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===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> β β75 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=478β480}} 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 β70 mV to β60 mV), the outward potassium current overwhelms the inward sodium current and the membrane repolarizes back to its normal resting potential around β70 mV.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150β151}}{{sfn|Junge|1981|pp=89β90}}{{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=150β151}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=48β49|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>β +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>.{{sfn|Bullock|Orkand|Grinnell|1977|pp=150β151}}{{sfn|Junge|1981|pp=89β90}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=49β50|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2pp=140β141|3a1=Schmidt-Nielsen|3y=1997|3pp=480β481}}{{sfn|Schmidt-Nielsen|1997|pp=483β484}} 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=150β151}}{{sfn|Junge|1981|pp=89β90}}{{sfnm|1a1=Purves|1a2=Augustine|1a3=Fitzpatrick|1a4=Hall|1y=2008|1pp=49β50|2a1=Bullock|2a2=Orkand|2a3=Grinnell|2y=1977|2pp=140β141|3a1=Schmidt-Nielsen|3y=1997|3pp=480β481}}{{sfn|Schmidt-Nielsen|1997|pp=483β484}} The critical threshold voltage for this runaway condition is usually around β45 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=19β20}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1p=151|2a1=Junge|2y=1981|2pp=4β5}} 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 β30 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=19β20}}{{sfnm|1a1=Bullock|1a2=Orkand|1a3=Grinnell|1y=1977|1p=151|2a1=Junge|2y=1981|2pp=4β5}}
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