The gastric H(+),K(+)-ATPase is responsible for gastric acid secretion. This ATPase is composed of two subunits, the catalytic α subunit and the structural β subunit. The α subunit with molecular mass of about 100 kDa has 10 transmembrane domains and is strongly associated with the β subunit with a single transmembrane segment and a peptide mass of 35 kDa. Its three-dimensional structure is based on homology modeling and site-directed mutagenesis resulting in a proton extrusion and K(+) reabsorption model. There are three conserved H3O(+)-binding sites in the middle of the membrane domain and H3O(+) secretion depends on a conformational change involving Lys(791) insertion into the second H3O(+) site enclosed by E795, E820, and D824 that allows export of protons at a concentration of 160 mM. K(+) countertransport involves binding to this site after the release of protons with retrograde displacement of Lys(791) and then K(+) transfer to E343 and exit to the cytoplasm. This ATPase is the major therapeutic target in treatment of acid-related diseases and there are several known luminal inhibitors allowing analysis of the luminal vestibule. One class contains the acid-activated covalent, thiophilic proton pump inhibitors, the most effective of current acid-suppressive drugs. Their binding sites and trypsinolysis allowed identification of all ten transmembrane segments of the ATPase. In addition, various K(+)-competitive inhibitors of the ATPase are being developed, with the advantage of complete and rapid inhibition of acid secretion independent of pump activity and allowing further refinement of the structure of the luminal vestibule of the E2 form of this ATPase.
2011 American Physiological Society