As noted previously, Na, K ATPase catalyzes the hydrolysis of ATP to adenosine diphosphate (ADP) and uses the energy to extrude three Na+ from the cell and take two K+ into the cell for each molecule of ATP hydrolyzed. It is an electrogenic pump in that it moves three positive charges out of the cell for each two that it moves in, and it is therefore said to have a coupling ratio of 3:2. It is found in all parts of the body. Its activity is inhibited by ouabain and related digitalis glycosides used in the treatment of heart failure. It is a heterodimer made up of an α subunit with a molecular weight of approximately 100,000 and a β subunit with a molecular weight of approximately 55,000. Both extend through the cell membrane (Figure 1). Separation of the subunits eliminates activity. The β subunit is a glycoprotein, whereas Na+ and K+ trans port occur through the α subunit. The β subunit has a single membrane-spanning domain and three extracellular glycosylation sites, all of which appear to have attached carbohydrate residues. These residues account for one-third of its molecular weight. The α subunit probably spans the cell membrane 10 times, with the amino and carboxyl terminals both located intracellularly. This subunit has intracellular Na+ and ATP binding sites and a phosphorylation site; it also has extracellular binding sites for K+ and ouabain. The endogenous ligand of the ouabain-binding site is unsettled. When Na+ binds to the α subunit, ATP also binds and is converted to ADP, with a phosphate being transferred to Asp 376, the phosphorylation site. This causes a change in the configuration of the protein, extruding Na+ into the ECF. K+ then binds extracellularly, dephosphorylating the α subunit, which returns to its previous conformation, releasing K+ into the cytoplasm.
Fig1. Na, K ATPase. The intracellular portion of the α subunit has a Na+-binding site (1), a phosphorylation site (4), and an ATP-binding site (5). The extracellular portion has a K+-binding site (2) and an ouabain-binding site (3). (Reproduced with permission from Horisberger JD, Lemas V, Kraehenbühl JP et al: Structure–function relationship of Na, K-ATPase, Annu Rev Physiol 1991; 53:565–584.)
The α and β subunits are heterogeneous, with α1 , α2 , and α3 subunits and β1 , β2 , and β3 subunits described so far. The α1 isoform is found in the membranes of most cells, whereas α2 is present in muscle, heart, adipose tissue, and brain, and α3 is present in heart and brain. The β1 subunit is widely distributed but is absent in certain astrocytes, vestibular cells of the inner ear, and glycolytic fast-twitch muscles. The fast-twitch muscles contain only β2 subunits. The different α and β subunit structures of Na, K ATPase in various tissues probably represent specialization for specific tissue functions.
