Editing Action potential (section)

==Biophysical basis==
{{more citations needed section|date=February 2014}}

Action potentials result from the presence in a cell's membrane of special types of [[voltage-gated ion channel]]s.<ref>{{cite book |veditors=Purves D, Augustine GJ, Fitzpatrick D, et al |title=Neuroscience |edition=2nd |place=Sunderland, MA |publisher=Sinauer Associates |date=2001 |chapter=Voltage-Gated Ion Channels |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK10883/ |access-date=2017-08-29 |url-status=live |archive-url=https://web.archive.org/web/20180605025823/https://www.ncbi.nlm.nih.gov/books/NBK10883/ |archive-date=5 June 2018 |df=dmy-all }}</ref> A voltage-gated ion channel is a transmembrane protein that has three key properties:
# It is capable of assuming more than one conformation.
# At least one of the conformations creates a channel through the membrane that is permeable to specific types of ions.
# The transition between conformations is influenced by the membrane potential.

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.

[[File:Blausen 0011 ActionPotential Nerve.png|thumb|300px|left|Action potential propagation along an axon]]
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, and 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 [[Hodgkin cycle|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 capable of producing the positive feedback necessary to generate an action potential do 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.

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.

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.

[[File:Membrane Permeability of a Neuron During an Action Potential.svg|thumb|upright=1.75|right|Ion movement during an action potential.<br />''Key:'' a) Sodium (Na<sup>+</sup>) ion. b) Potassium (K<sup>+</sup>) ion. c) Sodium channel. d) Potassium channel. e) Sodium-potassium pump.<br /> In the stages of an action potential, the permeability of the membrane of the neuron changes. At the '''resting state''' (1), sodium and potassium ions have limited ability to pass through the membrane, and the neuron has a net negative charge inside. Once the action potential is triggered, the '''depolarization''' (2) of the neuron activates sodium channels, allowing sodium ions to pass through the cell membrane into the cell, resulting in a net positive charge in the neuron relative to the extracellular fluid. After the action potential peak is reached, the neuron begins '''repolarization''' (3), where the sodium channels close and potassium channels open, allowing potassium ions to cross the membrane into the extracellular fluid, returning the membrane potential to a negative value. Finally, there is a '''refractory period''' (4), during which the voltage-dependent ion channels are [[Voltage-gated ion channel#Mechanism|inactivated]] while the Na<sup>+</sup> and K<sup>+</sup> ions return to their resting state distributions across the membrane (1), and the neuron is ready to repeat the process for the next action potential.]]

{{Anchor|Firing rate|Neural firing rate}}<!-- This anchor is for the bolded terms at the end of this paragraph; if that sentence is moved, this anchor should be moved along with that sentence to the same location in this article.
-->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&nbsp;mV.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150–151}}{{sfn|Junge|1981|pp=89–90}}{{sfn|Schmidt-Nielsen|1997|p=484}} However, if the voltage increases past a critical threshold, typically 15&nbsp;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.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150–151}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=48–49|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2p=141|3a1=Schmidt-Nielsen|3y=1997|3p=483|4a1=Junge|4y=1981|4p=89}}{{sfn|Stevens|1966|p=127}}{{refn|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.<ref group=lower-Greek>{{cite journal|title=FitzHugh-Nagumo model|journal=Scholarpedia|volume=1|issue=9|pages=1349|df=dmy-all|doi=10.4249/scholarpedia.1349|year=2006|last1=Fitzhugh|first1=Richard|last2=Izhikevich|first2=Eugene | name-list-style = vanc |bibcode=2006SchpJ...1.1349I|doi-access=free}}</ref>|group="note"}} The frequency at which a neuron elicits action potentials is often referred to as a '''firing rate''' or '''neural firing rate'''.<!--"Neural firing rate" redirects here; these terms are bolded per MOS:BOLD.-->

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, [[subthreshold membrane potential oscillations]], 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.

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 [[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.

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" group=lower-alpha>{{cite journal | vauthors = Golding NL, Kath WL, Spruston N | title = Dichotomy of action-potential backpropagation in CA1 pyramidal neuron dendrites | journal = Journal of Neurophysiology | volume = 86 | issue = 6 | pages = 2998–3010 | date = December 2001 | pmid = 11731556 | doi = 10.1152/jn.2001.86.6.2998 | s2cid = 2915815 | df = dmy-all }}</ref> These are thought to have a role in [[spike-timing-dependent plasticity]].

In the [[Hodgkin–Huxley model|Hodgkin–Huxley membrane capacitance model]], the speed of transmission of an action potential was undefined and it was assumed that adjacent areas became depolarized due to released ion interference with neighbouring channels. Measurements of ion diffusion and radii have since shown this not to be possible.{{citation needed|date=November 2019}} Moreover, contradictory measurements of entropy changes and timing disputed the capacitance model as acting alone.{{citation needed|date=November 2019}} Alternatively, Gilbert Ling's adsorption hypothesis, posits that the membrane potential and action potential of a living cell is due to the adsorption of mobile ions onto adsorption sites of cells.<ref>{{cite journal | vauthors = Tamagawa H, Funatani M, Ikeda K | title = Ling's Adsorption Theory as a Mechanism of Membrane Potential Generation Observed in Both Living and Nonliving Systems | journal = Membranes | volume = 6 | issue = 1 | pages = 11 | date = January 2016 | pmid = 26821050 | pmc = 4812417 | doi = 10.3390/membranes6010011 | doi-access = free }}</ref>

=== Maturation of the electrical properties of the action potential ===
A [[neuron]]'s ability to generate and propagate an action potential changes during [[Neural development|development]]. How much the [[membrane potential]] of a neuron changes as the result of a current impulse is a function of the membrane [[Input impedance|input resistance]]. As a cell grows, more [[Ion channel|channels]] are added to the membrane, causing a decrease in input resistance. A mature neuron also undergoes shorter changes in membrane potential in response to synaptic currents. Neurons from a ferret [[lateral geniculate nucleus]] have a longer [[time constant]] and larger [[voltage]] deflection at P0 than they do at P30.<ref name=":0">{{Cite book|title=Development of the nervous system|last1=Sanes|first1=Dan H.|last2=Reh|first2=Thomas A | name-list-style = vanc |date=2012-01-01|publisher=Elsevier Academic Press|isbn=9780080923208|pages=211–214|oclc=762720374|edition=Third}}</ref> One consequence of the decreasing action potential duration is that the fidelity of the signal can be preserved in response to high frequency stimulation. Immature neurons are more prone to synaptic depression than potentiation after high frequency stimulation.<ref name=":0" />

In the early development of many organisms, the action potential is actually initially carried by [[Calcium channel|calcium current]] rather than [[Sodium channel|sodium current]]. The [[Gating (electrophysiology)|opening and closing kinetics]] of calcium channels during development are slower than those of the voltage-gated sodium channels that will carry the action potential in the mature neurons. The longer opening times for the calcium channels can lead to action potentials that are considerably slower than those of mature neurons.<ref name=":0" /> [[Xenopus]] neurons initially have action potentials that take 60–90 ms. During development, this time decreases to 1 ms. There are two reasons for this drastic decrease. First, the [[Depolarization|inward current]] becomes primarily carried by sodium channels.<ref>{{Cite book|title=Calcium Channels: Their Properties, Functions, Regulation, and Clinical relevance|last=Partridge|first=Donald | name-list-style = vanc |publisher=CRC Press|year=1991|isbn=9780849388071|pages=138–142}}</ref> Second, the [[Voltage-gated potassium channel|delayed rectifier]], a [[potassium channel]] current, increases to 3.5 times its initial strength.<ref name=":0" />

In order for the transition from a calcium-dependent action potential to a sodium-dependent action potential to proceed new channels must be added to the membrane. If Xenopus neurons are grown in an environment with [[Transcription (biology)|RNA synthesis]] or [[Translation (biology)|protein synthesis]] inhibitors that transition is prevented.<ref>{{Cite book|url=https://www.springer.com/us/book/9780306415500|title=Cellular and Molecular Biology of Neuronal Development {{!}} Ira Black {{!}} Springer|last=Black|first=Ira | name-list-style = vanc |publisher=Springer|year=1984|isbn=978-1-4613-2717-2|pages=103|language=en|url-status=live|archive-url=https://web.archive.org/web/20170717154858/http://www.springer.com/us/book/9780306415500|archive-date=17 July 2017|df=dmy-all}}</ref> Even the electrical activity of the cell itself may play a role in channel expression. If action potentials in Xenopus [[myocyte]]s are blocked, the typical increase in sodium and potassium current density is prevented or delayed.<ref>{{Cite book|title=Current Topics in Developmental Biology, Volume 39|last=Pedersen|first=Roger | name-list-style = vanc |publisher=Elsevier Academic Press|year=1998|isbn=9780080584621|url=https://archive.org/details/currenttopicsind0000unse_x6e1}}</ref>

This maturation of electrical properties is seen across species. Xenopus sodium and potassium currents increase drastically after a neuron goes through its final phase of [[mitosis]]. The sodium current density of rat [[Cerebral cortex|cortical neurons]] increases by 600% within the first two postnatal weeks.<ref name=":0" />