Na⁺/K⁺-ATPase

The Na⁺
/K⁺
-ATPase, as well as effects of diffusion of the involved ions maintain the resting potential across the membranes.

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-circuit channel (i.e. a highly K-permeable ion channel) for potassium in the membrane, thus the voltage across the plasma membrane is close to the Nernst potential of potassium.

Even if both K+ and Na+ ions have the same charge, they can still have very different equilibrium potentials for both outside and/or inside concentrations. The sodium-potassium pump moves toward an equilibrium state with the relative concentrations of Na+ and K+ for both inside and outside of cell. For instance, the concentration of K+ in cytosol is 100mM, whereas the concentration of Na+ is 10mM. On the other hand, in extracellular space, the concentration of K+ is 5mM, whereas the concentration of Na+ is 150mM.

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 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⁺
-K⁺
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⁺
-K⁺
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⁺
-K⁺
pump helps to maintain the right concentrations of ions. Furthermore, when the cell begins to swell, this automatically activates the Na⁺
-K⁺
pump because it changes the internal concentrations of Na⁺
and K⁺
to which the pump is sensitive.[11]

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.[12]

Protein-protein interactions play a 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.[13] Src kinase is inhibited by Na⁺
-K⁺
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⁺
-K⁺
pump, was developed as a functional ouabain-Na⁺
-K⁺
pump-mediated signal transduction.[14] Na⁺
-K⁺
pump also interacts with ankyrin, IP3R, PI3K, PLC-gamma and cofilin.[15]

The Na⁺
/K⁺
pump has been shown to control and set the intrinsic activity mode of cerebellar Purkinje neurons,[16] accessory olfactory bulb mitral cells[17] and probably other neuron types.[18] 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.[19] Indeed, a mutation in the Na⁺
–K⁺
pump causes rapid onset dystonia-parkinsonism, which has symptoms to indicate that it is a pathology of cerebellar computation.[20] Furthermore, an ouabain block of Na⁺
–K⁺
pumps in the cerebellum of a live mouse results in it displaying ataxia and dystonia.[21] Alcohol inhibits sodium–potassium pumps in the cerebellum and this is likely how it corrupts cerebellar computation and body coordination.[22][23] The distribution of the Na⁺
–K⁺
pump on myelinated axons, in human brain, was demonstrated to be along the internodal axolemma, and not within the nodal axolemma as previously thought.[24]

The Na⁺
/K⁺
-ATPase is upregulated by cAMP.[25] 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.

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.

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 to the Blaustein-hypothesis,[26] this carrier enzyme (Na⁺
/Ca²⁺
exchanger, NCX) uses the Na gradient generated by the Na⁺
-K⁺
pump to remove Ca²⁺
from the intracellular space, hence slowing down the Na⁺
-K⁺
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 (K_d = 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.[27][28][29][30]

In certain conditions such as in the case of cardiac disease, the Na+/K+-ATPase may need to be inhibited via pharmacological means. A commonly used inhibitor used in the treatment of cardiac disease would be Digoxin which essentially binds "to the extracellular part of enzyme i.e. that binds potassium, when it is in a phosphorylated state, to transfer potassium inside the cell"[31] After this essential binding occurs, a dephosphorylation of the alpha subunit occurs which reduces the effect of cardiac disease. It is via the inhibiting of the Na+/K+-ATPase that sodium levels will begin to increase within the cell which ultimately increases the concentration of intracellular calcium via the sodium-calcium exchanger. This increased presence of calcium is what allows for the force of contraction to be increased. In the case of patients where the heart is not pumping hard enough to provide what is needed for the body this approach allows for the temporary overcoming of this.