Na /K -ATPase

The sodium potassium ATPase (or more precisely 3 Na / K 2 - ATPase), also called sodium pump, or sodium - potassium pump, is anchored in the cell membrane transmembrane protein. The enzyme catalyzes the hydrolysis of ATP ( ATPase) the transport of sodium ions from the cell and the transport of potassium ions into the cell to the chemical concentration gradient and the electrical Ladungsgradienten and serves as its maintenance.

History

The Na / K -ATPase was discovered in 1957 by the Danish physician Jens Christian Skou. Skou was awarded the 1997 Nobel Prize in Chemistry "for the discovery of the ion- transporting enzyme, sodium - potassium ATPase ."

Structure of the protein

After the TCDB ​​classification for membrane transport proteins include the sodium - potassium pump to the family of P- type ATPases ( type 2).

The sodium - potassium -ATPase consists of one α - and a β - subunit protein, which together form a stable and functional enzyme. The α - subunit consists of 10 transmembrane passages connected by intra-and extracellular loops. It hydrolyzes during the reaction cycle, ATP is in the range of the large cytoplasmic phophoryliert M4 -M5- loops and transports the sodium and potassium ions. Therefore, it is also referred to as the catalytic unit. From the α - subunit of the four isoforms are known so far: α1 - α4.

The β subunit is a type II membrane glycoprotein with a single passage. In functional enzyme it is close to the transmembrane passages M7 and M10 of the α - subunit and interacts with its extrazellulaeren M7/M8-Loop M7/M8 as well as their intracellular regions. During maturation of the protein β - subunit functions as a molecular Chaparons by assisting the correct folding and Membranintregration the α - subunit and protects it from degradation. It also has an influence on the affinity with which the α - subunit binds potassium and sodium ions. Of the β - subunit of four isoforms are known so far: β1, β2, β3 and βm.

A third molecule, which was itself associated with the α - and the β - subunit, and previously referred to as the γ - subunit belongs to the protein family FXYD and modulates the affinity of the sodium pump of sodium and potassium ions, as well as ATP. It also plays a role in the stabilization of the enzyme. For the formation of the functional enzyme, the presence of a γ - subunit is not necessary.

The sodium - potassium -ATPase is present in a plurality of combinations of isoforms of α - and β - subunits which have differences in distribution, affinity for cardiac glycosides and function. The α1 - Isoenzymtyp is found in all human cells, α2 - and α3 - types in the nerve cells and heart muscle (myocardium ). Rare mutations in the ATP1A2 and ATP1A3 genes can cause hereditary migraine, alternating hemiplegia and dystonia.

Function

The counter- transport ( antiport ) of 3 Na for 2 K via the cell membrane against the respective concentration gradient and in total against the electric resting membrane potential ( electrogenic ); he is thus equal to two times of externally supplied energy dependent: energy-dependent / active transport. That is set in this case, as the chemical binding energy by the hydrolysis of ATP available.

The phenomenon of ATP-driven transport is the best studied of the Na / K transport across the plasma membrane. Both cations are unequally distributed in cells:

• The Na concentration in the interior of the cell is low ( 0.2-2 mmol / l);
• The K concentration in the bulk is high ( 120-150 mmol / l).

This vital concentration gradient is caused on the one hand by potassium channels (see blood sugar sensor system ), the other by the electrogenic sodium-potassium ATPase.

Mechanism

ATP hydrolysis and Na / K transport are strictly coupled (electro genes principle):

• ATP per molecule three Na ions to the outside and two K ions are transported to the inside. In the balance sheet the intracellular space, a positive charge carriers is therefore withdrawn. This mechanism is the driving force for the preservation of, especially for nerve and muscle cells functionally important electrical resting membrane potential. However, it is not the charge balance of the pump alone, which leads to the generation of the resting membrane potential. The high permeability of the cell membrane of K ions, which is represented by potassium channels, and the low permeability to Na ions during the resting membrane potential is also required for its preservation.
• The pump mechanism conformational required by phosphorylation of aspartate ( Asp ) residue of the α - subunit can be produced. in this operation three Na ions are initially included;
• Their emission to the outside is performed in exchange for two K ions, which binding activates a phosphatase, which dephosphorylates the Asp residue again.

Effect of cardiac glycosides

Glycosides of digitalis group ( digoxin, digitoxin and its aglycone digitoxigenin ) and the group of Strophanthusgewächse (g- strophanthin (English Synonyms: ouabain ) and k - strophanthin ) - the latter, however, only at high concentrations - block the K conformation of the ATPase still in the phosphorylated state. In order to inhibit ion transport.

Indirectly thereby increases the concentration of intracellular Ca2 , and thus the contraction of the heart muscle, for

• The transport of Ca2 depends on the antiport principle of the Na concentration gradient from (sodium -calcium exchanger).
• Is this reduced Ca2 remains increasingly in the muscle cell, which intensified their contraction.

As the heart muscle cells of people with heart failure to contain a lot of calcium ( calcium overload, which leads to the reduction of contractility ), it was until recently incomprehensible why a further increase in cellular calcium content to increase contractility may result. A possible explanatory hypothesis: The α2 - α3 and - isoforms of the sodium-potassium pumps are located together with the sodium -calcium exchangers directly over the foothills of the calcium store of the cell ( sarcoplasmic reticulum table ). This functional unit is called Plasmerosom. This allows the local sodium or calcium concentration by inhibiting only relatively less sodium - potassium pump can be increased by cardiac glycosides, which the sarcoplasmic reticulum to release much larger amounts of calcium to the contractile proteins (with, for example, every heartbeat ) stimulates, without changing the total concentration of the cell in sodium - and calcium significantly changed. This is controlled more by the α1 isoform of the sodium-potassium pump. The Plasmerosome have already been demonstrated for nerve cells and arterial muscle cells and are probably also in skeletal and cardiac muscle cells present.

G - strophanthin is an endogenous cardiac glycoside, which is produced by the adrenal cortex of mammals. The endeogene synthesis, oral ingestion or a low-dose, slow intravenous administration of g- strophanthin only lead to low plasma concentrations, which initially lead to a stimulation of the sodium - potassium pump with consequent reduction of the cellular sodium and calcium content. This can lead to a negative inotropic effect as with a nitro - preparation or to a positive inotropic effect (probably depending on the starting position of the calcium concentration in heart muscle cells).

And K - strophanthin can stimulate the Na-K pump, but not digoxin. This explains, for example, the opposite effect of ouabain and digoxin in angina pectoris, with ouabain positive effect on ECG and seizure frequency, digoxin is well known, however, negative.