Physiology, Sodium Potassium Pump (Na+ K+ Pump)


Article Author:
Yasaman Pirahanchi


Article Editor:
Narothama Aeddula


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
1/21/2019 9:34:29 AM

Introduction

The Na+ K+ pump is an electrogenic transmembrane ATPase first discovered in 1957 and situated in the outer plasma membrane of the cells; on the cytosolic side.[1][2] The Na+ K+ ATPase pumps 3 Na+ out of the cell and 2K+ that into the cell, for every single ATP consumed. The plasma membrane is a lipid bilayer that arranged asymmetrically, containing cholesterol, phospholipids, glycolipids, sphingolipid, and proteins within the membrane.[3][4] The Na+K+-ATPase pump helps to maintain osmotic equilibrium and membrane potential in cells.

The sodium and potassium move against the concentration gradients. The Na+ K+-ATPase pump maintains the gradient of a higher concentration of sodium extracellularly and a higher level of potassium intracellularly. The sustained concentration gradient is crucial for physiological processes in many organs and has an ongoing role in stabilizing the resting membrane potential of the cell, regulation of the cell volume and in the cell signal transduction.[2] It plays a crucial role on other physiological processes, such as maintenance of filtering waste products in the nephrons (kidneys), sperm motility, and production of the neuronal action potential.[5] Furthermore, the physiologic consequences of inhibiting the Na+-K+ ATPase are useful and the target in many pharmacologic applications. 

Na, K-ATPase is a crucial scaffolding protein that can interact with signaling proteins such as protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K).[6]

Cellular

Structurally, the Na+ K+ ATPase is composed of a catalytic alpha subunit and an auxiliary beta subunit.[7] Some Na-K ATPases include a subunit that is tissue-specific and belongs to the FXYD protein family.[8] The alpha subunit contains a transmembrane region which is composed of 10 helices, referred to as MA1-M10. Within these ten helices, ion binding sites, specifically three binding sites that bind to Na+ in the E1 state and two binding sites that bind to K+ in the E2 state.[9][10][11][12] The structure of the Na-K ATPase is composed of three sites. Site one and two overlaps within both the E1 and E2 state. However, site three is exclusively in the E1 state and is between the M5, M6, and M8 transmembrane helices, which bind to Na+ and catalyze H+ transport as well,[13][14] dependent on the Na+, K+, and H+ concentrations.[15] According to previous studies, the pump’s E2 state selectivity for K+ may be due to ion binding pocket protonation.[16]

Function

Sodium and potassium gradients function in various organ systems' physiologic processes.[5] The kidneys have a high level of expression of the Na, K-ATPase, with the distal convoluted tubule expressing up to 50 million pumps per cell. This sodium gradient is necessary for the kidney to filter waste products in the blood, reabsorb amino acids, reabsorb glucose, regulate electrolyte levels in the blood, and to maintain pH.[17]

Sperm cells also use the Na, K-ATPase, but they use a different isoform necessary for preserving fertility in males. Sperm needs the Na, K ATPase to regulate membrane potential and ions, which is necessary for sperm motility and the sperm’s acrosome functioning during penetration into the egg.[18]

The brain also requires NA, K ATPase activity. Neurons need the Na, K ATPase pump to reverse postsynaptic sodium flux to re-establish the potassium and sodium gradients which are necessary to fire action potentials. Astrocytes also need Na, K ATPase pump to maintain the sodium gradient as the sodium gradient maintains neurotransmitter reuptake. Na, K ATPases in the gray matter consumes a significant amount of energy, up to three-quarters of energy is absorbed by Na, K ATPases in the gray matter while merely a quarter of the total energy gets utilized for protein synthesis and molecular synthesis.[19]

Pathophysiology

The Na+-K+ ATPase plays a prominent role in thyroid pathophysiology. In hyperparathyroidism, there is an increase in heat intolerance, increased sweating, and increased weight loss due to the increased synthesis of Na+-K+ ATPase induced by the excessive thyroid hormone. This increased synthesis of Na+-K+ ATPase then increases basal metabolic rate, which then increases oxygen consumption, respiratory rate, body temperature, and calorigenesis.[20]

Clinical Significance

As the Na+-K+ ATPase is essential for maintaining various cellular functions, its inhibition could result in diverse pathologic states. Studies show that patients with heart failure have a 40% lower concentration of total Na, K-ATPase.[21] One significant clinical application is in cardiovascular pharmacology. For example, ouabain is a cardiac glycoside which inhibits the Na+-K+ ATPase by binding to the K+ site. Other cardiac glycosides such as digoxin and digitoxin directly inhibit the Na+-K+ ATPase.[22] This inhibition causes a buildup of excessive K+ extracellularly, and accumulation of excessive Na+ intracellularly as the Na+-K+ ATPase can no longer pump K+ into the cell or pump Na+ out of the cell. This buildup of intracellular Na+ hinders the concentration gradient that usually drives the Na+/Ca 2+ channel exchanger, which generally pumps Na+ into the cell and Ca 2+ out of the cell because the concentration gradient is not favorable for Na+ to enter the cell as excessive Na+ has built up intracellularly. This indirect inhibition of Na+/Ca 2+ exchange, therefore, causes a buildup of Ca 2+ intracellularly because the exchanger cannot allow Ca 2+ to exit the cell since it cannot accept Na+ into the cell. This increased intracellular Ca 2+ then increases cardiac contractility. This positive inotropy stimulates the vagus nerve, causing a decrease in heart rate. This physiology is clinically significant in the treatment of heart failure as it increases contractility of the heart. It is also clinically significant in the treatment of atrial fibrillation as it decreases conduction of the atrioventricular node and causes depression of the sinoatrial node.[23] Diuretic therapy has also been shown to reduce myocardial Na, K-ATPase when there is potassium loss. In contrast, angiotensin-converting enzyme inhibitors could stimulate the activity of the Na, K pump.[21]

Another significant clinical application includes the effect of beta-adrenergic agonists in increasing the number of Na+/K+ ATPase channels; this is because beta-adrenergic agonists can enhance the gene expression of the Na+-K+-ATPase pump, which ultimately results in an increased quantity of the enzyme and therefore increased the activity of the enzyme. Because of this increased quantity of Na+/K+ ATPase, more potassium is pumped into the cell, causing a buildup of intracellular potassium. Therefore, extracellularly, this inward shift of potassium results in hypokalemia in the extracellular blood. Thus beta-adrenergic agonists can cause increased Na+ transport out of the cell as well. Increased Na+ transport extracellularly across alveolar epithelial cells for example, which would then cause lung liquid to follow this flow of Na+, ultimately stimulating lung liquid clearance.[24]]

Insulin also causes clinically significant effects on the Na+/K+ ATPase. Insulin increases the number of Na+/K+ ATPase pumps in the membrane as well, this leads to an intracellular shift of potassium, causing hypokalemia in the extracellular space of the blood.[25]

There are reports of abnormal expression levels, or activity of the Na+K+ pump in diabetes, hypertension, Alzheimer disease, and in various tumors including glioblastoma, non-small cell lung carcinoma, breast cancer, melanoma, colorectal carcinoma, and bladder cancer.[26].

Na+ K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), play a role in the in the etiology of bipolar disorder and is a potential target for drug development for the treatment.[27]

 Both RNA and DNA viruses can directly affect Na, K-ATPase function, in particular, viral infections targeting the host cell components. Na, K-ATPase holds promise as an antiviral strategy to minimize the resistance to antiviral drugs and has been shown to be effective.[28] Cardiac glycosides inhibit cytomegalovirus (CMV) replication, with an additive effect when combined with antiviral drugs such as ganciclovir.[29] Cardiac glycosides can also be active on other DNA viruses such as herpes simplex virus (HSV) by inhibiting the expression of a viral gene.[30]

There is evidence of a Na/K-ATPase oxidant amplification loop in the process of aging, obesity, and cardiovascular disease.[31]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Physiology, Sodium Potassium Pump (Na+ K+ Pump) - Questions

Take a quiz of the questions on this article.

Take Quiz
The sodium-potassium pump is stimulated by various molecules. Which of the following endogenous hormones stimulates the sodium-potassium (Na-K) pump?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
The sodium-potassium pump pushes two potassium molecules intracellularly and three sodium molecules extracellularly for each ATP molecule consumed. Which of the following will stimulate the sodium-potassium pump?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A certain pump allows cells to maintain a constant negative resting membrane potential necessary for cellular processes such as neuronal action potentials. How do cells maintain a constant negative resting membrane potential?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Ischemia, or inadequate oxygen supply, to a cell decreases adenosine 5´ triphosphate (ATP) production by limiting the function of which cell process?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
At resting membrane potential, there is a greater concentration of sodium outside the cell than inside the cell. Which is true of the unequal distribution of sodium inside and outside the cell?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Physiology, Sodium Potassium Pump (Na+ K+ Pump) - References

References

Kopec W,Loubet B,Poulsen H,Khandelia H, Molecular mechanism of Na( ),K( )-ATPase malfunction in mutations characteristic of adrenal hypertension. Biochemistry. 2014 Feb 4;     [PubMed]
Mercer RW,Biemesderfer D,Bliss DP Jr,Collins JH,Forbush B 3rd, Molecular cloning and immunological characterization of the gamma polypeptide, a small protein associated with the Na,K-ATPase. The Journal of cell biology. 1993 May;     [PubMed]
Bibert S,Liu CC,Figtree GA,Garcia A,Hamilton EJ,Marassi FM,Sweadner KJ,Cornelius F,Geering K,Rasmussen HH, FXYD proteins reverse inhibition of the Na -K pump mediated by glutathionylation of its beta1 subunit. The Journal of biological chemistry. 2011 May 27;     [PubMed]
Geering K, Functional roles of Na,K-ATPase subunits. Current opinion in nephrology and hypertension. 2008 Sep;     [PubMed]
Kanai R,Ogawa H,Vilsen B,Cornelius F,Toyoshima C, Crystal structure of a Na -bound Na ,K -ATPase preceding the E1P state. Nature. 2013 Oct 10;     [PubMed]
Laursen M,Gregersen JL,Yatime L,Nissen P,Fedosova NU, Structures and characterization of digoxin- and bufalin-bound Na ,K -ATPase compared with the ouabain-bound complex. Proceedings of the National Academy of Sciences of the United States of America. 2015 Feb 10;     [PubMed]
Morth JP,Pedersen BP,Toustrup-Jensen MS,Sørensen TL,Petersen J,Andersen JP,Vilsen B,Nissen P, Crystal structure of the sodium-potassium pump. Nature. 2007 Dec 13;     [PubMed]
Shinoda T,Ogawa H,Cornelius F,Toyoshima C, Crystal structure of the sodium-potassium pump at 2.4 A resolution. Nature. 2009 May 21;     [PubMed]
Poulsen H,Khandelia H,Morth JP,Bublitz M,Mouritsen OG,Egebjerg J,Nissen P, Neurological disease mutations compromise a C-terminal ion pathway in the Na( )/K( )-ATPase. Nature. 2010 Sep 2;     [PubMed]
Ratheal IM,Virgin GK,Yu H,Roux B,Gatto C,Artigas P, Selectivity of externally facing ion-binding sites in the Na/K pump to alkali metals and organic cations. Proceedings of the National Academy of Sciences of the United States of America. 2010 Oct 26;     [PubMed]
Mitchell TJ,Zugarramurdi C,Olivera JF,Gatto C,Artigas P, Sodium and proton effects on inward proton transport through Na/K pumps. Biophysical journal. 2014 Jun 17;     [PubMed]
Yu H,Noskov SY,Roux B, Two mechanisms of ion selectivity in protein binding sites. Proceedings of the National Academy of Sciences of the United States of America. 2010 Nov 23;     [PubMed]
Wang X,Liu J,Drummond CA,Shapiro JI, Sodium potassium adenosine triphosphatase (Na/K-ATPase) as a therapeutic target for uremic cardiomyopathy. Expert opinion on therapeutic targets. 2017 May;     [PubMed]
Virgadamo S,Charnigo R,Darrat Y,Morales G,Elayi CS, Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction. World journal of cardiology. 2015 Nov 26;     [PubMed]
Lei J,Nowbar S,Mariash CN,Ingbar DH, Thyroid hormone stimulates Na-K-ATPase activity and its plasma membrane insertion in rat alveolar epithelial cells. American journal of physiology. Lung cellular and molecular physiology. 2003 Sep;     [PubMed]
Minakata Y,Suzuki S,Grygorczyk C,Dagenais A,Berthiaume Y, Impact of beta-adrenergic agonist on Na channel and Na -K -ATPase expression in alveolar type II cells. The American journal of physiology. 1998 Aug;     [PubMed]
Sweeney G,Niu W,Canfield VA,Levenson R,Klip A, Insulin increases plasma membrane content and reduces phosphorylation of Na( )-K( ) pump alpha(1)-subunit in HEK-293 cells. American journal of physiology. Cell physiology. 2001 Dec;     [PubMed]
Clausen MV,Hilbers F,Poulsen H, The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease. Frontiers in physiology. 2017;     [PubMed]
el Mernissi G,Barlet-Bas C,Khadouri C,Marsy S,Cheval L,Doucet A, Characterization and localization of ouabain-insensitive Na-dependent ATPase activities along the rat nephron. Biochimica et biophysica acta. 1991 May 7;     [PubMed]
Jimenez T,McDermott JP,Sánchez G,Blanco G, Na,K-ATPase alpha4 isoform is essential for sperm fertility. Proceedings of the National Academy of Sciences of the United States of America. 2011 Jan 11;     [PubMed]
Attwell D,Laughlin SB, An energy budget for signaling in the grey matter of the brain. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2001 Oct;     [PubMed]
Kjeldsen K, Myocardial Na,K-ATPase: Clinical aspects. Experimental and clinical cardiology. 2003 Fall;     [PubMed]
SKOU JC, The influence of some cations on an adenosine triphosphatase from peripheral nerves. Biochimica et biophysica acta. 1957 Feb     [PubMed]
Pivovarov AS,Calahorro F,Walker RJ, Na{sup}+{/sup}/K{sup}+{/sup}-pump and neurotransmitter membrane receptors. Invertebrate neuroscience : IN. 2018 Nov 28     [PubMed]
Mohammadi K,Kometiani P,Xie Z,Askari A, Role of protein kinase C in the signal pathways that link Na+/K+-ATPase to ERK1/2. The Journal of biological chemistry. 2001 Nov 9     [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]
    [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pharmacy-Technician (PTCB). The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pharmacy-Technician (PTCB), it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pharmacy-Technician (PTCB), you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pharmacy-Technician (PTCB). When it is time for the Pharmacy-Technician (PTCB) board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pharmacy-Technician (PTCB).