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The sodium–potassium pump ( sodiumpotassium
adenosine Adenosine ( symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building ...
triphosphatase, also known as Na⁺/K⁺-ATPase, Na⁺/K⁺ pump, or sodium–potassium ATPase) is an enzyme (an electrogenic transmembrane
ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are ...
) found in the membrane of all animal cells. It performs several functions in cell physiology. The Na⁺/K⁺-ATPase enzyme is active (i.e. it uses energy from
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
). For every ATP molecule that the pump uses, three sodium ions are exported and two potassium ions are imported. Thus, there is a net export of a single positive charge per pump cycle. 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. This enzyme belongs to the family of P-type ATPases.


Function

The Na⁺/K⁺-ATPase helps maintain resting potential, affects transport, and regulates cellular volume. It also functions as a signal transducer/integrator to regulate the
MAPK pathway A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
, 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. For neurons, the Na⁺/K⁺-ATPase can be responsible for up to 3/4 of the cell's energy expenditure. In many types of tissue, ATP consumption by the Na⁺/K⁺-ATPases have been related to
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
. This was first discovered in red blood cells (Schrier, 1966), but has later been evidenced in renal cells, smooth muscles surrounding the blood vessels, and cardiac purkinje cells. Recently, glycolysis has also been shown to be of particular importance for Na⁺/K⁺-ATPases in skeletal muscles, where inhibition of
glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...
breakdown (a substrate for
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
) leads to reduced Na⁺/K⁺-ATPase activity and lower force production.


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 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 In a biological membrane, the reversal potential is the membrane potential at which the direction of ionic current reverses. At the reversal potential, there is no net flow of ions from one side of the membrane to the other. For channels that are ...
of potassium.


Reversal potential

Even if both K⁺ and 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 Na⁺ and K⁺ for both inside and outside of cell. For instance, the concentration of K⁺ in cytosol is 100mM, whereas the concentration of Na⁺ is 10mM. On the other hand, in extracellular space, the concentration of K⁺ is 5mM, whereas the concentration of Na⁺ is 150mM.


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 Na⁺-K⁺ pump is to provide a 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 Na⁺-K⁺ pump, whereas, on the reabsorbing (lumenal) side, the Na⁺-glucose
symporter A symporter is an integral membrane protein that is involved in the transport of two (or more) different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the ...
uses the created Na⁺ gradient as a source of energy to import both Na⁺ and glucose, which is far more efficient than simple diffusion. Similar processes are located in the
renal tubular system The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
.


Controlling cell volume

Failure of the Na⁺-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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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
lyse Lyse may refer to: * Lyse Abbey, a former Cistercian abbey in Norway * Lyse, an alternative name of Lysebotn, Norway * Lyse Energi, a Norwegian power company * Łyse, Masovian Voivodeship, a village in east-central Poland * Łyse, Podlaskie Voivode ...
. The Na⁺-K⁺ pump helps to maintain the right concentrations of ions. Furthermore, when the cell begins to swell, this automatically activates the Na⁺-K⁺ pump because it changes the internal concentrations of Na⁺-K⁺ to which the pump is sensitive.


Functioning as signal transducer

Within the last decade, many independent labs have demonstrated that, in addition to the classical ion transporting, this membrane protein can also relay extracellular
ouabain Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. ...
-binding signalling into the cell through regulation of protein tyrosine phosphorylation. For instance, a study investigated the function of Na+/K+ ATPase in foot muscle and hepatopancreas in land snail ''O.Lactea'' by comparing the active and estivating states. 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 A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular responses to ...
(MAPK) signal cascades, mitochondrial reactive oxygen species (ROS) production, as well as activation of
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(PLC) and inositol triphosphate (IP3) receptor (
IP3R Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca2+ channel activated by inositol trisphosphate (InsP3). InsP3R is very diverse among organisms, and is necessary for the control of cellular and physio ...
) in different intracellular compartments. Protein-protein interactions play a very important role in Na⁺-K⁺ pump-mediated signal transduction. For example, the Na⁺-K⁺ pump interacts directly with Src, a non-receptor tyrosine kinase, to form a signaling receptor complex. Src is initially inhibited by the Na⁺-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 Na⁺-K⁺ pump, was developed as a functional ouabain–Na⁺-K⁺ pump-mediated signal transduction. Na⁺-K⁺ pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin.


Controlling neuron activity states

The Na⁺-K⁺ pump has been shown to control and set the intrinsic activity mode of cerebellar
Purkinje neurons Purkinje cells, or Purkinje neurons, are a class of GABAergic inhibitory neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839. Structure The ...
, accessory olfactory bulb mitral cells and probably other neuron types. This suggests that the pump might not simply be a homeostatic, "housekeeping" molecule for ionic gradients, but could be a
computation Computation is any type of arithmetic or non-arithmetic calculation that follows a well-defined model (e.g., an algorithm). Mechanical or electronic devices (or, historically, people) that perform computations are known as ''computers''. An es ...
element in the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
and the brain. Indeed, a mutation in the Na⁺-K⁺ pump causes rapid onset
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
- parkinsonism, which has symptoms to indicate that it is a pathology of cerebellar computation. Furthermore, an ouabain block of Na⁺-K⁺ pumps in the cerebellum of a live mouse results in it displaying ataxia and
dystonia Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
.
Alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
inhibits sodium–potassium pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body coordination. The distribution of the Na⁺-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. The Na⁺-K⁺ pump disfunction has been tied to various diseases, including epilepsy and brain malformations.


Mechanism

Looking at the process starting from the interior of the cell: *The pump has a higher affinity for Na⁺ ions than K⁺ ions, thus after binding
ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...
, binds 3 intracellular Na⁺ ions. *ATP is
hydrolyzed Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolysis ...
, leading to
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the pump at a highly conserved
aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
residue and subsequent release of
ADP Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Air ...
. This process leads to a conformational change in the pump. *The conformational change exposes the Na⁺ ions to the extracellular region. The phosphorylated form of the pump has a low affinity for Na⁺ ions, so they are released; by contrast it has high affinity for the K⁺ ions. *The pump binds 2 extracellular K⁺ ions, which induces dephosphorylation of the pump, reverting it to its previous conformational state, thus releasing the K⁺ ions into the cell. *The unphosphorylated form of the pump has a higher affinity for Na⁺ ions. ATP binds, and the process starts again.


Regulation


Endogenous

The Na⁺/K⁺-ATPase is upregulated by cAMP. Thus, substances causing an increase in cAMP upregulate the Na⁺/K⁺-ATPase. These include the ligands of the Gs-coupled GPCRs. In contrast, substances causing a decrease in cAMP downregulate the Na⁺/K⁺-ATPase. These include the ligands of the Gi-coupled GPCRs. Note: Early studies indicated the ''opposite'' effect, but these were later found to be inaccurate due to additional complicating factors. The 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. The Na⁺/K⁺-ATPase is also regulated by reversible phosphorylation. Research has shown that in estivating animals, the Na⁺/K⁺-ATPase is in the phosphorylated and low activity form. Dephosphorylation of Na⁺/K⁺-ATPase can recover it to the high activity form.


Exogenous

The Na⁺/K⁺-ATPase can be pharmacologically modified by administrating drugs exogenously. Its expression can also be modified through hormones such as triiodothyronine, a thyroid hormone. For instance, Na⁺/K⁺-ATPase found in the membrane of heart cells is an important target of cardiac glycosides (for example
digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
and
ouabain Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. ...
), 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 Ca²⁺ concentration, which is caused by Ca²⁺ release from the muscle cells' sarcoplasmic reticulum. Immediately after muscle contraction, intracellular Ca²⁺ 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, this carrier enzyme (Na⁺/Ca²⁺ exchanger, NCX) uses the Na gradient generated by the Na⁺-K⁺ pump to remove Ca²⁺ from the intracellular space, hence slowing down the Na⁺-K⁺ pump results in a permanently elevated Ca²⁺ level in the
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
, 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''d = 32 nM) -- are inhibited, not enough to affect the intracellular concentration of 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.


Pharmacologic regulation

In certain conditions such as in the case of cardiac disease, the Na⁺/K⁺-ATPase may need to be inhibited via pharmacological means. A commonly used inhibitor used in the treatment of cardiac disease would be digoxin 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" 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 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 this approach allows for the temporary overcoming of this.


Discovery

Na⁺/K⁺-ATPase was discovered 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. In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, Na⁺,K⁺-ATPase."


Genes

* Alpha:
ATP1A1 Sodium/potassium-transporting ATPase subunit alpha-1 is an enzyme that in humans is encoded by the ''ATP1A1'' gene. The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+-AT ...
,
ATP1A2 Sodium/potassium-transporting ATPase subunit alpha-2 is a protein which in humans is encoded by the ''ATP1A2'' gene. Function The protein encoded by this gene belongs to the family of P-type cation transport ATPases and to the subfamily of ...
, ATP1A3,
ATP1A4 Sodium/potassium-transporting ATPase subunit alpha-4 is an enzyme that in humans is encoded by the ''ATP1A4'' gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity. ...
. #1 predominates in kidney. #2 is also known as "alpha(+)" * Beta: ATP1B1, , ATP1B3,


In insects

Mutagenesis studies conducted by Susanne Dobler have identified the conserved M3-M4 hairpin and M5-M6 hairpins. At position 312, insects feeding on '' Apocynum'' species differed from mammalian Na⁺/K⁺-ATPase through the change of glutamic acid to aspartic acid. Thus, the insects were found to have a higher degree of conservation in the C-terminal of the
ouabain Ouabain or (from Somali ''waabaayo'', "arrow poison" through French ''ouabaïo'') also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. ...
binding pocket. Dobler et al. found 87% amino acid identity among insect sequences, which shows a high level of molecular convergence among four orders of insect herbivores. Thus, some substitutions provide resistance to cardenolides as an adaptation even across phylogenetic branches.


See also

*
Thyroid hormone File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 25 ...
* V-ATPase


References


External links

*
RCSB Protein Data Bank: Sodium–Potassium Pump

A video
by Khan Academy. {{DEFAULTSORT:Na K ATPase EC 3.6.3 Transport proteins