The gastric H,K ATPase as a drug target: past, present, and future.
The recent progress in therapy if acid disease has relied heavily on the performance of drugs targeted against the H,K ATPase of the stomach and the H2 receptor antagonists. It has become apparent in the last decade that the proton pump is the target that has the likelihood of being the most sustainable area of therapeutic application in the regulation of acid suppression. The process of activation of acid secretion requires a change in location of the ATPase from cytoplasmic tubules into the microvilli of the secretory canaliculus of the parietal cell. Stimulation of the resting parietal cell, with involvement of F-actin and ezrin does not use significant numbers of SNARE proteins, because their message is depleted in the pure parietal cell transcriptome. The cell morphology and gene expression suggest a tubule fusion-eversion event. As the active H,K ATPase requires efflux of KCl for activity we have, using the transcriptome derived from 99% pure parietal cells and immunocytochemistry, provided evidence that the KCl pathway is mediated by a KCQ1/KCNE2 complex for supplying K and CLIC6 for supplying the accompanying Cl. The pump has been modeled on the basis of the structures of different conformations of the sr Ca ATPase related to the catalytic cycle. These models use the effects of site directed mutations and identification of the binding domain of the K competitive acid pump antagonists or the defined site of binding for the covalent class of proton pump inhibitors. The pump undergoes conformational changes associated with phosphorylation to allow the ion binding site to change exposure from cytoplasmic to luminal exposure. We have been able to postulate that the very low gastric pH is achieved by lysine 791 motion extruding the hydronium ion bound to carboxylates in the middle of the membrane domain. These models also allow description of the K entry to form the K liganded form of the enzyme and the reformation of the ion site inward conformation thus relating the catalytic cycle of the pump to conformational models. The mechanism of action of the proton pump inhibitor class of drug is discussed along with the cysteines covalently bound with these inhibitors. The review concludes with a discussion of the mechanism of action and binding regions of a possible new class of drug for acid control, the K competitive acid pump antagonists.
Sachs
George
G
Department of Physiology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA. gsachs@ucla.edu
Shin
Jai Moo
JM
Vagin
Olga
O
Lambrecht
Nils
N
Yakubov
Iskandar
I
Munson
Keith
K
D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D020134:Catalytic Domain; D002712:Chlorides / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000201:enzymology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010295:Parietal Cells, Gastric / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology; D011188:Potassium / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D021381:Protein Transport; D054328:Proton Pump Inhibitors; D013329:Structure-Activity Relationship
D000897:Anti-Ulcer Agents; D002712:Chlorides; D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium