Editing Action potential (section)

==Phases==
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 becomes more negative, returning towards resting potential. The undershoot, or [[afterhyperpolarization]], phase is the period during which the membrane potential temporarily becomes more negatively charged than when at rest (hyperpolarized). 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.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=38}}

The course of the action potential is determined by two coupled effects.{{sfn|Stevens|1966|pp=127–128}} 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.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|pp=61–65}} Second, according to the [[Goldman equation]], this change in permeability changes the equilibrium potential ''E<sub>m</sub>'', and, thus, the membrane voltage ''V<sub>m</sub>''.<ref name="goldman_1943" group=lower-alpha /> 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.{{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}} 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.{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=64–74|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2pp=149–150|3a1=Junge|3y=1981|3pp=84–85|4a1=Stevens|4y=1966|4pp=152–158}}<ref name="hodgkin_1952" group=lower-alpha /> 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.{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1p=47|2a1=Purves|2a2=Augustine|2a3=Fitzpatrick|2a4=Hall|2y=2008|2p=65|3a1=Bullock|3a2=Orkand|3a3=Grinnell|3y=1977|3pp=147–148|4a1=Stevens|4y=1966|4p=128}} Hence, when ''V<sub>m</sub>'' is raised suddenly, the sodium channels open initially, but then close due to the slower inactivation.

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" group=lower-alpha /> for which they were awarded the [[Nobel Prize in Physiology or Medicine]] in 1963.<ref name="Nobel_1963" group=lower-Greek>{{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 | access-date = 2010-02-21 | url-status = live | archive-url = https://web.archive.org/web/20070716195411/http://nobelprize.org/nobel_prizes/medicine/laureates/1963/index.html | archive-date = 16 July 2007 | df = dmy-all }}</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">Goldin, AL in {{harvnb|Waxman|2007|loc=''Neuronal Channels and Receptors'', pp. 43–58.}}</ref> and they do not always open and close independently.<ref group=lower-alpha>{{cite journal | vauthors = Naundorf B, Wolf F, Volgushev M | title = Unique features of action potential initiation in cortical neurons | journal = Nature | volume = 440 | issue = 7087 | pages = 1060–3 | date = April 2006 | pmid = 16625198 | doi = 10.1038/nature04610 | url = http://www.volgushev.uconn.edu/DownLoads/Naundorf_Nature2006v440p1060_Suppl_3_CoopModel.pdf | df = dmy-all | bibcode = 2006Natur.440.1060N | s2cid = 1328840 | access-date = 24 September 2019 | archive-date = 20 December 2018 | archive-url = https://web.archive.org/web/20181220232812/http://volgushev.uconn.edu/DownLoads/Naundorf_Nature2006v440p1060_Suppl_3_CoopModel.pdf | url-status = dead }}</ref>

===Stimulation and rising phase===
A typical action potential begins at the [[axon hillock]]{{sfn|Stevens|1966|p=49}} 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.{{cn|date=May 2024}}

For a neuron at rest, there is a high concentration of sodium and chloride 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. The difference in concentrations, which causes ions to move [[Second law of thermodynamics|from a high to a low concentration]], and electrostatic effects (attraction of opposite charges) are responsible for the movement of ions in and out of the neuron. The inside of a neuron has a negative charge, relative to the cell exterior, from the movement of K<sup>+</sup> out of the cell. The neuron membrane is more permeable to K<sup>+</sup> than to other ions, allowing this ion to selectively move out of the cell, down its concentration gradient. 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>&nbsp;≈&nbsp;−75&nbsp;mV.{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1p=34|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2p=134|3a1=Schmidt-Nielsen|3y=1997|3pp=478–480}} Since Na<sup>+</sup> ions are in higher concentrations outside of the cell, the concentration and voltage differences both drive them into the cell when Na<sup>+</sup> channels open. 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&nbsp;mV to −60&nbsp;mV), the outward potassium current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around −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 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.{{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}} 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&nbsp;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>.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150–151}}{{sfn|Junge|1981|pp=89–90}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=49–50|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2pp=140–141|3a1=Schmidt-Nielsen|3y=1997|3pp=480–481}}{{sfn|Schmidt-Nielsen|1997|pp=483–484}} The sharp rise in ''V<sub>m</sub>'' and sodium permeability correspond to the ''rising phase'' of the action potential.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150–151}}{{sfn|Junge|1981|pp=89–90}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=49–50|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2pp=140–141|3a1=Schmidt-Nielsen|3y=1997|3pp=480–481}}{{sfn|Schmidt-Nielsen|1997|pp=483–484}}

The critical threshold voltage for this runaway condition is usually around −45&nbsp;mV, but it depends on the recent activity of the axon. A cell that has just fired an action potential cannot fire another one immediately, since the Na<sup>+</sup> channels have not recovered from the inactivated state. The period during which no new action potential can be fired is called the ''absolute refractory period''.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=49}}{{sfn|Stevens|1966|pp=19–20}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1p=151|2a1=Junge|2y=1981|2pp=4–5}} 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&nbsp;mV. The period during which action potentials are unusually difficult to evoke is called the ''relative refractory period''.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=49}}{{sfn|Stevens|1966|pp=19–20}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1p=151|2a1=Junge|2y=1981|2pp=4–5}}

===Peak phase===
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''.{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1p=47|2a1=Purves|2a2=Augustine|2a3=Fitzpatrick|2a4=Hall|2y=2008|2p=65|3a1=Bullock|3a2=Orkand|3a3=Grinnell|3y=1977|3pp=147–148|4a1=Stevens|4y=1966|4p=128}} 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>.{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1p=47|2a1=Purves|2a2=Augustine|2a3=Fitzpatrick|2a4=Hall|2y=2008|2p=65|3a1=Bullock|3a2=Orkand|3a3=Grinnell|3y=1977|3pp=147–148|4a1=Stevens|4y=1966|4p=128}} 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.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=49}}{{sfn|Bullock|Orkand|Grinnell|1977|p=152}}{{sfn|Schmidt-Nielsen|1997|pp=483–484}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1pp=147–149|2a1=Stevens|2y=1966|2pp=126–127}}

===<!--"Afterhyperpolarization" is a single word; please do not divide it into two words!-->Afterhyperpolarization===
The depolarized voltage opens additional voltage-dependent potassium channels, 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 intracellular concentration of potassium ions is transiently unusually low, making the membrane voltage ''V<sub>m</sub>'' even closer to the potassium equilibrium voltage ''E''<sub>K</sub>. The membrane potential goes below the resting membrane potential. Hence, there is an undershoot or [[hyperpolarization (biology)|hyperpolarization]], termed an [[afterhyperpolarization]], that persists until the membrane potassium permeability returns to its usual value, restoring the membrane potential to the resting state.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=37}}{{sfn|Bullock|Orkand|Grinnell|1977|p=152}}

===Refractory period===
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.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=49}}{{sfn|Stevens|1966|pp=19–20}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1p=151|2a1=Junge|2y=1981|2pp=4–5}} 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.{{cn|date=May 2024}}

The absolute refractory period is largely responsible for the unidirectional propagation of action potentials along axons.{{sfn|Purves|Augustine|Fitzpatrick|Hall|2008|p=56}} 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.