Flow of ions.

Alpha and beta units.

Sodium-potassium pump, E2-Pi state. Calculated hydrocarbon boundaries of the lipid bilayer are shown as blue (intracellular) and red (extracellular) planes

Na⁺/K⁺-ATPase (also known as the Na⁺/K⁺ pump, sodium-potassium pump, or simply sodium pump, for short) is an enzyme (EC 3.6.3.9) located in the plasma membrane (specifically an electrogenic transmembrane ATPase) in all animals.

[edit] Sodium-Potassium pumps

Active transport is responsible for the well-established observation that cells contain relatively high concentrations of potassium ions but low concentrations of sodium 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 1950’s by a Danish scientist, Jens Christian Skou, 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, Grace Monger. 2000)

[edit] Function

The Na⁺/K⁺-ATPase helps maintain resting potential, avail transport and regulate cellular volume.^{[citation needed]} It also functions as signal transducer/integrator to regulate MAPK pathway, ROS as well as intracellular calcium.

[edit] Resting potential

In order to maintain the cell membrane potential, cells must keep a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular)^{[citation needed]}. After the formation of an action potential, when the cell is repolarizing, that is within the cell it is becoming more and more negative as K+ ions flood out, there is a stage where the membrane potential undershoots its resting membrane potential as K+ channels take too long to close^{[citation needed]}. This is called hyperpolarization^{[citation needed]}. This process only changes 1 in 100,000,000,000 of bulk concentration however, over time there would be run down of the ionic gradients with the sodium-potassium pump action 3 sodium ions out by hydrolysing ATP and allows 2 potassium ions in through active transport^{[citation needed]}. The pump undergoes a conformational change in order to do this. However this does not contribute to the restoration of the resting membrane potential in any way, which is mainly accomplished by potassium leak channels that are always active.^{[citation needed]}

[edit] Transport

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⁺-K⁺ pump is to provide an 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 (luminal) 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.

[edit] 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 a large number of 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 osmosis of water into the cell which, unless checked, can cause the cell to swell up and lyse. The Na⁺-K⁺ pump is a mechanism to prevent this. The pump 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 sodium ions have a tendency to stay there. This represents a continual net loss of ions out of the cell. The opposing osmotic tendency that results operates to drive the water 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.

[edit] 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 binding signalling into the cell through regulation of protein tyrosine phosphorylation. The downstream signals through ouabain-triggered protein phosphorylation events include the activation of 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^[1].

Protein-protein interactions play very important role in Na⁺-K⁺ pump - mediated signal transduction. For example, Na⁺-K⁺ pump interacts directly with Src, a non-receptor tyrosine kinase, to form a signaling receptor complex^[2]. 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 ^[3]. Na⁺-K⁺ pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin^[4].

[edit] Mechanism

• The pump, with bound ATP, binds 3 intracellular Na⁺ ions.
• ATP is hydrolyzed, leading to phosphorylation of the pump at a highly conserved aspartate residue and subsequent release of ADP.^{[citation needed]}
• 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.^{[citation needed]}
• The pump binds 2 extracellular K⁺ ions. This causes the dephosphorylation of the pump, reverting it to its previous conformational state, transporting the K⁺ ions into the cell.^{[citation needed]}
• 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.^{[citation needed]}

[edit] Regulation

[edit] Endogenous

The Na⁺/K⁺-ATPase is upregulated by cAMP.^[5] Thus, substances causing an increase in cAMP upregulate the Na⁺/K⁺-ATPase. These include the ligands of the G_s-coupled GPCRs. In contrast, substances causing a decrease in cAMP downregulate the Na⁺/K⁺-ATPase. These include the ligands of the G_i-coupled GPCRs.

Note: Early studies indicated the opposite effect, but these were later found to be inaccurate due to additional complicating factors.^{[citation needed]}

[edit] 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 glycosides (for example digoxin and ouabain), inotropic drugs used to improve heart performance by increasing its force of contraction.

Contraction of any muscle is dependent on a 100- to 10,000-times higher-than-resting intracellular Ca²⁺ 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⁺-Ca²⁺ translocator) uses the Na gradient generated by the Na⁺-K⁺ pump to remove Ca²⁺ from the intracellular space, slowing down the Na⁺-K⁺ pump results in a permanently-higher Ca²⁺ level in the muscle, which will eventually lead to stronger contractions.

[edit] 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 in 1957.^[6]

In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, Na⁺, K⁺ -ATPase."^[7]

[edit] Genes

• Alpha: ATP1A1[1], ATP1A2[2], ATP1A3[3], ATP1A4[4]. #1 predominates in kidney. #2 is also known as "alpha(+)"
• Beta: ATP1B1[5], ATP1B2, ATP1B3[6], ATP1B4

[edit] See also

• V-ATPase
• active transport

[edit] References

[edit] External links

• MeSH Sodium,+Potassium+ATPase