The future of the pump

Since it was discovered 3 decades ago the H,K-ATPase has come to be recognized as the key both to the generation and pharmacologic suppression of gastric acid secretion. Although 30 years of concerted research has answered many questions, it is perhaps not surprising that these efforts have raised many new and crucial issues that await elucidation. These can be divided into 5 broad categories that relate to structure, mechanism, regulation, trafficking, and macromolecular interactions. It is probably safe to predict that the growing sophistication of x-ray crystallographic techniques will yield a picture of the pump's molecular structure in the near future. These insights will, in turn, illuminate the details of the process through which enzymatic hydrolysis is coupled to ion translocation with unprecedented clarity. The gastric parietal cell employs an extremely complicated system of receptors, kinases, and second messengers to maintain tight control over pump function. Upon activation, this cell also performs a massive and elegant membrane trafficking transformation that plays a critical role in the regulatory process. Finally, it is becoming clear that every ion transport protein is a component in a large macromolecular complex whose constituents help to determine all of the transport system's fundamental physiologic properties. These are the major topics that will drive H,K pump research in the future, and it is likely that their resolution will create the foundations for the next generation of therapies aimed at controlling gastric acid secretion and its clinical consequences.