{{Short description|Ion channel enzyme pump found in the membrane of all animal cells}} {{Infobox enzyme | Name = {{chem2|Na+/K+}}-ATPase pump | EC_number = 7.2.2.13 | CAS_number = | GO_code = | image = 3b8e.png | width = | caption = Sodium–potassium pump, E2-Pi state. Calculated hydrocarbon boundaries of the lipid bilayer are shown as blue (intracellular) and red (extracellular) planes }} thumb|200px|Flow of ions thumb|200px|Alpha and beta units
The '''sodium–potassium pump''' (sodium–potassium adenosine triphosphatase, also known as '''{{chem2|Na+/K+}}-ATPase''', '''{{chem2|Na+/K+}} pump''', or '''sodium–potassium ATPase''') is an enzyme (an electrogenic transmembrane ATPase) found in the cell membrane of all animal cells. It performs several functions in cell physiology.
The {{chem2|Na+/K+}}-ATPase enzyme is active (i.e. it uses energy from ATP). For every ATP molecule that the pump uses, three sodium ions are exported and two potassium ions are imported.<ref name="pmid33716756">{{cite journal | vauthors=Gagnon KB, Delpire E| title=Sodium Transporters in Human Health and Disease (Figure 2) | journal=Frontiers in Physiology | volume=11 | article-number=588664 | year=2021 | doi = 10.3389/fphys.2020.588664 | pmc=7947867 | pmid=33716756 | doi-access=free }}</ref> Thus, there is a net export of a single positive charge per pump cycle. The net effect is an extracellular concentration of sodium ions which is 5 times the intracellular concentration, and an intracellular concentration of potassium ions which is 30 times the extracellular concentration.<ref name="pmid33716756" />
The sodium–potassium pump was discovered in 1957 by the Danish scientist Jens Christian Skou, who was awarded a Nobel Prize for his work in 1997. Its discovery marked an important step forward in the understanding of how ions get into and out of cells, and it has particular significance for excitable cells such as nerve cells, which depend on this pump to respond to stimuli and transmit impulses.
All mammals have four different sodium pump sub-types, or isoforms. Each has unique properties and tissue expression patterns.<ref>{{cite journal | vauthors = Clausen MV, Hilbers F, Poulsen H | title = The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease | journal = Frontiers in Physiology | volume = 8 | pages = 371 | date = June 2017 | pmid = 28634454 | pmc = 5459889 | doi = 10.3389/fphys.2017.00371 | doi-access = free }}</ref> This enzyme belongs to the family of P-type ATPases.
== 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 pathway, reactive oxygen species (ROS), as well as intracellular calcium.
=== Energy expenditure===
The {{chem2|Na+/K+}}-ATPase is an active enzyme. It uses energy from ATP to move ions against their concentration gradient. 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 three-fourths 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 cells.<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 100-140 mM, whereas the concentration of {{chem2|Na+}} is 5-15 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.<ref name="ISBN_9780815341055_652">{{Cite book |title=Molecular biology of the cell |publisher=Garland Science |year=2008 |isbn=978-0-8153-4105-5 |editor-last=Alberts |editor-first=Bruce |edition=5 |location=New York |pages=652}}</ref>
=== Transport === Export of sodium ions from the cell provides the driving force for several secondary active transporters such as membrane transport proteins, which import glucose, amino acids 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, 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 osmotic concentration 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 osmotic concentration outside of the cell, water flows into the cell through osmosis. This will cause the cell to swell up and 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 |bibcode=2006JExpB.209..677R |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, 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 | article-number= e51169 | date = December 2012 | pmid = 23284664 | pmc = 3527461 | doi = 10.1371/journal.pone.0051169 | bibcode = 2012PLoSO...751169F | doi-access = free }}</ref> 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 | article-number= 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 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 | article-number = 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 | article-number= e2023333118 | date = June 2021 | pmid = 34161264 | doi = 10.1073/pnas.2023333118 | pmc = 8237684 | bibcode = 2021PNAS..11823333S | doi-access = free }}</ref>
== Mechanism ==
thumb|right|350px|The sodium–potassium pump is found in many cell (plasma) membranes. Powered by ATP, the pump moves sodium and potassium ions in opposite directions, each against its concentration gradient. In a single cycle of the pump, three sodium ions are extruded from and two potassium ions are imported into the cell.
Looking at the process starting from the interior of the cell: *The pump has a higher affinity for {{chem2|Na+}} ions than {{chem2|K+}} ions, thus after binding ATP, binds 3 intracellular {{chem2|Na+}} ions.<ref name=guyton/> *ATP is hydrolyzed, leading to phosphorylation of the pump at a highly conserved aspartate residue and subsequent release of ADP. This process leads to a conformational change in the pump. *The conformational change exposes the {{chem2|Na+}} ions to the extracellular region. The phosphorylated form of the pump has a low affinity for {{chem2|Na+}} ions, so they are released; by contrast it has high affinity for the {{chem2|K+}} ions. *The pump binds 2 extracellular {{chem2|K+}} ions, which induces dephosphorylation of the pump, reverting it to its previous conformational state, thus releasing the {{chem2|K+}} ions into the cell. *The unphosphorylated form of the pump has a higher affinity for {{chem2|Na+}} ions. ATP binds, and the process starts again.<ref name="ISBN_9780878936953_72">{{Cite book |title=Neuroscience |publisher=Sinauer |year=2012 |isbn=978-0-87893-695-3 |editor-last=Purves |editor-first=Dale |edition=5 |location=Sunderland, Mass |pages=72-73 |chapter=Chapter 4: Ion Channels and Transporters}}</ref>
== Regulation ==
=== Endogenous === The {{chem2|Na+/K+}}-ATPase is upregulated by cAMP.<ref>{{cite book | vauthors = Burnier M |title=Sodium In Health And Disease |url=https://books.google.com/books?id=RZK8c6eV76MC&pg=PA15 |year=2008 |publisher=CRC Press |isbn=978-0-8493-3978-3 |page=15}}</ref> Thus, substances causing an increase in cAMP upregulate the {{chem2|Na+/K+}}-ATPase. These include the ligands of the G<sub>s</sub>-coupled GPCRs. In contrast, substances causing a decrease in cAMP downregulate the {{chem2|Na+/K+}}-ATPase. These include the ligands of the G<sub>i</sub>-coupled GPCRs. Note: Early studies indicated the ''opposite'' effect, but these were later found to be inaccurate due to additional complicating factors. {{Citation needed|date=February 2010}}
The {{chem2|Na+/K+}}-ATPase is endogenously negatively regulated by the inositol pyrophosphate 5-InsP7, an intracellular signaling molecule generated by IP6K1, which relieves an autoinhibitory domain of PI3K p85α to drive endocytosis and degradation.<ref>{{cite journal | vauthors = Chin AC, Gao Z, Riley AM, Furkert D, Wittwer C, Dutta A, Rojas T, Semenza ER, Felder RA, Pluznick JL, Jessen HJ, Fiedler D, Potter BV, Snyder SH, Fu C | display-authors = 6 | title = The inositol pyrophosphate 5-InsP<sub>7</sub> drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85α | journal = Science Advances | volume = 6 | issue = 44 | article-number= eabb8542 | date = October 2020 | pmid = 33115740 | pmc = 7608788 | doi = 10.1126/sciadv.abb8542 | s2cid = 226036261 | bibcode = 2020SciA....6.8542C }}</ref>
The {{chem2|Na+/K+}}-ATPase is also regulated by reversible phosphorylation. Research has shown that in estivating animals, the {{chem2|Na+/K+}}-ATPase is in the phosphorylated and low activity form. Dephosphorylation of {{chem2|Na+/K+}}-ATPase can recover it to the high activity form.{{r|Ramnanan}}
=== Exogenous === The {{chem2|Na+/K+}}-ATPase can be pharmacologically modified by administering drugs exogenously. Its expression can also be modified through hormones such as triiodothyronine, a thyroid hormone.{{r|Ramnanan}}<ref>{{Cite journal| vauthors = Lin HH, Tang MJ |date= January 1997|title=Thyroid hormone upregulates Na,K-ATPase α and β mRNA in primary cultures of proximal tubule cells |journal=Life Sciences |volume=60 |issue=6 |pages=375–382 |doi=10.1016/S0024-3205(96)00661-3 |pmid= 9031683}}</ref>
For instance, {{chem2|Na+/K+}}-ATPase found in the membrane of heart cells is an important target of cardiac glycosides (for example digoxin and ouabain), inotropic drugs used to improve heart performance by increasing its force of contraction.
Muscle contraction is dependent on a 100- to 10,000-times-higher-than-resting intracellular {{chem2|Ca^{2+}|}} concentration, which is caused by {{chem2|Ca^{2+}|}} release from the muscle cells' sarcoplasmic reticulum. Immediately after muscle contraction, intracellular {{chem2|Ca^{2+}|}} is quickly returned to its normal concentration by a carrier enzyme in the plasma membrane, and a calcium pump in sarcoplasmic reticulum, causing the muscle to relax.
According to the Blaustein-hypothesis,<ref name="pmid324293">{{cite journal | vauthors = Blaustein MP | s2cid = 9814212 | title = Sodium ions, calcium ions, blood pressure regulation, and hypertension: a reassessment and a hypothesis | journal = The American Journal of Physiology | volume = 232 | issue = 5 | pages = C165-73 | date = May 1977 | pmid = 324293 | doi = 10.1152/ajpcell.1977.232.5.C165 }}</ref> this carrier enzyme ({{chem2|Na+/Ca^{2+}|}} exchanger, NCX) uses the Na gradient generated by the {{chem2|Na+}}-{{chem2|K+}} pump to remove {{chem2|Ca^{2+}|}} from the intracellular space, hence slowing down the {{chem2|Na+}}-{{chem2|K+}} pump results in a permanently elevated {{chem2|Ca^{2+}|}} level in the muscle, which may be the mechanism of the long-term inotropic effect of cardiac glycosides such as digoxin. The problem with this hypothesis is that at pharmacological concentrations of digitalis, less than 5% of Na/K-ATPase molecules – specifically the α2 isoform in heart and arterial smooth muscle (''K''<sub>d</sub> = 32 nM) – are inhibited, not enough to affect the intracellular concentration of {{chem2|Na+}}. However, apart from the population of Na/K-ATPase in the plasma membrane, responsible for ion transport, there is another population in the caveolae which acts as digitalis receptor and stimulates the EGF receptor.<ref name="pmid18556748">{{cite journal | vauthors = Schoner W, Scheiner-Bobis G | title = Role of endogenous cardiotonic steroids in sodium homeostasis | journal = Nephrology, Dialysis, Transplantation | volume = 23 | issue = 9 | pages = 2723–9 | date = September 2008 | pmid = 18556748 | doi = 10.1093/ndt/gfn325 | doi-access = }}</ref><ref name="pmid20211726">{{cite journal | vauthors = Blaustein MP, Hamlyn JM | title = Signaling mechanisms that link salt retention to hypertension: endogenous ouabain, the Na<sup>+</sup> pump, the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger and TRPC proteins | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1802 | issue = 12 | pages = 1219–29 | date = December 2010 | pmid = 20211726 | pmc = 2909369 | doi = 10.1016/j.bbadis.2010.02.011 }}</ref><ref name="pmid21642827">{{cite journal | vauthors = Fuerstenwerth H | s2cid = 20180376 | title = On the differences between ouabain and digitalis glycosides | journal = American Journal of Therapeutics | volume = 21 | issue = 1 | pages = 35–42 | date = 2014 | pmid = 21642827 | doi = 10.1097/MJT.0b013e318217a609 }}</ref><ref name="pmid25341357">{{cite journal | vauthors = Pavlovic D | title = The role of cardiotonic steroids in the pathogenesis of cardiomyopathy in chronic kidney disease | journal = Nephron Clinical Practice | volume = 128 | issue = 1–2 | pages = 11–21 | date = 2014 | pmid = 25341357 | doi = 10.1159/000363301 | s2cid = 2066801 | doi-access = }}</ref>
=== Pharmacological regulation === In certain conditions such as in the case of cardiac disease, the {{chem2|Na+/K+}}-ATPase may need to be inhibited via pharmacological means. A commonly used inhibitor used in the treatment of cardiac disease is digoxin (a cardiac glycoside) which essentially binds "to the extracellular part of enzyme i.e. that binds potassium, when it is in a phosphorylated state, to transfer potassium inside the cell"<ref>{{cite web | url=https://www.pharmacorama.com/en/Sections/NAK-ATPase-Digoxin.php | title=Na<sup>+</sup>/K<sup>+</sup>-ATPase and inhibitors (Digoxin) | work=Pharmacorama | url-status=dead | access-date=2019-11-08 | archive-date=2020-09-28 | archive-url=https://web.archive.org/web/20200928033426/https://www.pharmacorama.com/en/Sections/NAK-ATPase-Digoxin.php }}</ref> After this essential binding occurs, a dephosphorylation of the alpha subunit occurs which reduces the effect of cardiac disease. It is via the inhibiting of the {{chem2|Na+/K+}}-ATPase that sodium levels will begin to increase within the cell which ultimately increases the concentration of intracellular calcium via the sodium-calcium exchanger. This increased presence of calcium is what allows for the force of contraction to be increased. In the case of patients where the heart is not pumping hard enough to provide what is needed for the body, use of digoxin helps to temporarily overcome this.
== Discovery == {{chem2|Na+/K+}}-ATPase was proposed by Jens Christian Skou in 1957 while working as assistant professor at the Department of Physiology, University of Aarhus, Denmark. He published his work that year.<ref>{{cite journal | vauthors = Skou JC | title = The influence of some cations on an adenosine triphosphatase from peripheral nerves | journal = Biochimica et Biophysica Acta | volume = 23 | issue = 2 | pages = 394–401 | date = February 1957 | pmid = 13412736 | doi = 10.1016/0006-3002(57)90343-8 | s2cid = 32516710 }}</ref>
In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, {{chem2|Na+,K+}}-ATPase."<ref>{{cite web | title = The Nobel Prize in Chemistry 1997 | url = https://www.nobelprize.org/prizes/chemistry/1997/summary/ | work = NobelPrize.org | publisher = Nobel Media AB | date = 15 October 1997 }}</ref>
== Genes == * Alpha: ATP1A1, ATP1A2, ATP1A3, ATP1A4. ATP1A1 is expressed ubiquitously in vertebrates, and ATP1A3 in neural tissue. ATP1A2 is also known as "alpha(+)". ATP1A4 is specific to mammals. * Beta: ATP1B1, {{Gene2|ATP1B2|805}}, ATP1B3
{{Gene2|ATP1B4|808}}, although closely related to ATP1B1, ATP1B2, and ATP1B3, lost its function as {{chem2|Na+/K+}}-ATPase beta subunit.<ref>{{cite web|title=ATPase Na+/K+ transporting subunits (ATP1)|publisher=HGNC|url=https://www.genenames.org/data/genegroup/#!/group/1208|access-date=26 June 2024}}</ref>
== Parallel evolution of cardiotonic steroid resistance in vertebrates == Several studies have detailed the evolution of cardiotonic steroid resistance of the alpha-subunit gene family of Na/K-ATPase (ATP1A) in vertebrates via amino acid substitutions most often located in the first extracellular loop domain.<ref name=":0">{{Cite journal |last1=Moore |first1=David J. |last2=Halliday |first2=Damien C. T. |last3=Rowell |first3=David M. |last4=Robinson |first4=Anthony J. |last5=Keogh |first5=J. Scott |date=2009-08-23 |title=Positive Darwinian selection results in resistance to cardioactive toxins in true toads (Anura: Bufonidae) |journal=Biology Letters |volume=5 |issue=4 |pages=513–516 |doi=10.1098/rsbl.2009.0281 |issn=1744-9561 |pmc=2781935 |pmid=19465576}}</ref><ref name=":1">Hernández Poveda M (2022) Convergent evolution of neo-functionalized duplications of ATP1A1 in dendrobatid and grass frogs. MS Thesis Dissertation. Universidad de los Andes</ref><ref name=":2">{{Cite journal |last1=Mohammadi |first1=Shabnam |last2=Yang |first2=Lu |last3=Harpak |first3=Arbel |last4=Herrera-Álvarez |first4=Santiago |last5=Rodríguez-Ordoñez |first5=María del Pilar |last6=Peng |first6=Julie |last7=Zhang |first7=Karen |last8=Storz |first8=Jay F. |last9=Dobler |first9=Susanne |last10=Crawford |first10=Andrew J. |last11=Andolfatto |first11=Peter |date=2021-06-21 |title=Concerted evolution reveals co-adapted amino acid substitutions in frogs that prey on toxic toads |journal=Current Biology |volume=31 |issue=12 |pages=2530–2538.e10 |doi=10.1016/j.cub.2021.03.089 |issn=0960-9822 |pmc=8281379 |pmid=33887183}}</ref><ref>{{Cite journal |last1=Mohammadi |first1=Shabnam |last2=Brodie |first2=Edmund D. |last3=Neuman-Lee |first3=Lorin A. |last4=Savitzky |first4=Alan H. |date=2016-05-01 |title=Mutations to the cardiotonic steroid binding site of Na+/K+-ATPase are associated with high level of resistance to gamabufotalin in a natricine snake |url=https://www.sciencedirect.com/science/article/pii/S0041010116300368 |journal=Toxicon |volume=114 |pages=13–15 |doi=10.1016/j.toxicon.2016.02.019 |pmid=26905927 |issn=0041-0101|url-access=subscription }}</ref><ref name=":3">{{Cite journal |last1=Mohammadi |first1=Shabnam |last2=Herrera-Álvarez |first2=Santiago |last3=Yang |first3=Lu |last4=Rodríguez-Ordoñez |first4=María del Pilar |last5=Zhang |first5=Karen |last6=Storz |first6=Jay F. |last7=Dobler |first7=Susanne |last8=Crawford |first8=Andrew J. |last9=Andolfatto |first9=Peter |date=2022-08-16 |title=Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |journal=PLOS Genetics |volume=18 |issue=8 |article-number=e1010323 |doi=10.1371/journal.pgen.1010323 |issn=1553-7390 |pmc=9462791 |pmid=35972957 |doi-access=free }}</ref><ref>{{Cite journal |last1=Mohammadi |first1=Shabnam |last2=Özdemir |first2=Halil İbrahim |last3=Ozbek |first3=Pemra |last4=Sumbul |first4=Fidan |last5=Stiller |first5=Josefin |last6=Deng |first6=Yuan |last7=Crawford |first7=Andrew J |last8=Rowland |first8=Hannah M |last9=Storz |first9=Jay F |last10=Andolfatto |first10=Peter |last11=Dobler |first11=Susanne |date=2022-12-06 |title=Epistatic Effects Between Amino Acid Insertions and Substitutions Mediate Toxin resistance of Vertebrate Na+,K+-ATPases |journal=Molecular Biology and Evolution |volume=39 |issue=12 |article-number=msac258 |doi=10.1093/molbev/msac258 |issn=0737-4038 |pmc=9778839 |pmid=36472530}}</ref><ref>{{Cite journal |last1=Ujvari |first1=Beata |last2=Mun |first2=Hee-chang |last3=Conigrave |first3=Arthur D. |last4=Bray |first4=Alessandra |last5=Osterkamp |first5=Jens |last6=Halling |first6=Petter |last7=Madsen |first7=Thomas |date=January 2013 |title=Isolation Breeds Naivety: Island Living Robs Australian Varanid Lizards of Toad-Toxin Immunity Via Four-Base-Pair Mutation |journal=Evolution |language=en |volume=67 |issue=1 |pages=289–294 |doi=10.1111/j.1558-5646.2012.01751.x|doi-access=free |pmid=23289579 }}</ref> Amino acid substitutions conferring cardiotonic steroid resistance have evolved independently many times in all major groups of tetrapods.<ref name=":3" /> ATP1A1 has been duplicated in some groups of frogs and neofunctionlised duplicates carry the same cardiotonic steroid resistance substitutions (Q111R and N122D) found in mice, rats and other muroids.<ref>{{Cite journal |last1=Price |first1=Elmer M. |last2=Lingrel |first2=Jerry B. |date=1988-11-01 |title=Structure-function relationships in the sodium-potassium ATPase .alpha. subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme |url=https://pubs.acs.org/doi/abs/10.1021/bi00422a016 |journal=Biochemistry |language=en |volume=27 |issue=22 |pages=8400–8408 |doi=10.1021/bi00422a016 |pmid=2853965 |issn=0006-2960|url-access=subscription }}</ref><ref name=":0" /><ref name=":1" /><ref name=":2" />
== In insects == In ''Drosophila melanogaster'', the alpha-subunit of {{chem2|Na+/K+}}-ATPase has two paralogs, ATPα (ATPα1) and JYalpha (ATPα2), resulting from an ancient duplication in insects.<ref name="Zhen_et_al_2012">{{cite journal|last1=Zhen|first1=Ying|last2=Aardema|first2=Matthew L.|last3=Medina|first3=Edgar M.|last4=Schumer|first4=Molly|last5=Andolfatto|first5=Peter|date=2012-09-28|title=Parallel Molecular Evolution in an Herbivore Community|url= |journal=Science|language=en|volume=337|issue=6102|pages=1634–1637|doi=10.1126/science.1226630|issn=0036-8075|pmid=23019645|pmc=3770729|bibcode=2012Sci...337.1634Z}}</ref> In Drosophila, ATPα1 is ubiquitously and highly expressed, whereas ATPα2 is most highly expressed in male testes and is essential for male fertility. Insects have at least one copy of both genes, and occasionally duplications. Low expression of ATPα2 has also been noted in other insects. Duplications and neofunctionalization of ATPα1 have been observed in insects that are adapted to cardiotonic steroid toxins such as cardenolides and bufadienolides.<ref name="Zhen_et_al_2012" /><ref name="Yang_et_al_2019">{{cite journal |last1=Yang|first1=L.|last2=Ravikanthachari|first2=N.|last3=Mariño-Pérez|first3=R.|last4=Deshmukh|first4=R.|last5=Wu|first5=M.|last6=Rosenstein|first6=A.|last7=Kunte|first7=K.|last8=Song|first8=H.|last9=Andolfatto|first9=P.|title=Predictability in the evolution of Orthopteran cardenolide insensitivity|journal=Philosophical Transactions of the Royal Society of London, Series B|date=2019 |volume=374 |issue=1777 |article-number=20180246 |doi=10.1098/rstb.2018.0246|pmid=31154978 | pmc=6560278}}</ref><ref>Petschenka Georg, Vera Wagschal, Michael von Tschirnhaus, Alexander Donath, Susanne Dobler 2017 {{cite journal | title= Convergently Evolved Toxic Secondary Metabolites in Plants Drive the Parallel Molecular Evolution of Insect Resistance | date=2017| pmid=28731826| last1=Petschenka| first1=G.| last2=Wagschal| first2=V.| last3=von Tschirnhaus| first3=M.| last4=Donath| first4=A.| last5=Dobler| first5=S.| journal=The American Naturalist| volume=190| issue=S1| pages=S29–S43| doi=10.1086/691711| bibcode=2017ANat..190S..29P| s2cid=3908073}}</ref> Insects adapted to cardiotonic steroids typically have a number of amino acid substitutions, most often in the first extra-cellular loop of ATPα1, that confer resistance to cardiotonic steroid inhibition.<ref>{{cite journal | vauthors = Labeyrie E, Dobler S | title = Molecular adaptation of Chrysochus leaf beetles to toxic compounds in their food plants | journal = Molecular Biology and Evolution | volume = 21 | issue = 2 | pages = 218–21 | date = 2004 | pmid = 12949136 | doi = 10.1093/molbev/msg240 | url = https://academic.oup.com/mbe/article/21/2/218/1187788 | doi-access = | url-access = subscription }}</ref><ref>{{cite journal | doi=10.1073/pnas.1202111109 | title=Community-wide convergent evolution in insect adaptation to toxic cardenolides by substitutions in the Na,K-ATPase | date=2012 | last1=Dobler | first1=Susanne | last2=Dalla | first2=Safaa | last3=Wagschal | first3=Vera | last4=Agrawal | first4=Anurag A. | journal=Proceedings of the National Academy of Sciences | volume=109 | issue=32 | pages=13040–13045 | doi-access=free | pmid=22826239 | pmc=3420205 }}</ref>
== See also == * Sodium-calcium exchanger * Thyroid hormone * V-ATPase
== References == {{reflist}}
== External links == * {{MeshName|Sodium,+Potassium+ATPase}} * [http://www.pdb.org/pdb/static.do?p=education_discussion%2Fmolecule_of_the_month%2Fpdb118_1.html&sms_ss=blogger&at_xt=4d54c0c2c278bc46%2C0 RCSB Protein Data Bank: Sodium–Potassium Pump] * [http://www.khanacademy.org/video/correction-to-sodium-and-potassium-pump-video?playlist=Biology A video] by Khan Academy. {{Ion pumps}} {{Acid anhydride hydrolases}} {{Enzymes}} {{Portal bar|Biology|border=no}}
{{DEFAULTSORT:Na K ATPase}} Category:EC 3.6.3 Category:Transport proteins