Sodium-potassium pump, E2-Pi state. Calculated hydrocarbon boundaries of the lipid bilayer are shown as blue (intracellular) and red (extracellular) planes
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Na⁺/K⁺-ATPase (sodium-potassium adenosine triphosphatase, also known as the Na⁺/K⁺ pump or sodium–potassium pump) is an enzyme (an electrogenic transmembrane ATPase) found in the plasma membrane of all animal cells. It performs several functions in cell physiology.
Sodium is a chemical element with symbol Na (from Latin natrium) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table, because it has a single electron in its outer shell that it readily donates, creating a positively charged ion—the Na+ cation. Its only stable isotope is 23Na. The free metal does not occur in nature, and must be prepared from compounds. Sodium is the sixth most abundant element in the Earth's crust and exists in numerous minerals such as feldspars, sodalite, and rock salt (NaCl). Many salts of sodium are highly water-soluble: sodium ions have been leached by the action of water from the Earth's minerals over eons, and thus sodium and chlorine are the most common dissolved elements by weight in the oceans.
Potassium is a chemical element with symbol K and atomic number 19. It was first isolated from potash, the ashes of plants, from which its name derives. In the periodic table, potassium is one of the alkali metals. All of the alkali metals have a single valence electron in the outer electron shell, which is easily removed to create an ion with a positive charge – a cation, which combines with anions to form salts. Potassium in nature occurs only in ionic salts. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and reacts vigorously with water, generating sufficient heat to ignite hydrogen emitted in the reaction, and burning with a lilac-colored flame. It is found dissolved in sea water, and is part of many minerals.
Adenosine is both a chemical found in many living systems and a medication. As a medication it is used to treat certain forms of supraventricular tachycardia that do not improve with vagal maneuvers. Common side effects include chest pain, feeling faint, shortness of breath along with tingling of the senses. Serious side effects include a worsening dysrhythmia and low blood pressure. It appears to be safe in pregnancy.
-ATPase enzyme is a solute pump that pumps potassium out of cells while pumping sodium into cells, both against their concentration gradients. This pumping 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; there is hence a net export of a single positive charge per pump cycle.
Solute pumping is a form of active transport of a solute through a cell membrane.
In cellular biology, active transport is the movement of molecules across a membrane from a region of their lower concentration to a region of their higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses ATP, and secondary active transport that uses an electrochemical gradient. An example of active transport in human physiology is the uptake of glucose in the intestines.
Adenosine triphosphate (ATP) is a complex organic chemical that provides energy to drive many processes in living cells, e.g. muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all forms of life, ATP is often referred to as the "molecular unit of currency" of intracellular energy transfer. When consumed in metabolic processes, it converts either to adenosine diphosphate (ADP) or to adenosine monophosphate (AMP). Other processes regenerate ATP so that the human body recycles its own body weight equivalent in ATP each day. It is also a precursor to DNA and RNA, and is used as a coenzyme.
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.
Jens Christian Skou was a Danish biochemist and Nobel laureate.
A neuron, also known as a neurone and nerve cell, is an electrically excitable cell that communicates with other cells via specialized connections called synapses. All multicellular organisms except sponges and Trichoplax have neurons. A neuron is the main component of nervous tissue.
An alternative theory, Ling’s adsorption theory, posits that the membrane potential and action potential of a living cell is due to the adsorption of mobile ions onto adsorption sites of cells.
All mammals have four different sodium pump sub-types, or isoforms. Each has unique properties and tissue expression patterns.
-ATPase helps maintain resting potential, affects transport, and regulates cellular volume. It also functions as a signal transducer/integrator to regulate the MAPK pathway, 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.( Voet Biochemistry section 20-3 p759)
The relatively static membrane potential of quiescent cells is called the resting membrane potential, as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential.
Volume is the quantity of three-dimensional space enclosed by a closed surface, for example, the space that a substance or shape occupies or contains. Volume is often quantified numerically using the SI derived unit, the cubic metre. The volume of a container is generally understood to be the capacity of the container; i. e., the amount of fluid that the container could hold, rather than the amount of space the container itself displaces. Three dimensional mathematical shapes are also assigned volumes. Volumes of some simple shapes, such as regular, straight-edged, and circular shapes can be easily calculated using arithmetic formulas. Volumes of complicated shapes can be calculated with integral calculus if a formula exists for the shape's boundary. One-dimensional figures and two-dimensional shapes are assigned zero volume in the three-dimensional space.
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
For neurons, the Na+
-ATPase can be responsible for up to 3/4 of the cell's energy expenditure.
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 (please see Mechanism for details). In addition, there is a short-circut channel for potassium in the membrane, thus the voltage across the plasma membrane is close to the Nernst-potential of potassium.
Export of sodium from the cell provides the driving force for several secondary active transporters membrane transport proteins, which import glucose, amino acids, and other nutrients into the cell by use of the sodium gradient.
Another important task of the Na+
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+
pump, whereas, on the reabsorbing (lumenal) side, the Na+
-glucose symporter 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.
Failure of the Na+
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 lyse. The Na+
pump helps to maintain the right concentrations of ions. Furthermore, when the cell begins to swell, this automatically activates the Na+
pump. [ citation needed ]
Within the last decade[ when? ], 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. 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.
Protein-protein interactions play a very important role in Na+
pump-mediated signal transduction. For example, Na+
pump interacts directly with Src, a non-receptor tyrosine kinase, to form a signaling receptor complex. Src kinase is inhibited by Na+
pump, while, upon ouabain binding, the Src kinase domain will be released and then activated. Based on this scenario, NaKtide, a peptide Src inhibitor derived from Na+
pump, was developed as a functional ouabain-Na+
pump-mediated signal transduction. Na+
pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin.
pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons, 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 element in the cerebellum and the brain. Indeed, a mutation in the Na+
pump causes rapid onset dystonia-parkinsonism, which has symptoms to indicate that it is a pathology of cerebellar computation. Furthermore, an ouabain block of Na+
pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia. Alcohol inhibits sodium-potassium pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body co-ordination. The distribution of the Na+
pump on myelinated axons, in human brain, was demonstrated to be along the internodal axolemma, and not within the nodal axolemma as previously thought.
-ATPase is upregulated by cAMP. Thus, substances causing an increase in cAMP upregulate the Na+
-ATPase. These include the ligands of the Gs-coupled GPCRs. In contrast, substances causing a decrease in cAMP downregulate the Na+
-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. [ citation needed ]
-ATPase can be pharmacologically modified by administrating drugs exogenously.
For instance, Na+
-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 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 tho the Blaustein-hypothesis, Na+
exchanger, NCX) uses the Na gradient generated by the Na+
pump to remove Ca2+
from the intracellular space, hence slowing down the Na+
pump results in a permanently elevated Ca2+
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 (Kd = 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.
-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+
ATPases (EC 220.127.116.11, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, SV40 T-antigen, adenosine 5'-triphosphatase, ATP hydrolase, complex V (mitochondrial electron transport), (Ca2+ + Mg2+)-ATPase, HCO3−-ATPase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or the inverse reaction. This dephosphorylation reaction releases energy, which the enzyme (in most cases) harnesses to drive other chemical reactions that would not otherwise occur. This process is widely used in all known forms of life.
Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. With respect to the exterior of the cell, typical values of membrane potential, normally given in millivolts, range from –40 mV to –80 mV.
Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.
Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl–) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.
Purkinje cells, or Purkinje neurons, are a class of GABAergic neurons located in the cerebellum. They are named after their discoverer, Czech anatomist Jan Evangelista Purkyně, who characterized the cells in 1839.
An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts, the chemical gradient, or difference in solute concentration across a membrane, and the electrical gradient, or difference in charge across a membrane. When there are unequal concentrations of an ion across a permeable membrane, the ion will move across the membrane from the area of higher concentration to the area of lower concentration through simple diffusion. Ions also carry an electric charge that forms an electric potential across a membrane. If there is an unequal distribution of charges across the membrane, then the difference in electric potential generates a force that drives ion diffusion until the charges are balanced on both sides of the membrane.
In biology, an ion transporter is a transmembrane protein that moves ions across a biological membrane against their concentration gradient through active transport. These primary transporters are enzymes that convert energy from various sources—including adenosine triphosphate (ATP), sunlight, and other redox reactions—to potential energy stored in an electrochemical gradient. This potential energy is then used by secondary transporters, including ion carriers and ion channels, to drive vital cellular processes, such as ATP synthesis.
Gastric hydrogen potassium ATPase, also known as H+/K+ ATPase, is an enzyme which functions to acidify the stomach.
The Na-K-Cl cotransporter (NKCC) is a protein that aids in the active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.
The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). A single calcium ion is exported for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.
Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:
The plasma membrane Ca2+ ATPase (PMCA) is a transport protein in the plasma membrane of cells and functions to remove calcium (Ca2+) from the cell. PMCA function is vital for regulating the amount of Ca2+ within all eukaryotic cells. There is a very large transmembrane electrochemical gradient of Ca2+ driving the entry of the ion into cells, yet it is very important that they maintain low concentrations of Ca2+ for proper cell signalling. Thus, it is necessary for cells to employ ion pumps to remove the Ca2+. The PMCA and the sodium calcium exchanger (NCX) are together the main regulators of intracellular Ca2+ concentrations. Since it transports Ca2+ into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the extracellular space.
Calcium concentration microdomains (CCMs) are sites in a cell's cytoplasm with a localised high calcium ion (Ca2+) concentration. They are found immediately around the intracellular opening of calcium channels; when a calcium channel opens, the Ca2+ concentration in the adjacent CCM increases up to several hundred micromolar (µM). These microdomains take part in calcium signaling, which has a diverse range of potential outcomes.
Sodium/potassium-transporting ATPase subunit alpha-3 is an enzyme that in humans is encoded by the ATP1A3 gene.
Calcium pumps are a family of ion transporters found in the cell membrane of all animal cells. They are responsible for the active transport of calcium out of the cell for the maintenance of the steep Ca2+ electrochemical gradient across the cell membrane. Calcium pumps play a crucial role in proper cell signalling by keeping the intracellular calcium concentration roughly 10,000 times lower than the extracellular concentration. Failure to do so is one cause of muscle cramps.
Anoxic depolarization is a progressive and uncontrollable depolarization of neurons during stroke or brain ischemia in which there is an inadequate supply of blood to the brain. Anoxic depolarization is induced by the loss of neuronal selective membrane permeability and the ion gradients across the membrane that are needed to support neuronal activity. Normally, the Na+/K+-ATPase pump maintains the transmembrane gradients of K+ and Na+ ions, but with anoxic brain injury, the supply of energy to drive this pump is lost. The hallmarks of anoxic depolarization are increased concentrations of extracellular K+ ions, intracellular Na+ and Ca2+ ions, and extracellular glutamate and aspartate. Glutamate and aspartate are normally present as the brain's primary excitatory neurotransmitters, but high concentrations activate a number of downstream apoptotic and necrotic pathways. This results in neuronal dysfunction and death.
Dark cells are specialized nonsensory epithelial cells found on either side of the vestibular organs, and lining the endolymphatic space. These dark-cell areas in the vestibular organ are structures involved in the production of endolymph, an inner ear fluid, secreting potassium towards the endolymphatic fluid. Dark cells take part in fluid homeostasis to preserve the unique high-potassium and low-sodium content of the endolymph and also maintain the calcium homeostasis of the inner ear.