Editing Sodium–potassium pump (section)

== Regulation ==

=== Endogenous ===
The {{chem2|Na+/K+}}-ATPase is upregulated by [[Cyclic adenosine monophosphate|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 [[Gs alpha subunit|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 [[Gi alpha subunit|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 [[IHPK1|IP6K1]], which relieves an autoinhibitory domain of [[Phosphoinositide 3-kinase|PI3K]] [[PIK3R1|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 | page = 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 glycoside]]s (for example [[digoxin]] and [[ouabain]]), [[inotrope|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 [[Calcium in biology|{{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.