | doi = 10.1002/bies.950100213 | issue = 2–3}}</ref> 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.<ref name="hodgkin_1952" /><ref name=Meunier>{{cite journal |author=Meunier C, Segev I |title=Playing the devil's advocate: is the Hodgkin-Huxley model useful? |journal=Trends Neurosci. |volume=25 |issue=11 |pages=558–63 |year=2002 |pmid=12392930 |doi=10.1016/S0166-2236(02)02278-6}}</ref> However, the ''Loligo'' axons are not representative of all excitable cells, and numerous other systems with action potentials have been studied.
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| The second problem was addressed with the crucial development of the [[voltage clamp]],<ref name="cole_1949">{{cite journal | author = [[Kenneth Stewart Cole|Cole KS]] | year = 1949 | title = Dynamic electrical characteristics of the squid axon membrane | journal = Arch. Sci. Physiol. | volume = 3 | pages = 253–8}}</ref> which permitted experimenters to study the ionic currents underlying an action potential in isolation, and eliminated a key source of [[electronic noise]], the current ''I<sub>C</sub>'' associated with the [[capacitance]] ''C'' of the membrane.<ref name="junge_63_82">Junge, pp. 63–82.</ref> Since the current equals ''C'' times the rate of change of the transmembrane voltage ''V<sub>m</sub>'', the solution was to design a circuit that kept ''V<sub>m</sub>'' fixed (zero rate of change) regardless of the currents flowing across the membrane. Thus, the current required to keep ''V<sub>m</sub>'' at a fixed value is a direct reflection of the current flowing through the membrane. Other electronic advances included the use of [[Faraday cage]]s and electronics with high [[input impedance]], so that the measurement itself did not affect the voltage being measured.<ref name="kettenmann_1992">{{cite book | author = Kettenmann H, Grantyn R | year = 1992 | title = Practical Electrophysiological Methods | publisher = Wiley | location = New York | isbn = 978-0-471-56200-9}}</ref>
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| 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,<ref name="ling_1949">{{cite journal | author = Ling G, Gerard RW | year = 1949 | title = The normal membrane potential of frog sartorius fibers | journal = J. Cell. Comp. Physiol. | volume = 34 | pages = 383–396 |pmid=15410483 | doi = 10.1002/jcp.1030340304 | issue = 3}}</ref> which was quickly adopted by other researchers.<ref name="nastuk_1950">{{cite journal | author = Nastuk WL, [[Alan Lloyd Hodgkin|Hodgkin AL]] | year = 1950 | title = The electrical activity of single muscle fibers | journal = J. Cell. Comp. Physiol. | volume = 35 | pages = 39–73 | doi = 10.1002/jcp.1030350105}}</ref><ref name="brock_1952">{{cite journal | author = Brock LG, Coombs JS, Eccles JC | year = 1952 | title = The recording of potentials from motoneurones with an intracellular electrode | journal = J. Physiol. (London) | volume = 117 | pages = 431–460}}</ref> Refinements of this method are able to produce electrode tips that are as fine as 100 [[Ångström|Å]] (10 [[nanometre|nm]]), which also confers high input impedance.<ref>{{cite book | author = Snell FM | year = 1969 | chapter = Some Electrical Properties of Fine-Tipped Pipette Microelectrodes | title = Glass Microelectrodes | editor = M. Lavallée, OF Schanne, NC Hébert | publisher = John Wiley and Sons | location = New York | lccn = 689252}}</ref> Action potentials may also be recorded with small metal electrodes placed just next to a neuron, with [[neurochip]]s containing [[EOSFET]]s, or optically with dyes that are [[Calcium imaging|sensitive to Ca<sup>2+</sup>]] or to voltage.<ref name="dyes">{{cite journal | author = Ross WN, Salzberg BM, Cohen LB, Davila HV | year = 1974 | title = A large change in dye absorption during the action potential | journal = Biophysical Journal | volume = 14 | pages = 983–986 | doi = 10.1016/S0006-3495(74)85963-1 | pmid = 4429774 | issue = 12 | pmc = 1334592|bibcode = 1974BpJ....14..983R }}<br />* {{cite journal | author = Grynkiewicz G, Poenie M, Tsien RY | year = 1985 | title = A new generation of Ca<sup>2+</sup> indicators with greatly improved fluorescence properties | journal = J. Biol. Chem. | volume = 260 | pages = 3440–3450 | pmid = 3838314 | issue = 6}}</ref>
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| [[Image:Single channel.png|thumb|left|As revealed by a [[patch clamp]] electrode, an [[ion channel]] has two states: open (high conductance) and closed (low conductance).|alt=Plot of membrane potential versus time. The channel is primarily in a high conductance state punctuated by random and relatively brief transitions to a low conductance states ]]
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| 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.<ref name = "Nobel_1991">{{cite press release | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1991/press.html | title = The Nobel Prize in Physiology or Medicine 1991 | publisher = The Royal Swedish Academy of Science | year = 1991 | accessdate = 2010-02-21 }}</ref> Patch-clamping verified that ionic channels have discrete states of conductance, such as open, closed and inactivated.
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| [[Optical imaging]] technologies have been developed in recent years to measure action potentials, either via simultaneous multisite recordings or with ultra-spatial resolution. Using [[Potentiometric dyes|voltage-sensitive dyes]], action potentials have been optically recorded from a tiny patch of [[cardiomyocyte]] membrane.<ref name="pmid19289075">{{cite journal | author = Bu G, Adams H, Berbari EJ, Rubart M | title = Uniform action potential repolarization within the sarcolemma of in situ ventricular cardiomyocytes | journal = Biophys. J. | volume = 96 | issue = 6 | pages = 2532–46 |date=March 2009 | pmid = 19289075 | pmc = 2907679 | doi = 10.1016/j.bpj.2008.12.3896 | url = | issn = |bibcode = 2009BpJ....96.2532B }}</ref>
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| ==Neurotoxins==
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| [[Image:Puffer Fish DSC01257.JPG|thumb|right|[[Tetrodotoxin]] is a lethal toxin found in [[pufferfish]] that inhibits the [[voltage-gated ion channel|voltage-sensitive sodium channel]], halting action potentials.|alt=Photograph of a pufferfish.]]
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| Several [[neurotoxin]]s, 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 "[[Paralytic shellfish poisoning|red tide]]s") block action potentials by inhibiting the voltage-sensitive sodium channel;<ref name="TTX_refs">{{cite journal | author = Nakamura Y, Nakajima S, Grundfest H | year = 1965 | title = The effect of tetrodotoxin on electrogenic components of squid giant axons | journal = J. Gen. Physiol. | volume = 48 | pages = 985–996 | doi = 10.1085/jgp.48.6.975 | issue = 6}}<br />* {{cite journal | author = Ritchie JM, Rogart RB | year = 1977 | title = The binding of saxitoxin and tetrodotoxin to excitable tissue | journal = Rev. Physiol. Biochem. Pharmacol. | volume = 79 | pages = 1–50 | doi = 10.1007/BFb0037088 | pmid = 335473 | series = Reviews of Physiology, Biochemistry and Pharmacology | isbn = 0-387-08326-X}}<br />* {{cite journal | author = Keynes RD, Ritchie JM | year = 1984 | title = On the binding of labelled saxitoxin to the squid giant axon | journal = Proc. R. Soc. Lond. | volume = 239 | pages = 393–434}}</ref> similarly, [[dendrotoxin]] from the [[mamba|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 warfare|chemical weapon]]s. Neurotoxins aimed at the ion channels of insects have been effective [[insecticide]]s; 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 [[chemical synapse|synapses]], especially at the [[neuromuscular junction]].
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| ==History==
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| [[Image:PurkinjeCell.jpg|thumb|left|Image of two [[Purkinje cell]]s (labeled as '''A''') drawn by [[Santiago Ramón y Cajal]] in 1899. Large trees of [[dendrite]]s feed into the [[soma (biology)|soma]], from which a single [[axon]] emerges and moves generally downwards with a few branch points. The smaller cells labeled '''B''' are [[granule cell]]s.|alt=Hand drawn figure of two Purkinje cells side by side with dendrites projecting upwards that look like tree branches and a few axons projected downwards that connect to a few granule cells at the bottom of the drawing.]]
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| The role of electricity in the nervous systems of animals was first observed in dissected [[frog]]s by [[Luigi Galvani]], who studied it from 1791 to 1797.<ref name="piccolino_1997">{{cite journal | author = Piccolino M | year = 1997 | title = Luigi Galvani and animal electricity: two centuries after the foundation of electrophysiology | journal = Trends in Neuroscience | volume = 20 | pages = 443–448 | doi = 10.1016/S0166-2236(97)01101-6 | issue = 10}}</ref> Galvani's results stimulated [[Alessandro Volta]] to develop the [[Voltaic pile]]—the earliest-known [[battery (electricity)|electric battery]]—with which he studied animal electricity (such as [[electric eel]]s) and the physiological responses to applied [[direct current|direct-current]] [[voltage]]s.<ref name="piccolino_2000">{{cite journal | author = Piccolino M | year = 2000 | title = The bicentennial of the Voltaic battery (1800–2000): the artificial electric organ | journal = Trends in Neuroscience | volume = 23 | pages = 147–151 | doi = 10.1016/S0166-2236(99)01544-1 | issue = 4}}</ref>
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| Scientists of the 19th century studied the propagation of electrical signals in whole [[nerve]]s (i.e., bundles of [[neuron]]s) and demonstrated that nervous tissue was made up of [[cell (biology)|cells]], instead of an interconnected network of tubes (a ''reticulum'').<ref name="history">{{cite book | author = Brazier MAB | year = 1961 | title = A History of the Electrical Activity of the Brain | publisher = Pitman | location = London}}<br />* {{cite book | author = McHenry LC | year = 1969 | title = Garrison's History of Neurology | publisher = Charles C. Thomas | location = Springfield, IL}}<br />* {{cite book | author = Swazey J, Worden FG | year = 1975 | title = Paths of Discovery in the Neurosciences | publisher = The MIT Press | location = Cambridge, MA}}</ref> [[Carlo Matteucci]] followed up Galvani's studies and demonstrated that [[cell membrane]]s 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 is 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 or Medicine|Nobel Prize in Physiology]].<ref name = "Nobel_1906">{{cite press release | url = http://nobelprize.org/medicine/laureates/1906/index.html | title = The Nobel Prize in Physiology or Medicine 1906 | publisher = The Royal Swedish Academy of Science | year = 1906 | accessdate = 2010-02-21 }}</ref> 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.
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| [[Image:3b8e.gif|thumb|right|[[Ribbon diagram]] of the sodium–potassium pump in its E2-Pi state. The estimated boundaries of the [[lipid bilayer]] are shown as blue (intracellular) and red (extracellular) planes.|alt=Cartoon diagram of the sodium–potassium pump drawn vertically imbedded in a schematic diagram of a lipid bilayer represented by two parallel horizontal lines. The portion of the protein that is imbedded in the lipid bilayer is composed largely of anti-parallel beta sheets. There is also a large intracellular domain of the protein with a mixed alpha-helix/beta-sheet structure.]]
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| 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 [[permeation|permeability]] of the axonal membrane to ions.<ref name="bernstein_1902_1912">{{cite journal | author = [[Julius Bernstein|Bernstein J]] | year = 1902 | title = Untersuchungen zur Thermodynamik der bioelektrischen Ströme | journal = Pflüger's Arch. Ges. Physiol. | volume = 92 | pages = 521–562 | doi = 10.1007/BF01790181 | issue = 10–12}}<br />* {{cite book | author = [[Julius Bernstein|Bernstein J]] | year = 1912 | title = Elektrobiologie | publisher = Vieweg und Sohn | location = Braunschweig}}</ref> Bernstein's hypothesis was confirmed by [[Kenneth Stewart Cole|Ken Cole]] and Howard Curtis, who showed that membrane conductance increases during an action potential.<ref>{{cite journal | author = [[Kenneth Stewart Cole|Cole KS]], Curtis HJ | year = 1939 | title = Electrical impedance of the squid giant axon during activity | journal = J. Gen. Physiol. | volume = 22 | pages = 649–670 | doi = 10.1085/jgp.22.5.649 | pmid = 19873125 | issue = 5 | pmc = 2142006}}</ref> In 1907, [[Louis Lapicque]] suggested that the action potential was generated as a threshold was crossed,<ref>{{cite journal | author = [[Lapicque L]] | year = 1907 | title = Recherches quantitatives sur l'excitationelectrique des nerfs traitee comme une polarisation | journal = J. Physiol. Pathol. Gen | volume = 9| pages = 620– 635}}</ref> what would be later shown as a product of the [[dynamical system]]s of ionic conductances. In 1949, [[Alan Lloyd Hodgkin|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.<ref name="hodgkin_1949">{{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Bernard Katz|Katz B]] | year = 1949 | title = The effect of sodium ions on the electrical activity of the giant axon of the squid | journal = J. Physiology | volume = 108 | pages = 37–77}}</ref> They made the first actual recording of the electrical changes across the neuronal membrane that mediate the action potential.<ref>{{cite web|last=Warlow|first=Charles|title=The Recent Evolution of a Symbiotic Ion Channel in the Legume Family Altered Ion Conductance and Improved Functionality in Calcium Signaling|url=http://pn.bmj.com.myaccess.library.utoronto.ca/content/7/3/192.full#cited-by|publisher=BMJ Publishing Group|accessdate=23 March 2013}}</ref> 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.<ref name="hodgkin_1952">{{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Andrew Huxley|Huxley AF]], [[Bernard Katz|Katz B]] |title = Measurements of current-voltage relations in the membrane of the giant axon of ''Loligo'' | journal = Journal of Physiology | year = 1952 | volume = 116 | pages = 424–448 | pmid = 14946713 | issue = 4 | pmc = 1392213}}<br />* {{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Andrew Huxley|Huxley AF]] |title = Currents carried by sodium and potassium ions through the membrane of the giant axon of ''Loligo''|journal=Journal of Physiology | year = 1952 | volume = 116 | pages = 449–472 | pmid = 14946713 | issue = 4 | pmc = 1392213}}<br />* {{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Andrew Huxley|Huxley AF]] | title = The components of membrane conductance in the giant axon of ''Loligo'' | journal = J Physiol | year = 1952 | volume = 116 | pages= 473–496 | pmid = 14946714 | issue = 4 | pmc = 1392209}}<br />* {{cite journal | author=[[Alan Lloyd Hodgkin|Hodgkin AL]], [[Andrew Huxley|Huxley AF]] | title = The dual effect of membrane potential on sodium conductance in the giant axon of ''Loligo'' | journal = J Physiol | year = 1952 | volume = 116 | pages = 497–506 | pmid = 14946715 | issue=4 | pmc=1392212}}<br />* {{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Andrew Huxley|Huxley AF]] | title = A quantitative description of membrane current and its application to conduction and excitation in nerve | journal = J Physiol | year = 1952 | volume = 117 | pages = 500–544 | pmid = 12991237 | issue = 4 | pmc = 1392413}}</ref> Hodgkin and Huxley correlated the properties of their mathematical model with discrete [[ion channel]]s 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 clamp]]ing to examine the conductance states of individual ion channels.<ref name="patch_clamp">{{cite journal | author = [[Erwin Neher|Neher E]], [[Bert Sakmann|Sakmann B]] | year = 1976 | title = Single-channel currents recorded from membrane of denervated frog muscle fibres | journal = Nature | volume = 260 | pages = 779–802 | pmid=1083489 | doi = 10.1038/260799a0 |bibcode = 1976Natur.260..799N | issue=5554}}<br />* {{cite journal | author = Hamill OP, Marty A, [[Erwin Neher|Neher E]], [[Bert Sakmann|Sakmann B]], Sigworth FJ | year = 1981 | title = Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches | journal = Pflugers Arch. | volume = 391 | pages = 85–100 | doi = 10.1007/BF00656997 | pmid = 6270629 | issue = 2}}<br />* {{cite journal | doi = 10.1038/scientificamerican0392-44 | author = [[Erwin Neher|Neher E]], [[Bert Sakmann|Sakmann B]] | year = 1992 | title = The patch clamp technique | journal = Scientific American | volume = 266 | pages = 44–51 | pmid = 1374932 | issue = 3}}</ref> 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,<ref name="yellen_2002">{{cite journal | author = Yellen G | year = 2002 | title = The voltage-gated potassium channels and their relatives | journal = Nature | volume = 419 | pages = 35–42 | doi = 10.1038/nature00978 | pmid = 12214225 | issue = 6902}}</ref> through the atomic-resolution [[X-ray crystallography|crystal structures]],<ref name="doyle_1998">{{cite journal | author = Doyle DA | year = 1998 | title = The structure of the potassium channel, molecular basis of K<sup>+</sup> conduction and selectivity | journal = Science | volume = 280 | pages = 69–77 | doi = 10.1126/science.280.5360.69 | pmid = 9525859 | issue = 5360|bibcode = 1998Sci...280...69D | author-separator = , | author2 = Morais Cabral J | author3 = Pfuetzner RA | author4 = Kuo A | author5 = Gulbis JM | author6 = Cohen SL | display-authors = 6 | last7 = Chait | first7 = BT | last8 = MacKinnon | first8 = R }}<br />* {{cite journal | author = Zhou Y, Morias-Cabrak JH, Kaufman A, MacKinnon R | year = 2001 | title = Chemistry of ion coordination and hydration revealed by a K<sup>+</sup>-Fab complex at 2.0 A resolution | journal = Nature | volume = 414 | pages = 43–48 | doi = 10.1038/35102009 | pmid = 11689936 | issue = 6859}}<br />* {{cite journal | author = Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT, MacKinnon R | year = 2003 | title = X-ray structure of a voltage-dependent K<sup>+</sup> channel | journal = Nature | volume = 423 | pages = 33–41 | doi = 10.1038/nature01580 | pmid = 12721618 | issue = 6935|bibcode = 2003Natur.423...33J }}</ref> fluorescence distance measurements<ref name="FRET">{{cite journal | author = Cha A, Snyder GE, Selvin PR, Bezanilla F | year = 1999 | title = Atomic-scale movement of the voltage-sensing region in a potassium channel measured via spectroscopy | journal = Nature | volume = 402 | pages = 809–813 | doi = 10.1038/45552 | pmid = 10617201 | issue = 6763}}<br />* {{cite journal | author = Glauner KS, Mannuzzu LM, Gandhi CS, Isacoff E | year = 1999 | title = Spectroscopic mapping of voltage sensor movement in the ''Shaker'' potassium channel | journal = Nature | volume = 402 | pages = 813–817 | doi = 10.1038/45561 | pmid = 10617202 | issue = 6763|bibcode = 1999Natur.402..813G }}<br />* {{cite journal | author = Bezanilla F | year = 2000 | title = The voltage sensor in voltage-dependent ion channels | journal = Physiol. Rev. | volume = 80 | pages = 555–592 | pmid = 10747201 | issue = 2}}</ref> and [[cryo-electron microscopy]] studies.<ref name="cryoEM">{{cite journal | author = Catterall WA | year = 2001 | title = A 3D view of sodium channels | journal = Nature | volume = 409 | pages = 988–999 | doi = 10.1038/35059188 | pmid = 11234048 | issue = 6823}}<br />* {{cite journal | author = Sato C | year = 2001 | title = The voltage-sensitive sodium channel is a bell-shaped molecule with several cavities | journal = Nature | volume = 409 | pages = 1047–1051 | doi = 10.1038/35059098 | pmid = 11234014 | issue = 6823 | author-separator = , | author2 = Ueno Y | author3 = Asai K | author4 = Takahashi K | author5 = Sato M | author6 = Engel A | display-authors = 6 | last7 = Fujiyoshi | first7 = Yoshinori}}</ref>
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| 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.<ref name="goldman_1943">{{cite journal | author = Goldman DE | year = 1943 | title = Potential, impedance and rectification in membranes | journal = J. Gen. Physiol. | volume = 27 | pages = 37–60 | doi = 10.1085/jgp.27.1.37 | pmid = 19873371 | issue = 1 | pmc = 2142582}}</ref> The [[Na+/K+-ATPase|sodium–potassium pump]] was identified in 1957<ref>{{cite journal | author = Skou J | title = The influence of some cations on an adenosine triphosphatase from peripheral nerves | journal = Biochim Biophys Acta | volume = 23 | issue = 2 | pages = 394–401 | year = 1957 | pmid = 13412736 | doi = 10.1016/0006-3002(57)90343-8}}; {{cite press release | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html | title = The Nobel Prize in Chemistry 1997 | publisher = The Royal Swedish Academy of Science | year = 1997 | accessdate = 2010-02-21 }}</ref> and its properties gradually elucidated,<ref name="hodgkin_1955">{{cite journal | author = [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Richard Keynes|Keynes RD]] | year = 1955 | title = Active transport of cations in giant axons from ''Sepia'' and ''Loligo'' | journal = J. Physiol. | volume = 128 | pages = 28–60 | pmid = 14368574 | issue = 1 | pmc = 1365754}}</ref><ref name="caldwell_1960">{{cite journal | author = Caldwell PC, [[Alan Lloyd Hodgkin|Hodgkin AL]], [[Richard Keynes|Keynes RD]], Shaw TI | year = 1960 | title = The effects of injecting energy-rich phosphate compounds on the active transport of ions in the giant axons of ''Loligo'' | journal = J. Physiol. | volume = 152 | issue = 3 | pages = 561–90 | pmid = 13806926 | pmc = 1363339}}</ref><ref name="caldwell_1957">{{cite journal | author = Caldwell PC, Keynes RD | year = 1957 | title = The utilization of phosphate bond energy for sodium extrusion from giant axons | journal = J. Physiol. (London) | volume = 137 | pages = 12–13P | pmid=13439598 | issue=1}}</ref> culminating in the determination of its atomic-resolution structure by [[X-ray crystallography]].<ref name="Na_K_pump_structure">{{cite journal | author = Morth JP, Pedersen PB, Toustrup-Jensen MS, Soerensen TLM, Petersen J, Andersen JP, Vilsen B, Nissen P | year = 2007 | title = Crystal structure of the sodium–potassium pump | journal = Nature | volume = 450 | pages = 1043–1049 | doi = 10.1038/nature06419 | pmid = 18075585 | issue = 7172|bibcode = 2007Natur.450.1043M }}</ref> The crystal structures of related ionic pumps have also been solved, giving a broader view of how these molecular machines work.<ref>{{cite journal | author = Lee AG, East JM | year = 2001 | title = What the structure of a calcium pump tells us about its mechanism | journal = Biochemical Journal | volume = 356 | pages = 665–683|pmid= 11389676 | doi = 10.1042/0264-6021:3560665 | issue = Pt 3 | pmc = 1221895}}</ref>
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| ==Quantitative models==
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| {{Main|Quantitative models of the action potential}}
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| [[Image:MembraneCircuit.svg|thumb|336px|right|Equivalent electrical circuit for the Hodgkin–Huxley model of the action potential. ''I<sub>m</sub>'' and ''V<sub>m</sub>'' represent the current through, and the voltage across, a small patch of membrane, respectively. The ''C<sub>m</sub>'' represents the capacitance of the membrane patch, whereas the four ''g'''s represent the [[electrical conductance|conductances]] of four types of ions. The two conductances on the left, for potassium (K) and sodium (Na), are shown with arrows to indicate that they can vary with the applied voltage, corresponding to the [[voltage-gated ion channel|voltage-sensitive ion channels]]. The two conductances on the right help determine the [[resting membrane potential]].|alt=Circuit diagram depicting five parallel circuits that are interconnected at the top to the extracellular solution and at the bottom to the intracellular solution.]]
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| Mathematical and computational models are essential for understanding the action potential, and offer predictions that may be tested against experimental data, providing a stringent test of a theory. The most important and accurate of these models is the [[Hodgkin–Huxley model]], which describes the action potential by a coupled set of four [[ordinary differential equation]]s (ODEs).<ref name="hodgkin_1952" /> Although the Hodgkin–Huxley model may be a simplification of a realistic nervous membrane as it exists in nature, its complexity has inspired several even-more-simplified models,<ref>{{cite book | author = Hoppensteadt FC | year = 1986 | title = An introduction to the mathematics of neurons | publisher = Cambridge University Press | location = Cambridge | isbn = 0-521-31574-3}}<br />* {{cite journal | author = FitzHugh R | year = 1960 | title = Thresholds and plateaus in the Hodgkin-Huxley nerve equations | journal = J. Gen. Physiol. | volume = 43 | pages = 867–896 | doi = 10.1085/jgp.43.5.867 | pmid = 13823315 | pmc = 2195039 | issue = 5}}<br />* {{cite journal | author = Kepler TB, Abbott LF, Marder E | year = 1992 | title = Reduction of conductance-based neuron models | journal = Biological Cybernetics | volume = 66 | pages = 381–387 | doi = 10.1007/BF00197717 | pmid = 1562643 | issue = 5}}</ref> such as the Morris–Lecar model<ref name="morris_1981">{{cite journal | author = Morris C, Lecar H | year = 1981 | title = Voltage oscillations in the barnacle giant muscle fiber | journal = Biophysical Journal | volume = 35 | pages = 193–213 | doi = 10.1016/S0006-3495(81)84782-0 | pmid = 7260316 | issue = 1 | pmc = 1327511|bibcode = 1981BpJ....35..193M }}</ref> and the [[FitzHugh–Nagumo model]],<ref name="fitzhugh">{{cite journal | author = FitzHugh R | year = 1961 | title = Impulses and physiological states in theoretical models of nerve membrane | journal = Biophysical Journal | volume = 1 | pages = 445–466 | doi = 10.1016/S0006-3495(61)86902-6 | pmid = 19431309 | issue = 6 | pmc = 1366333|bibcode = 1961BpJ.....1..445F }}<br />* {{cite journal | author = Nagumo J, Arimoto S, Yoshizawa S | year = 1962 | title = An active pulse transmission line simulating nerve axon | journal = Proceedings of the IRE | volume = 50 | pages = 2061–2070 | doi = 10.1109/JRPROC.1962.288235 | issue = 10}}</ref> 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,<ref name="bonhoeffer_vanderPol">{{cite journal | author = Bonhoeffer KF | year = 1948 | title = Activation of Passive Iron as a Model for the Excitation of Nerve | journal = J. Gen. Physiol. | volume = 32 | pages = 69–91 | doi = 10.1085/jgp.32.1.69 | pmid = 18885679 | issue = 1 | pmc = 2213747}}<br />* {{cite journal | author = Bonhoeffer KF | year = 1953 | title = Modelle der Nervenerregung | journal = Naturwissenschaften | volume = 40 | pages = 301–311 | doi = 10.1007/BF00632438|bibcode = 1953NW.....40..301B | issue = 11 }}<br />* {{cite journal | author = [[Balthasar van der Pol|van der Pol B]] | year = 1926 | title = On relaxation-oscillations | journal = Philosophical Magazine | volume = 2 | pages = 977–992}}<br />* {{cite journal | author = [[Balthasar van der Pol|van der Pol B]], van der Mark J | year = 1928 | title = The heartbeat considered as a relaxation oscillation, and an electrical model of the heart | journal = Philosophical Magazine | volume = 6 | pages = 763–775}}<br />* {{cite journal | author = [[Balthasar van der Pol|van der Pol B]], van der Mark J | year = 1929 | title = The heartbeat considered as a relaxation oscillation, and an electrical model of the heart | journal = Arch. Neerl. Physiol. | volume = 14 | pages = 418–443}}</ref> have been well-studied within mathematics,<ref name="math_studies">{{cite book | author = Sato S, Fukai H, Nomura T, Doi S | year = 2005 | chapter = Bifurcation Analysis of the Hodgkin-Huxley Equations | title = Modeling in the Neurosciences: From Biological Systems to Neuromimetic Robotics | edition = 2nd | editor = Reeke GN, Poznanski RR, Lindsay KA, Rosenberg JR, Sporns O| publisher = CRC Press | location = Boca Raton | isbn = 978-0-415-32868-5 | pages = 459–478}}<br />* {{cite journal | author = Evans JW | year = 1972 | title = Nerve axon equations. I. Linear approximations | journal = Indiana U. Math. Journal | volume = 21 | pages = 877–885 | doi = 10.1512/iumj.1972.21.21071 | issue = 9}}<br />* {{cite journal | author = Evans JW, Feroe J | year = 1977 | title = Local stability theory of the nerve impulse | journal = Math. Biosci. | volume = 37 | pages = 23–50 | doi = 10.1016/0025-5564(77)90076-1}}<br />* {{cite book | author = FitzHugh R | year = 1969 | chapter = Mathematical models of axcitation and propagation in nerve | title = Biological Engineering | editor = HP Schwann | publisher = McGraw-Hill | location = New York | pages = 1–85}}<br />* {{cite book | author = [[John Guckenheimer|Guckenheimer J]], [[Philip Holmes|Holmes P]] | year = 1986 | title = Nonlinear Oscillations, Dynamical Systems and Bifurcations of Vector Fields | edition = 2nd printing, revised and corrected | publisher = Springer Verlag | location = New York | isbn = 0-387-90819-6| pages = 12–16}}</ref> computation<ref name="computational_studies">{{cite book | author = Nelson ME, Rinzel J| year= 1994|chapter= The Hodgkin-Huxley Model|title=The Book of GENESIS: Exploring Realistic Neural Models with the GEneral NEural SImulation System| editor= Bower J, Beeman D | publisher = Springer Verlag | location = New York|pages= 29–49 | chapterurl=http://www.genesis-sim.org/GENESIS/iBoG/iBoGpdf/chapt4.pdf}}<br />* {{cite book | author = Rinzel J, Ermentrout GB | year = 1989 | chapter = Analysis of Neural Excitability and Oscillations | title = Methods in Neuronal Modeling: From Synapses to Networks | editor = [[Christof Koch|C. Koch]], I Segev | publisher = Bradford Book, The MIT Press | location = Cambridge, MA | isbn = 0-262-11133-0 | pages = 135–169}}</ref> and electronics.<ref name="keener_1983">{{cite journal | author = Keener JP | year = 1983 | title = Analogue circuitry for the van der Pol and FitzHugh-Nagumo equations | journal = IEEE Trans. on Systems, Man and Cybernetics | volume = 13 | issue = 5 | pages = 1010–1014 | doi = 10.1109/TSMC.1983.6313098 }}</ref> 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]]<ref>{{cite book | author = [[Warren Sturgis McCulloch|McCulloch WS]] | year = 1988 | title = Embodiments of Mind | publisher = The MIT Press | location = Cambridge MA | isbn = 0-262-63114-8 | pages = 19–39, 46–66, 72–141}}<br />* {{cite book | title = Neurocomputing:Foundations of Research | editors = JA Anderson, E Rosenfeld | publisher = The MIT Press | location = Cambridge, MA | isbn = 0-262-01097-6 | pages = 15–41 | author = edited by James A. Anderson and Edward Rosenfeld. | year = 1988}}</ref> and simple [[reflex]]es, such as [[escape reflex]]es and others controlled by [[central pattern generator]]s.<ref name="cpg">{{cite book | author = Getting PA | year = 1989 | chapter = Reconstruction of Small Neural Networks | title = Methods in Neuronal Modeling: From Synapses to Networks | editor = [[Christof Koch|C Koch]] and I Segev | publisher = Bradford Book, The MIT Press | location = Cambridge, MA | isbn = 0-262-11133-0 | pages = 171–194}}</ref><ref name="pmid10713861">{{cite journal | author = Hooper SL | title = Central pattern generators | journal = Curr. Biol. | volume = 10 | issue = 5 | pages = R176 |date=March 2000 | pmid = 10713861 | doi = 10.1016/S0960-9822(00)00367-5 | id = {{citeseerx|10.1.1.133.3378}} | issn = }}</ref>
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| {{Clear}}
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| ==See also==
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| {{Portal|Neuroscience}}
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| * [[Anode break excitation]]
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| * [[Bursting]]
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| * [[Central pattern generator]]
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| * [[Chronaxie]]
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| * [[Neural accommodation]]
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| * [[Single-unit recording]]
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| ==Notes==
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| <references group=note/>
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| ==References==
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| {{Reflist|2}}
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| ==Bibliography==
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| * {{cite book | author = Bear MF, Connors BW, Paradiso MA | year = 2001 | title = Neuroscience: Exploring the Brain | publisher = Lippincott | location = Baltimore | isbn = 0-7817-3944-6}}
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| * {{cite book | author = [[Theodore Holmes Bullock|Bullock TH]], Orkand R, Grinnell A | year = 1977 | title = Introduction to Nervous Systems | publisher = W. H. Freeman | location = New York | isbn = 0-7167-0030-1}}
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| * {{cite journal|author=Clay JR|title= Axonal excitability revisited|journal=Prog Biophys Mol Biol|date=May 2005|volume=88|issue=1|pages=59–90|pmid=15561301|doi=10.1016/j.pbiomolbio.2003.12.004}}
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| * {{cite book | author = Deutsch S, [[Evangelia Micheli-Tzanakou|Micheli-Tzanakou E]] | year = 1987 | title = Neuroelectric Systems | publisher = New York University Press | location = New York | isbn = 0-8147-1782-9}}
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| * {{cite book | author = [[Bertil Hille|Hille B]] | year = 2001 | title = Ion Channels of Excitable Membranes | edition = 3rd | publisher = Sinauer Associates | location = Sunderland, MA | isbn = 978-0-87893-321-1}}
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| * {{cite book | author = Hoppensteadt FC | year = 1986 | title = An Introduction to the Mathematics of Neurons | publisher = Cambridge University Press | location = Cambridge | isbn = 0-521-31574-3}}
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| * {{cite book | author = Johnston D, Wu SM-S | year = 1995 | title = Foundations of Cellular Neurophysiology | publisher = Bradford Book, The MIT Press | location = Cambridge, MA | isbn = 0-262-10053-3}}
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| * {{cite book | author = Junge D | year = 1981 | title = Nerve and Muscle Excitation | edition = 2nd | publisher = Sinauer Associates | location = Sunderland MA | isbn = 0-87893-410-3}}
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| * {{cite book | author = [[Eric R. Kandel|Kandel ER]], Schwartz JH, Jessell TM | year = 2000 | title = [[Principles of Neural Science]] | edition = 4th | publisher = McGraw-Hill | location = New York | isbn = 0-8385-7701-6}}
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| * {{cite book | author = [[Richard Keynes|Keynes RD]], Aidley DJ | year = 1991 | title = Nerve and Muscle | edition = 2nd | publisher = Cambridge University Press | location = Cambridge | isbn = 0-521-41042-8}}
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| * {{cite book | author = Miller C | year = 1987 | chapter = How ion channel proteins work | title = Neuromodulation: The Biochemical Control of Neuronal Excitability | editor = LK Kaczmarek, IB Levitan | publisher = Oxford University Press | location = New York | isbn = 978-0-19-504097-5 | pages = 39–63}}
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| * {{cite book | author = Nelson DL, Cox MM | year = 2008 | title = Lehninger Principles of Biochemistry | edition = 5th | publisher = W. H. Freeman | location = New York | isbn= 978-0-7167-7108-1}}
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| * {{cite book | author = Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A-S, McNamara JO, Williams SM | title = Neuroscience | edition= 2nd | year = 2001| publisher = Sinauer Associates | location = Sunderland, MA |chapter= Release of Transmitters from Synaptic Vesicles | isbn = 0-87893-725-0 | chapterurl=http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=neurosci.section.326}}
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| * {{cite book | author = Purves D, Augustine GJ, Fitzpatrick D, Hall WC, Lamantia A-S, McNamara JO, White LE | title = Neuroscience | edition= 4th | year = 2008 | publisher = Sinauer Associates | location = Sunderland, MA | isbn = 978-0-87893-697-7}}
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| * {{cite book | author = [[Knut Schmidt-Nielsen|Schmidt-Nielsen K]] | year = 1997 | title = Animal Physiology: Adaptation and Environment | edition = 5th | publisher = Cambridge University Press | location = Cambridge | isbn = 978-0-521-57098-5}}
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| * {{cite book | author = Stevens CF | year = 1966 | title = Neurophysiology: A Primer | publisher = John Wiley and Sons | location = New York | lccn = 6615872 }}
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| ==External links==
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| {{Spoken Wikipedia|Action_potential.ogg|2005-06-22}}
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| ;Animations
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| * [http://www.blackwellpublishing.com/matthews/channel.html Ionic flow in action potentials] at [[Blackwell Publishing]]
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| * [http://www.blackwellpublishing.com/matthews/actionp.html Action potential propagation in myelinated and unmyelinated axons] at [[Blackwell Publishing]]
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| * [http://thevirtualheart.org/CAPindex.html Generation of AP in cardiac cells] and [http://thevirtualheart.org/java/neuron/apneuron.html generation of AP in neuron cells]
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| * [http://bcs.whfreeman.com/thelifewire/content/chp44/4402001.html Resting membrane potential] from ''Life: The Science of Biology'', by WK Purves, D Sadava, GH Orians, and HC Heller, 8th edition, New York: WH Freeman, ISBN 978-0-7167-7671-0.
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| * [http://www.nernstgoldman.physiology.arizona.edu/ Ionic motion and the Goldman voltage for arbitrary ionic concentrations] at The [[University of Arizona]]
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| * [http://www.brainu.org/files/movies/action_potential_cartoon.swf A cartoon illustrating the action potential]
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| * [http://www.1lecture.com/Biochemistry/Action%20Potential/index.html Action potential propagation]
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| * [http://people.virginia.edu/~hvg2s/ Production of the action potential: voltage and current clamping simulations]
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| * [http://cese.sourceforge.net/ Open-source software to simulate neuronal and cardiac action potentials] at [[SourceForge.net]]
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| * [http://nba.uth.tmc.edu/neuroscience/s1/chapter01.html Introduction to the Action Potential], ''Neuroscience Online'' (electronic neuroscience textbook by UT Houston Medical School)
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| {{Use dmy dates|date=May 2011}}
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| {{DEFAULTSORT:Action Potential}}
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| [[Category:Neural coding]]
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| [[Category:Electrophysiology]]
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| [[Category:Electrochemistry]]
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| [[Category:Computational neuroscience]]
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| [[Category:Cellular neuroscience]]
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| [[Category:Cellular processes]]
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| [[Category:Membrane biology]]
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| [[Category:Nervous system]]
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| {{Link FA|es}}
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| {{Link FA|eu}}
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