The mammalian parietal cell is dedicated to the secretion of HCl in response to various stimuli and second messengers. Oxidative metabolism in the cell increases about 10-fold in order to supply ATP to the gastric proton pump, the H+,K+-ATPase. This pump appears to be present only in the parietal cell. This membrane-embedded enzyme uses the scalar energy of ATP hydrolysis to carry out the vectorial transport of H+ in one direction in exchange for K+ in the other direction. In the cytoplasmic vesicle, K+ does not permeate the membrane, whereas in the secretory canaliculus, there is a Cl- channel and a KCl cotransport pathway which allow K+ and Cl- to exit from the cell. The K+ is then recycled back into the cell by the ATPase, and H+ secretion occurs into the canalicular space. Although there are other proton pumps, only the gastric H+,K+-ATPase has this exchange mechanism and only the gastric H+,K+-ATPase is able to generate a pH of less than 4. Thus the gastric proton pump has a unique structure and mechanism, and produces a unique luminal pH. This enzyme is therefore an appropriate target for rational drug design.
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