Editing Sodium–potassium pump (section)

== Function ==
The {{chem2|Na+/K+}}-ATPase helps maintain [[resting potential]], affects transport, and regulates cellular [[volume]].<ref name=guyton>{{cite book | vauthors = Hall JE, Guyton AC |title=Textbook of medical physiology |publisher=Elsevier Saunders |location=St. Louis, Mo |year=2006 |isbn=978-0-7216-0240-0 }}</ref> It also functions as a signal transducer/integrator to regulate the [[MAPK/ERK pathway|MAPK pathway]], [[reactive oxygen species]] (ROS), as well as intracellular calcium. In fact, all cells expend a large fraction of the ATP they produce (typically 30% and up to 70% in
nerve cells) to maintain their required cytosolic Na and K
concentrations.<ref>{{cite book | vauthors = Voet D, Voet JG | chapter = Section 20-3: ATP-Driven Active Transport |title=Biochemistry | date = December 2010 |publisher=John Wiley & Sons |isbn=978-0-470-57095-1 |page=759 |edition=4th}}</ref>
For neurons, the {{chem2|Na+/K+}}-ATPase can be responsible for up to 3/4 of the cell's energy expenditure.<ref name=Howarth2012>{{cite journal | vauthors = Howarth C, Gleeson P, Attwell D | title = Updated energy budgets for neural computation in the neocortex and cerebellum | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 32 | issue = 7 | pages = 1222–32 | date = July 2012 | pmid = 22434069 | pmc = 3390818 | doi = 10.1038/jcbfm.2012.35 }}</ref> In many types of tissue, ATP consumption by the {{chem2|Na+/K+}}-ATPases have been related to [[glycolysis]]. This was first discovered in red blood cells (Schrier, 1966), but has later been evidenced in renal cells,<ref>{{cite journal | vauthors = Sanders MJ, Simon LM, Misfeldt DS | title = Transepithelial transport in cell culture: bioenergetics of Na-, D-glucose-coupled transport | journal = Journal of Cellular Physiology | volume = 114 | issue = 3 | pages = 263–6 | date = March 1983 | pmid = 6833401 | doi = 10.1002/jcp.1041140303 | s2cid = 22543559 }}</ref> smooth muscles surrounding the blood vessels,<ref>{{cite journal | vauthors = Lynch RM, Paul RJ | title = Compartmentation of carbohydrate metabolism in vascular smooth muscle | journal = The American Journal of Physiology | volume = 252 | issue = 3 Pt 1 | pages = C328-34 | date = March 1987 | pmid = 3030131 | doi = 10.1152/ajpcell.1987.252.3.c328 }}</ref> and [[cardiac Purkinje cell]]s.<ref>{{cite journal | vauthors = Glitsch HG, Tappe A | title = The Na<sup>+</sup>/K<sup>+</sup> pump of cardiac Purkinje cells is preferentially fuelled by glycolytic ATP production | journal = Pflügers Archiv | volume = 422 | issue = 4 | pages = 380–5 | date = January 1993 | pmid = 8382364 | doi = 10.1007/bf00374294 | s2cid = 25076348 }}</ref> Recently, glycolysis has also been shown to be of particular importance for {{chem2|Na+/K+}}-ATPase in skeletal muscles, where inhibition of [[glycogen]] breakdown (a substrate for [[glycolysis]]) leads to reduced {{chem2|Na+/K+}}-ATPase activity and lower force production.<ref>{{cite journal | vauthors = Dutka TL, Lamb GD | title = Na<sup>+</sup>-K<sup>+</sup> pumps in the transverse tubular system of skeletal muscle fibers preferentially use ATP from glycolysis | journal = American Journal of Physiology. Cell Physiology | volume = 293 | issue = 3 | pages = C967-77 | date = September 2007 | pmid = 17553934 | doi = 10.1152/ajpcell.00132.2007 | s2cid = 2291836 }}</ref><ref>{{cite journal | vauthors = Watanabe D, Wada M | s2cid = 195329741 | title = Effects of reduced muscle glycogen on excitation-contraction coupling in rat fast-twitch muscle: a glycogen removal study | journal = Journal of Muscle Research and Cell Motility | volume = 40 | issue = 3–4 | pages = 353–364 | date = December 2019 | pmid = 31236763 | doi = 10.1007/s10974-019-09524-y }}</ref><ref>{{cite journal | vauthors = Jensen R, Nielsen J, Ørtenblad N | title = Inhibition of glycogenolysis prolongs action potential repriming period and impairs muscle function in rat skeletal muscle | journal = The Journal of Physiology | volume = 598 | issue = 4 | pages = 789–803 | date = February 2020 | pmid = 31823376 | doi = 10.1113/JP278543 | s2cid = 209317559 | doi-access = free }}</ref>

=== Resting potential ===
[[File:Sodium-potassium pump and diffusion.png|thumb|250px|The {{chem2|Na+/K+}}-ATPase, as well as effects of diffusion of the involved ions maintain the [[resting potential]] across the membranes.]]
{{See also|Resting potential}}
In order to maintain the cell membrane potential, cells keep a low concentration of sodium ions and high levels of potassium ions within the cell ([[intracellular]]). The sodium–potassium pump mechanism moves 3 sodium ions out and moves 2 potassium ions in, thus, in total, removing one positive charge carrier from the [[intracellular space]] (see {{slink||Mechanism}} for details). In addition, there is a short-circuit channel (i.e. a highly K-permeable ion channel) for potassium in the membrane, thus the voltage across the plasma membrane is close to the [[Nernst potential]] of potassium.

=== Reversal potential ===
Even if both {{chem2|K+}} and {{chem2|Na+}} ions have the same charge, they can still have very different equilibrium potentials for both outside and/or inside concentrations. The sodium-potassium pump moves toward a nonequilibrium state with the relative concentrations of {{chem2|Na+}} and {{chem2|K+}} for both inside and outside of cell. For instance, the concentration of {{chem2|K+}} in cytosol is 100 [[Molar concentration|mM]], whereas the concentration of {{chem2|Na+}} is 10 mM. On the other hand, in extracellular space, the usual concentration range of {{chem2|K+}} is about 3.5-5 mM, whereas the concentration of {{chem2|Na+}} is about 135-145 mM.{{citation needed|date=October 2023}}

=== Transport ===
Export of sodium ions from the cell provides the driving force for several secondary active transporters such as [[membrane transport protein]]s, which import [[glucose]], [[amino acid]]s and other nutrients into the cell by use of the sodium ion gradient.

Another important task of the {{chem2|Na+}}-{{chem2|K+}} pump is to provide a {{chem2|Na+}} gradient that is used by certain carrier processes. In the [[Gut (zoology)|gut]], for example, sodium is transported out of the reabsorbing cell on the blood ([[interstitial fluid]]) side via the {{chem2|Na+}}-{{chem2|K+}} pump, whereas, on the reabsorbing (lumenal) side, the {{chem2|Na+}}-glucose [[symporter]] uses the created {{chem2|Na+}} gradient as a source of energy to import both {{chem2|Na+}} and glucose, which is far more efficient than simple diffusion. Similar processes are located in the [[renal tubular system]].

=== Controlling cell volume ===

Failure of the {{chem2|Na+}}-{{chem2|K+}} pumps can result in swelling of the cell. A cell's [[osmolarity]] is the sum of the concentrations of the various [[ion]] species and many [[proteins]] and other organic compounds inside the cell. When this is higher than the [[osmolarity]] outside of the cell, water flows into the cell through [[osmosis]]. This can cause the cell to swell up and [[lysis|lyse]]. The {{chem2|Na+}}-{{chem2|K+}} pump helps to maintain the right concentrations of ions.
Furthermore, when the cell begins to swell, this automatically activates the {{chem2|Na+}}-{{chem2|K+}} pump because it changes the internal concentrations of {{chem2|Na+}}-{{chem2|K+}} to which the pump is sensitive.<ref>{{cite journal | vauthors = Armstrong CM | title = The Na/K pump, Cl ion, and osmotic stabilization of cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 10 | pages = 6257–62 | date = May 2003 | pmid = 12730376 | pmc = 156359 | doi = 10.1073/pnas.0931278100 | bibcode = 2003PNAS..100.6257A | doi-access = free }}</ref>

=== Functioning as signal transducer ===
Within the last decade{{when|date=February 2018}}, many independent labs have demonstrated that, in addition to the classical ion transporting, this membrane protein can also relay extracellular [[ouabain]]-binding signalling into the cell through regulation of [[protein tyrosine phosphorylation]]. For instance, a study investigated the function of {{chem2|Na+/K+}}-ATPase in foot muscle and hepatopancreas in land snail ''Otala lactea'' by comparing the active and estivating states.<ref name= Ramnanan >{{cite journal |vauthors=Ramnanan CJ, Storey KB |date=February 2006 |title=Suppression of Na<sup>+</sup>/K<sup>+</sup>-ATPase activity during estivation in the land snail ''Otala lactea'' |journal=The Journal of Experimental Biology |volume=209 |issue=Pt 4 |pages=677–88 |doi=10.1242/jeb.02052 |pmid=16449562 |doi-access=free |s2cid=39271006}}</ref> They concluded that reversible phosphorylation can control the same means of coordinating ATP use by this ion pump with the rates of the ATP generation by catabolic pathways in estivating ''O. lactea''. The downstream signals through ouabain-triggered protein phosphorylation events include activation of the [[mitogen-activated protein kinase]] (MAPK) signal cascades, mitochondrial [[reactive oxygen species]] (ROS) production, as well as activation of [[phospholipase C]] (PLC) and [[inositol triphosphate]] (IP3) receptor ([[IP3R]]) in different intracellular compartments.<ref>{{cite journal | vauthors = Yuan Z, Cai T, Tian J, Ivanov AV, Giovannucci DR, Xie Z | title = Na/K-ATPase tethers phospholipase C and IP3 receptor into a calcium-regulatory complex | journal = Molecular Biology of the Cell | volume = 16 | issue = 9 | pages = 4034–45 | date = September 2005 | pmid = 15975899 | pmc = 1196317 | doi = 10.1091/mbc.E05-04-0295 }}</ref>

Protein-protein interactions play a very important role in {{chem2|Na+}}-{{chem2|K+}} pump-mediated signal transduction. For example, the {{chem2|Na+}}-{{chem2|K+}} pump interacts directly with [[Src (gene)|Src]], a [[non-receptor tyrosine kinase]], to form a signaling receptor complex.<ref>{{cite journal | vauthors = Tian J, Cai T, Yuan Z, Wang H, Liu L, Haas M, Maksimova E, Huang XY, Xie ZJ | display-authors = 6 | title = Binding of Src to Na<sup>+</sup>/K<sup>+</sup>-ATPase forms a functional signaling complex | journal = Molecular Biology of the Cell | volume = 17 | issue = 1 | pages = 317–26 | date = January 2006 | pmid = 16267270 | pmc = 1345669 | doi = 10.1091/mbc.E05-08-0735 }}</ref> Src is initially inhibited by the {{chem2|Na+}}-{{chem2|K+}} pump. However, upon subsequent ouabain binding, the Src kinase domain is released and then activated. Based on this scenario, NaKtide, a peptide Src inhibitor derived from the {{chem2|Na+}}-{{chem2|K+}} pump, was developed as a functional ouabain–{{chem2|Na+}}-{{chem2|K+}} pump-mediated signal transduction.<ref>{{cite journal | vauthors = Li Z, Cai T, Tian J, Xie JX, Zhao X, Liu L, Shapiro JI, Xie Z | display-authors = 6 | title = NaKtide, a Na/K-ATPase-derived peptide Src inhibitor, antagonizes ouabain-activated signal transduction in cultured cells | journal = The Journal of Biological Chemistry | volume = 284 | issue = 31 | pages = 21066–76 | date = July 2009 | pmid = 19506077 | pmc = 2742871 | doi = 10.1074/jbc.M109.013821 | doi-access = free }}</ref> {{chem2|Na+}}-{{chem2|K+}} pump also interacts with [[ankyrin]], [[IP3R]], [[PI3K]], [[PLCgamma1]] and [[cofilin]].<ref>{{cite journal | vauthors = Lee K, Jung J, Kim M, Guidotti G | title = Interaction of the alpha subunit of Na,K-ATPase with cofilin | journal = The Biochemical Journal | volume = 353 | issue = Pt 2 | pages = 377–85 | date = January 2001 | pmid = 11139403 | pmc = 1221581 | doi = 10.1042/0264-6021:3530377 }}</ref>

=== Controlling neuron activity states ===
The {{chem2|Na+}}-{{chem2|K+}} pump has been shown to control and set the intrinsic activity mode of [[cerebellar]] [[Purkinje neurons]],<ref>{{cite journal | vauthors = Forrest MD, Wall MJ, Press DA, Feng J | title = The sodium-potassium pump controls the intrinsic firing of the cerebellar Purkinje neuron | journal = PLOS ONE | volume = 7 | issue = 12 | pages = e51169 | date = December 2012 | pmid = 23284664 | pmc = 3527461 | doi = 10.1371/journal.pone.0051169 | bibcode = 2012PLoSO...751169F | doi-access = free }}</ref> [[Olfactory bulb|accessory olfactory bulb]] mitral cells<ref>{{cite journal | vauthors = Zylbertal A, Kahan A, Ben-Shaul Y, Yarom Y, Wagner S | title = Prolonged Intracellular Na<sup>+</sup> Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells | journal = PLOS Biology | volume = 13 | issue = 12 | pages = e1002319 | date = December 2015 | pmid = 26674618 | pmc = 4684409 | doi = 10.1371/journal.pbio.1002319 | doi-access = free }}</ref> and probably other neuron types.<ref>{{cite journal | vauthors = Zylbertal A, Yarom Y, Wagner S | title = The Slow Dynamics of Intracellular Sodium Concentration Increase the Time Window of Neuronal Integration: A Simulation Study | language = English | journal = Frontiers in Computational Neuroscience | volume = 11 | pages = 85 | date = 2017 | pmid = 28970791 | pmc = 5609115 | doi = 10.3389/fncom.2017.00085 | doi-access = free }}</ref> This suggests that the pump might not simply be a [[homeostatic]], "housekeeping" molecule for ionic gradients, but could be a [[computation]] element in the [[cerebellum]] and the [[brain]].<ref>{{cite journal | vauthors = Forrest MD | title = The sodium-potassium pump is an information processing element in brain computation | journal = Frontiers in Physiology | volume = 5 | issue = 472 | pages = 472 | date = December 2014 | pmid = 25566080 | pmc = 4274886 | doi = 10.3389/fphys.2014.00472 | doi-access = free }}</ref> Indeed, a [[mutation]] in the {{chem2|Na+}}-{{chem2|K+}} pump causes rapid onset [[dystonia]]-[[parkinsonism]], which has symptoms to indicate that it is a pathology of cerebellar computation.<ref>{{cite journal | vauthors = Cannon SC | title = Paying the price at the pump: dystonia from mutations in a Na<sub>+</sub>/K<sub>+</sub>-ATPase | journal = Neuron | volume = 43 | issue = 2 | pages = 153–4 | date = July 2004 | pmid = 15260948 | doi = 10.1016/j.neuron.2004.07.002 | doi-access = free }}</ref> Furthermore, an [[ouabain]] block of {{chem2|Na+}}-{{chem2|K+}} pumps in the cerebellum of a live mouse results in it displaying [[ataxia]] and [[dystonia]].<ref>{{cite journal | vauthors = Calderon DP, Fremont R, Kraenzlin F, Khodakhah K | title = The neural substrates of rapid-onset Dystonia-Parkinsonism | journal = Nature Neuroscience | volume = 14 | issue = 3 | pages = 357–65 | date = March 2011 | pmid = 21297628 | pmc = 3430603 | doi = 10.1038/nn.2753 }}</ref> [[Alcohol (drug)|Alcohol]] inhibits sodium–potassium pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body coordination.<ref>{{cite journal | vauthors = Forrest MD | title = Simulation of alcohol action upon a detailed Purkinje neuron model and a simpler surrogate model that runs >400 times faster | journal = BMC Neuroscience | volume = 16 | issue = 27 | pages = 27 | date = April 2015 | pmid = 25928094 | pmc = 4417229 | doi = 10.1186/s12868-015-0162-6 | doi-access = free }}</ref><ref>{{cite web |url=http://www.science20.com/michael_forrest/the_neuroscience_reason_we_fall_over_when_drunk-155301 | title=The Neuroscience Reason We Fall Over When Drunk | vauthors = Forrest M |date=4 April 2015 |website=Science 2.0 |access-date=30 May 2018}}</ref> The distribution of the {{chem2|Na+}}-{{chem2|K+}} pump on myelinated axons in the human brain has been demonstrated to be along the internodal [[axolemma]], and not within the nodal axolemma as previously thought.<ref>{{cite journal | vauthors = Young EA, Fowler CD, Kidd GJ, Chang A, Rudick R, Fisher E, Trapp BD | title = Imaging correlates of decreased axonal Na<sup>+</sup>/K<sup>+</sup> ATPase in chronic multiple sclerosis lesions | journal = Annals of Neurology | volume = 63 | issue = 4 | pages = 428–35 | date = April 2008 | pmid = 18438950 | doi = 10.1002/ana.21381 | s2cid = 14658965 }}</ref> The {{chem2|Na+}}-{{chem2|K+}} pump disfunction has been tied to various diseases, including epilepsy and brain malformations.<ref>{{cite journal | vauthors = Smith RS, Florio M, Akula SK, Neil JE, Wang Y, Hill RS, Goldman M, Mullally CD, Reed N, Bello-Espinosa L, Flores-Sarnat L, Monteiro FP, Erasmo CB, Pinto E, Vairo F, Morava E, Barkovich AJ, Gonzalez-Heydrich J, Brownstein CA, McCarroll SA, Walsh CA | display-authors = 6 | title = Early role for a Na<sup>+</sup>,K<sup>+</sup>-ATPase (''ATP1A3'') in brain development | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 118 | issue = 25 | pages = e2023333118 | date = June 2021 | pmid = 34161264 | doi = 10.1073/pnas.2023333118 | pmc = 8237684 | bibcode = 2021PNAS..11823333S | doi-access = free }}</ref>