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Na⁺/K⁺-ATPase

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Na⁺/K⁺-ATPase



-ATPase (Sodium-potassium adenosine triphosphatase, also known as pump, sodium-potassium pump, or sodium pump) is an animal cells. The -ATPase enzyme pumps sodium out of cells, while pumping potassium into cells.

Sodium-potassium pumps

Active transport is responsible for cells containing 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 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 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 this pump for responding to stimuli and transmitting impulses.

Function

The -ATPase helps maintain resting potential, avail transport, and regulate cellular volume.[1] It also functions as signal transducer/integrator to regulate MAPK pathway, ROS, as well as intracellular calcium. In most animal cells, the -ATPase is responsible for about 1/5 of the cell's energy expenditure. For neurons, the -ATPase can be responsible for up to 2/3 of the cell's energy expenditure.[2]

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 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.

The action of the sodium-potassium pump is not the only mechanism 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.

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 - pump is to provide a 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 - pump, whereas, on the reabsorbing (luminal) side, the -Glucose symporter uses the created gradient as a source of energy to import both and glucose, which is far more efficient than simple diffusion. Similar processes are located in the renal tubular system.

Controlling cell volume

Failure of the - 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 - pump helps to maintain the right concentrations of ions. Furthermore, when the cell begins to swell, this automatically activates the - pump.

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 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.[3]

Protein-protein interactions play a very important role in - pump-mediated signal transduction. For example, - pump interacts directly with Src, a non-receptor tyrosine kinase, to form a signaling receptor complex.[4] Src kinase is inhibited by - 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 - pump, was developed as a functional ouabain-- pump-mediated signal transduction.[5] - pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin.[6]

Controlling neuron activity states

The - pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons.[7] 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 - pump causes rapid onset dystonia parkinsonism, which has symptoms to indicate that it is a pathology of cerebellar computation.[8] Furthermore, an ouabain block of - pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia.[9]

Mechanism


  • The pump, while binding ATP, binds 3 intracellular ions.[1]
  • ATP is hydrolyzed, leading to phosphorylation of the pump at a highly conserved aspartate residue and subsequent release of ADP.
  • A conformational change in the pump exposes the ions to the outside. The phosphorylated form of the pump has a low affinity for ions, so they are released.
  • The pump binds 2 extracellular ions. This causes the dephosphorylation of the pump, reverting it to its previous conformational state, transporting the ions into the cell.
  • The unphosphorylated form of the pump has a higher affinity for ions than ions, so the two bound ions are released. ATP binds, and the process starts again.

Regulation

Endogenous

The -ATPase is upregulated by cAMP.[10] Thus, substances causing an increase in cAMP upregulate the -ATPase. These include the ligands of the Gs-coupled GPCRs. In contrast, substances causing a decrease in cAMP downregulate the -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.

Exogenous

The --ATPase can be pharmacologically modified by administrating drugs exogenously.

For instance, --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 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 (- translocator) uses the Na gradient generated by the - pump to remove from the intracellular space, slowing down the - pump results in a permanently elevated level in the muscle, which may be the mechanism of the long-term inotropic effect of cardiac glycosides such as digoxin.

Discovery

-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.[11]

In 1997, he received one-half of the Nobel Prize in Chemistry "for the first discovery of an ion-transporting enzyme, , -ATPase."[12]

Genes

  • Alpha: [4]. #1 predominates in kidney. #2 is also known as "alpha(+)"
  • Beta: ATP1B4

See also

References

Additional images


External links

  • Medical Subject Headings (MeSH)
  • RCSB Protein Data Bank : Sodium-Potassium Pump
  • .

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