Helicobacter pylori persistently colonize the human stomach and have been linked to atrophic gastritis and gastric carcinoma. Although it is well known that H. pylori infection can result in hypochlorhydria, the molecular mechanisms underlying this phenomenon remain poorly understood. Here we show that VacA permeabilizes the apical membrane of gastric parietal cells and induces hypochlorhydria. The functional consequences of VacA infection on parietal cell physiology were studied using freshly isolated rabbit gastric glands and cultured pari- Helicobacter pylori are Gram-negative bacteria that colonize the gastric mucosa in more than half of the world's human population and persist despite a vigorous host immune response. Infection with these organisms consistently results in gastric inflammation and is a risk factor for the development of peptic ulcer disease, distal gastric adenocarcinoma, and gastric lymphoma (1, 2). Some individuals who are persistently infected with H. pylori develop a body-predominant atrophic gastritis and profound suppression of gastric acid secretion (3, 4). Atrophic gastritis is considered a risk factor for the development of gastric adenocarcinoma (5). In addition to causing hypochlorhydria in the setting of chronic infection, H. pylori also can cause hypochlorhydria in the setting of acute infection (6). The molecular mechanisms underlying H. pylori-induced hypochlorhydria have remained incompletely understood.Acid secretion by the gastric parietal cell is regulated by paracrine, endocrine, and neural pathways. The physiological stimuli for acid secretion include histamine, acetylcholine, and gastrin, each of which binds to receptors located on the basolateral plasma membranes. Stimulation of acid secretion typically involves an activation of a cAMP-dependent protein kinase cascade that triggers the translocation and insertion of the proton pump enzyme, H,K-ATPase, into the apical plasma membrane of parietal cells (7). Ezrin is an actin-binding protein of the ezrin/radixin/moesin family of cytoskeleton-membrane linker proteins (8, 9) and, within the gastric epithelium, has been localized exclusively to parietal cells and primarily to the apical canalicular membrane of these cells (10). Our previous studies show that gastric ezrin is co-distributed with the -actin isoform in vivo (11) and preferentially binds to the -actin isoform in vitro (9). Based on the cytolocalization and observed stimulation-dependent phosphorylation of ezrin, it was postulated that ezrin couples the activation of protein kinase A to the apical membrane remodeling associated with parietal cell secretion (10, 12). Indeed, we have recently mapped the protein kinase A phosphorylation site on ezrin and elucidated the phosphoregulation of gastric acid secretion (13).