Na+/K+-ATPase is an
enzymeEnzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
located in the plasma membrane (to be specific, an electrogenic
transmembraneA transmembrane protein is a protein that goes from one side of a membrane through to the other side of the membrane. Many TPs function as gateways or "loading docks" to deny or permit the transport of specific substances across the biological membrane, to get into the cell, or out of the cell as...
ATPaseATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
) in all
animalAnimals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s.
Sodium-potassium pumps
Active transportActive transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
is responsible for cells containing relatively high concentrations of
potassiumPotassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
ions but low concentrations of
sodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ions. The mechanism responsible for this is the sodium-potassium pump, which moves these two ions in opposite directions across the plasma membrane. This was investigated by following the passage of radioactively labeled ions across the plasma membrane of certain cells. It was found that the concentrations of sodium and potassium ions on the two other sides of the membrane are interdependent, suggesting that the same carrier transports both ions. It is now known that the carrier is an ATP-ase and that it pumps three sodium ions out of the cell for every two potassium ions pumped in.
The sodium-potassium pump was discovered in the 1950s by a Danish scientist,
Jens Christian SkouJens Christian Skou is a Danish chemist and Nobel laureate.Skou was born in Lemvig, Denmark to a wealthy family. His father Magnus Martinus Skou was a timber and coal merchant. His mother Ane-Margrethe Skou took over the company after the death of his father. At the age of 15 Skou entered a...
, who was awarded a Nobel Prize in 1997. It marked an important step forward in our understanding of how ions get into and out of cells, and it has a particular significance for excitable cells such as nervous cells, which depend on it for responding to stimuli and transmitting impulses.
(Advanced Biology - Michael Roberts, Michael Reiss, nasif mohammed, Grace Monger. 2000)
Function
The Na
+/K
+-ATPase helps maintain
resting potentialThe 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....
, avail transport, and regulate cellular
volumeVolume is the quantity of three-dimensional space enclosed by some closed boundary, for example, the space that a substance or shape occupies or contains....
. It also functions as signal transducer/integrator to regulate
MAPK pathwayThe 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. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
, ROS, as well as intracellular calcium. For most animal cells, the Na
+/K
+-ATPase is responsible for 1/3 of the cell's energy expenditure. For neurons, the Na
+/K
+-ATPase is responsible for 2/3 of the cell's energy expenditure.
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 (
intracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
). The sodium-potassium pump 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.
Not only the mechanism of the sodium-potassium pump alone is responsible for the generation of the resting membrane potential. Also the selective permeability of the cell's plasma membrane for the different Ions plays an important role. All mechanisms involved are explained in the main article on generation of the resting membrane potential. The importance of membrane permeability is explained in a
video on
Khan AcademyThe Khan Academy is a not-for-profit educational organization, created in 2006 by Bangladeshi American educator Salman Khan, a graduate of MIT. With the stated mission of "providing a high quality education to anyone, anywhere", the website supplies a free online collection of more than 2,700 micro...
.
Transport
Export of sodium from the cell provides the driving force for several secondary active transporters membrane transport proteins, which import
glucoseGlucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
,
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, and other nutrients into the cell by use of the sodium gradient.
Another important task of the Na
+-K
+ pump is to provide a
NaSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
+ gradient that is used by certain carrier processes. In the
gutIn zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
, 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 (luminal) side, the Na
+-Glucose
symporterA cotransporter is an integral membrane protein that is involved in secondary active transport. It works by binding to two molecules or ions at a time and using the gradient of one solute's concentration to force the other molecule or ion against its gradient....
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.
Controlling cell volume
One of the important functions of Na
+-K
+ pump is to maintain the volume of the cell.
Inside the cell, there are many proteins and other organic compounds that cannot escape from the cell. Most, being negatively charged, collect around them a large number of positive ions. All these substances tend to cause the
osmosisOsmosis is the movement of solvent molecules through a selectively permeable membrane into a region of higher solute concentration, aiming to equalize the solute concentrations on the two sides...
of water into the cell, which, unless checked, can cause the cell to swell up and
lyseLysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
. The Na
+-K
+ pump is a mechanism to prevent this. The
pumpA pump is a device used to move fluids, such as liquids, gases or slurries.A pump displaces a volume by physical or mechanical action. Pumps fall into three major groups: direct lift, displacement, and gravity pumps...
transports 3 Na
+ ions out of the cell and in exchange takes 2 K
+ ions into the cell. As the membrane is far less permeable to Na
+ ions than K
+ ions, the
sodiumSodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
ions have a tendency to stay there. In addition, while the cell membrane is impermeable to sodium ions, potassium leak channels embedded in the membrane allow for K
+ ions to "leak" back out of the cell down their concentration gradient. This represents a continual net loss of ions out of the cell. The opposing osmotic tendency that results operates to drive the
waterWater is a chemical substance with the chemical formula H2O. A water molecule contains one oxygen and two hydrogen atoms connected by covalent bonds. Water is a liquid at ambient conditions, but it often co-exists on Earth with its solid state, ice, and gaseous state . Water also exists in a...
molecules out of the cells. Furthermore, when the cell begins to swell, this automatically activates the Na
+-K
+ pump, which moves still more ions to the exterior.
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
ouabainOuabain which is also named g-strophanthin, is a poisonous cardiac glycoside.-Sources:Ouabain is found in the ripe seeds of African plants Strophanthus gratus and the bark of Acokanthera ouabaio.-Function:...
-binding signalling into the cell through regulation of protein tyrosine phosphorylation. The downstream signals through ouabain-triggered protein phosphorylation events include to activate 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 very important role in Na
+-K
+ pump-mediated signal transduction. For example, Na
+-K
+ pump interacts directly with
SrcProto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
, a non-receptor tyrosine kinase, to form a signaling receptor complex. Src kinase is inhibited by Na
+-K
+ pump, while, upon ouabain binding, Src kinase domain will be released and then activated. Based on this scenario, NaKtide, a peptide Src inhibitor derived from Na
+-K
+ pump, was developed as a functional ouabain antagonist. Na
+-K
+ pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin.
Mechanism
- The pump, with good binds ATP
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
, binds 3 intracellular Na+ ions.
- ATP is hydrolyzed, leading to phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the pump at a highly conserved aspartate residue and subsequent release of ADPAdenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
.
- A conformational change in the pump exposes the Na+ ions to the outside. The phosphorylated form of the pump has a low affinity for Na+ ions, so they are released.
- The pump binds 2 extracellular K
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
+ ions. This causes the dephosphorylationDephosphorylation is the essential process of removing phosphate groups from an organic compound by hydrolysis. Its opposite is phosphorylation...
of the pump, reverting it to its previous conformational state, transporting the K+ ions into the cell.
- The unphosphorylated form of the pump has a higher affinity for Na+ ions than K+ ions, so the two bound K+ ions are released. ATP binds, and the process starts again.
Endogenous
The Na
+/K
+-ATPase is upregulated by
cAMPCyclic adenosine monophosphate is a second messenger important in many biological processes...
. Thus, substances causing an increase in cAMP upregulate the Na
+/K
+-ATPase. These include the ligands of the
GsThe Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:...
-coupled
GPCRs. In contrast, substances causing a decrease in cAMP downregulate the Na
+/K
+-ATPase. These include the ligands of the
GiGi alpha subunit is a heterotrimeric G protein subunit that inhibits the production of cAMP from ATP.- Receptors :The following G protein-coupled receptors couple to the Gi subunit:* Acetylcholine M2 & M4 receptors...
-coupled GPCRs.
Note: Early studies indicated the
opposite effect, but these were later found to be inaccurate due to additional complicating factors.
Exogenous
The Na
+-K
+-ATPase can be pharmacologically modified by administrating drugs exogenously.
For instance, Na
+-K
+-ATPase found in the membrane of heart cells is an important target of
cardiac glycosideCardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...
s (for example
digoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and
ouabainOuabain which is also named g-strophanthin, is a poisonous cardiac glycoside.-Sources:Ouabain is found in the ripe seeds of African plants Strophanthus gratus and the bark of Acokanthera ouabaio.-Function:...
),
inotropicAn inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions...
drugs used to improve
heartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
performance by increasing its force of contraction.
Contraction of any muscle is dependent on a 100- to 10,000-times-higher-than-resting intracellular
CaCalcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
2+ concentration, which, as soon as it is put back again on its normal level by a carrier enzyme in the plasma membrane, and a calcium pump in sarcoplasmic reticulum, muscle relaxes.
Since this carrier enzyme (Na
+-Ca
2+ translocator) uses the Na gradient generated by the Na
+-K
+ pump to remove Ca
2+ from the intracellular space, slowing down the Na
+-K
+ pump results in a permanently-higher Ca
2+ level in the
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, which will eventually lead to stronger contractions.
Discovery
Na
+/K
+-ATPase was discovered by
Jens Christian SkouJens Christian Skou is a Danish chemist and Nobel laureate.Skou was born in Lemvig, Denmark to a wealthy family. His father Magnus Martinus Skou was a timber and coal merchant. His mother Ane-Margrethe Skou took over the company after the death of his father. At the age of 15 Skou entered a...
in 1957 while working as assistant professor at the Department of Physiology,
University of AarhusAarhus University , located in the city of Aarhus, Denmark, is Denmark's second oldest and second largest university...
,
DenmarkDenmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
. He published his work that year.
In 1997, he received one-half of the
Nobel Prize in ChemistryThe Nobel Prize in Chemistry is awarded annually by the Royal Swedish Academy of Sciences to scientists in the various fields of chemistry. It is one of the five Nobel Prizes established by the will of Alfred Nobel in 1895, awarded for outstanding contributions in chemistry, physics, literature,...
"for the first discovery of an ion-transporting enzyme, Na
+, K
+ -ATPase."
Genes
- Alpha: ATP1A1, ATP1A2
ATPase, Na+/K+ transporting, alpha 2 polypeptide, also known as ATP1A2, is a protein which in humans is encoded by the ATP1A2 gene.- Function :...
, ATP1A3Sodium/potassium-transporting ATPase subunit alpha-3 is an enzyme that in humans is encoded by the ATP1A3 gene.The protein encoded by this gene belongs to the family of P-type cation transport ATPases, and to the subfamily of Na+/K+-ATPases...
, ATP1A4Sodium/potassium-transporting ATPase subunit alpha-4 is an enzyme that in humans is encoded by the ATP1A4 gene.-Further reading:...
. #1 predominates in kidney. #2 is also known as "alpha(+)"
- Beta: ATP1B1
Sodium/potassium-transporting ATPase subunit beta-1 is an enzyme that in humans is encoded by the ATP1B1 gene.-Further reading:...
, , ATP1B3Sodium/potassium-transporting ATPase subunit beta-3 is an enzyme that in humans is encoded by the ATP1B3 gene. ATP1B3 has also been designated as CD298 .-External links:...
,
External links