Gastric hydrogen potassium ATPase, also known as H+/K+ ATPase, is an enzyme which functions to acidify the stomach. It is a member of the P-type ATPases, also known as E1-E2 ATPases due to its two states. Biological function and location The gastric hydrogen potassium ATPase or H+/K+ ATPase is the proton pump of the stomach. It exchanges potassium from the intestinal lumen with cytoplasmic hydronium and is the enzyme primarily responsible for the acidification of the stomach contents and the activation of the digestive enzyme pepsin (see gastric acid). The H+/K+ ATPase is found in parietal cells, which are highly specialized epithelial cells located in the inner cell lining of the stomach called the gastric mucosa. Parietal cells possess an extensive secretory membrane system and the H+/K+ ATPase is the major protein constituent of these membranes. A small amount of H+/K+ ATPase is also found in the renal medulla. Genes and protein structure The H+/K+ ATPase is a heterodimeric protein, the product of 2 genes. The gene ATP4A encodes the H+/K+ ATPase α subunit, and is a ~1000-amino acid protein that contains the catalytic sites of the enzyme and forms the pore through the cell membrane that allows the transport of ions. Hydronium ions bind to two active sites present in the α subunit. The α subunit also has a phosphorylation site (Asp385). The gene ATP4B encodes the β subunit of the H+/K+ ATPase, which is a ~300-amino acid protein with a 36-amino acid N-terminal cytoplasmic domain, a single transmembrane domain, and a highly glycosylated extracellular domain. The H+/K+ ATPase β subunit stabilizes the H+/K+ ATPase α subunit and is required for function of the enzyme. The β subunit prevents the pump from running in reverse, and it also appears to contain signals that direct the heterodimer to membrane destinations within the cell, although some of these signals are subordinate to signals found in H+/K+ ATPase α subunit. The structure of H+/K+ ATPase has been determined for humans, dogs, hogs, rats, and rabbits and is 98% homologous across all species. Enzyme mechanism and activity H+/K+ ATPase is a P2-type ATPase, a member of the eukaryotic class of P-type ATPases. Like the Ca2+ and the Na+/K+ ATPases, the H+/K+ ATPase functions as an α, β protomer. Unlike other eukaryotic ATPases, the H+/K+ ATPase is electroneutral, transporting one proton into the stomach lumen per potassium ion retrieved from the gastric lumen. As