an ion pump the H+/K+ ATPase is able to transport ions against a concentration gradient using energy derived from the hydrolysis of ATP. Like all P-type ATPases, a phosphate group is transferred from adenosine triphosphate (ATP) to the H+/K+ ATPase during the transport cycle. This phosphate transfer powers a conformational change in the enzyme that helps drive ion transport. The hydrogen potassium ATPase is activated indirectly by gastrin that causes ECL cells to release histamine. The histamine binds to H2 receptors on the parietal cell, activating a cAMP-dependent pathway which causes the enzyme to move from the cytoplasmic tubular membranes to deeply folded canaliculi of the stimulated parietal cell. Once localized, the enzyme alternates between two conformations, E1 and E2, to transport ions across the membrane. The E1 conformation binds a phosphate from ATP and hydronium ion on the cytoplasmic side. The enzyme then changes to the E2 conformation, allowing hydronium to be released in the lumen. The E2 conformation binds potassium, and reverts to the E1 conformation to release phosphate and K+ into the cytoplasm where another ATP can be hydrolyzed to repeat the cycle. The β subunit prevents the E2-P conformation from reverting to the E1-P conformation, making proton pumping unidirectional. The number of ions transported per ATP varies from 2H+/2K+ to 1H+/1K+depending on the pH of the stomach. Disease relevance and inhibition Inhibiting the hydrogen potassium pump to decrease stomach acidity has been the most common method of treating diseases including gastroesophageal reflux disease (GERD/GORD) and peptic ulcer disease (PUD). Reducing acidity alleviates disease symptoms but does not treat the actual cause of GERD (abnormal relaxation of the esophageal sphincter) or PUD (Helicobacter pylori and NSAIDs). Three drug classes have been used to inhibit H+/K+-ATPases. H2-receptor antagonists, like cimetidine (Tagamet), inhibit the signaling pathway that leads to activation of the ATPase. This type of inhibitor is effective in treating ulcers but does not prevent them from forming, and patients develop tolerance to them after about one week, leading to a 50% reduction in efficacy. Proton pump inhibitors (PPIs) were later developed, starting with Timoprazole in 1975. PPIs are acid-activated prodrugs that inhibit the hydrogen-potassium ATPase by binding covalently to active pumps. Current PPIs like Omeprazole have a short half-life of approximately 90 minutes. Acid pump antagonists (APAs) or potassium-competitive acid blockers (PCABs) are a third type of inhibitor that blocks acid secretion by binding to the K+