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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 NAKA, for short) is an enzyme (EC 3.6.3.9) located in the plasma membrane (specifically an electrogenic transmembrane ATPase). It is found in the human cell and is found in all metazoa (animals).

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 ones. 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 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)

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.

Resting potential

See also: Resting potential

In order to maintain the cell potential, cells must keep a low concentration of sodium ions and high levels of potassium ions within the cell (intracellular). 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 it resting membrane potential as K+ channels take too long to close. This is called Hyperpolarisation. In order to restore the appropriate concentrations, the sodium-potassium pump pumps 3 sodium ions out by hydrolysing ATP and allows 2 potassium ions in through active transport. The carrier (pump) undergoes a conformational change in order to do this. The end result is that the resting membrane potential is restored and another action potential can occur. However, one must not be mistaken as the Na+/K+ ATPase has no direct action in the formation of an action potential.

The resting potential avails action potentials of nerves and muscles.^{citation needed}

Transport

Export of sodium from the cell provides the driving force for several facilitated membrane transport proteins, which import glucose, amino acids and other nutrients into the cell. Translocation of sodium from one side of a cell membrane to the other side creates an osmotic gradient that drives the absorption of water.^{citation needed}

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 resorbing cell on the blood side via the Na⁺-K⁺ pump, whereas, on the resorbing 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.Nam Currie-Nyugen was the founder of this mechanism in 1892^{citation needed}

Controlling of cell volume

One of the important functions of Na⁺-K⁺ pump is to maintain the volume of the cell.The mechanism is as follows: Inside the cell a large number of proteins and other organic compounds that cannot escape from the cell. Most of them being negatively charged , collect around them a large number of positive ions. All these substances tend to cause osmosis of water into the cell which unless checked can cause the cell to swell up and burst. 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 (as hydrated Na is much larger in size than hydrated K) the sodium ions have a tendency to stay there. This represents a continual net loss of ions out of the cell. As a result an opposing osmotic tendency operates to drive the water molecules out of the cells. Further when the cell begins to swell this automatically activates the Na⁺-K⁺ pump moving 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 ouabain binding signaling 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 receptor complex^[2]. Na⁺-K⁺ pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin^[3].

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}

Regulation

Endogenous

The Na⁺/K⁺-ATPase is thought to be downregulated by cAMP.^[4]

Thus, substances causing an increase in cAMP downregulates Na⁺/K⁺-ATPase. These include the ligands of the G_s-coupled GPCRs.

In contrast, substances causing a decrease in cAMP upregulates Na⁺/K⁺-ATPase. These include the ligands of the G_i-coupled GPCRs. It should be noted that cAMP also acts as a second messenger causing an increase in protein abundance of Na-K-ATPase.

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.

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.^[5]

In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, Na⁺, K⁺ -ATPase."^[6]

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

See also

• V-ATPase
• active transport

References

1. ^ Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex by Zhaokan Yuan, Ting Cai, Jiang Tian, Alexander V. Ivanov, David R. Giovannucci, and Zijian Xie in Molecular Biology of the Cell (2005) volume 16, pages 4034-4045.
2. ^ Binding of Src to Na+/K+-ATPase Forms a Functional Signaling Complex by Jiang Tian, Ting Cai, Zhaokan Yuan, Haojie Wang, Lijun Liu, Michael Haas, Elena Maksimova,‡ Xin-Yun Huang and Zi-Jian Xie in Molecular Biology of the Cell (2005) volume 17, pages 317-326.
3. ^ Interaction of the alpha subunit of Na,K-ATPase with cofilin by K. Lee, J. Jung, M. Kim and G. Guidotti in The Biochemical Journal (2001) volume 353, pages 377–385.
4. ^ Regulation of Na+-K+-ATPase by cAMP-dependent protein kinase anchored on membrane via its anchoring protein Kinji Kurihara, Nobuo Nakanishi, and Takao Ueha. Departments of 1 Oral Physiology and 2 Biochemistry, School of Dentistry, Meikai University, Sakado, Saitama 350-0283, Japan
5. ^ Skou J (1957). "The influence of some cations on an adenosine triphosphatase from peripheral nerves.". Biochim Biophys Acta 23 (2): 394–401. doi:10.1016/0006-3002(57)90343-8. PMID 13412736. 
6. ^ Chemistry 1997

A pdf copy of the paper (reference 1) appears on http://jasn.asnjournals.org/cgi/reprint/9/11/2170.pdf

External links

• MeSH Sodium,+Potassium+ATPase

Wikipedia content modification information:

• This page was last modified on 1 September 2008, at 15:03.

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