Gastric acid secretion by parietal cells is a highly intricate and dynamic process regulated by neural (efferent and afferent), hormonal (gastrin), and paracrine (histamine and somatostatin) pathways as well as mechanical (distension) and chemical (protein, glutamate, coffee, and ethanol) stimuli. Histamine, secreted from nearby enterochromaffin-like (ECL) cells, diffuses to parietal cells where it activates histamine-2 (H-2) receptors coupled to generation of intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) and subsequent activation of H+K+-adenosine triphosphatase (H+K+-ATPase), the proton pump.
Parietal cells have a limited life span (54 days in mice) and are continuously renewed from stem cells anchored in the isthmus region of the gastric glands [1•]. The stem cells give rise to three main progenitors: prepit, preneck, and preparietal cells. Parietal cells develop either directly from the preparietal cells or less commonly via differentiation of the prepit and preneck cell progenitors. The formation of a parietal cell involves a process of differentiation whereby there is production of cytoplasmic tubulovesicles, an increase in the number and length of microvilli, an increase in number and size of mitochondria, and expansion and invagination of the apical membrane with the formation of a canalicular system. It has been calculated that six parietal cells are produced in one isthmus each month. The most robust acid-producing parietal cells are located in the isthmus whereas the cells become more senescent as they migrate downward towards the base.
Improved understanding of the regulation of gastric acid secretion led to the development of acid-suppressive therapies, histamine H-2 receptor antagonists in the 1970s, and proton pump inhibitors (PPIs) in the 1980s, which have revolutionized the treatment of acid-related disorders including gastroesophageal reflux disease and peptic ulcer disease. More recently, concerns have been raised regarding potential risks of profound acid suppression including hypergastrinemia, rebound acid secretion, fundic gland polyps, infection, osteoporosis, and alterations in drug absorption . Murray et al.[3•] report that ex-vivo addition of PPIs (omeprazole, esomeprazole, and lansoprazole) to isolated rat gastric corpus increases transmucosal permeability in a dose-dependent manner and allows solutes at least as large as 4000 Da (i.e., polyethylene glycol) to permeate. The precise location and mechanism of the leak as well as the clinical consequences are not known. The authors postulate that PPI-induced unregulated transit of peptides and proteins (e.g., luminal epidermal growth factor, bacterial antigens, and food antigens) may potentially contribute to neoplasia. They further posit that increased diffusion of certain drugs may be deleterious (e.g., digoxin) or beneficial (e.g., antibiotics used to eradicate Helicobacter pylori). It should be noted that the absorption of certain drugs, such as levothyroxin, which is enhanced in an acid environment, is decreased during PPI treatment, despite the apparent leak .
Parietal cells secrete hydrochloric acid (HCl) as well as intrinsic factor, transforming growth factor-α, amphiregulin, heparin-binding epidermal growth factor-like growth factor, and sonic hedgehog [5,6]. Autoimmune gastritis is an autoimmune disease characterized by loss of parietal cells and consequently achlorhydria, hypergastrinemia, iron deficiency, and, in late stages, cobalamin deficiency. Autoantibodies directed against the parietal cell H+K+-ATPase (i.e., parietal cell antibodies) and against intrinsic factor are found in 80–90% and 30–50%, respectively; the specificity of intrinsic factor antibodies approaches 100% . The prevalence of autoimmune gastritis is ∼2% in the general population but increased three to five-fold in patients with other autoimmune disorders such as type I diabetes, thyroid disease, and primary biliary cirrhosis .
Central regulation of gastric acid secretion
The cephalic phase of acid secretion is induced by sensory inputs driven by the thought, sight, smell, taste, and swallowing of food. It primes the stomach to assist digestion by contributing ∼50% to the overall acid response to a meal. Pavlov's pioneering work studying the influence of conditioned reflexes on salivary secretion has recently been applied to the study of gastric acid secretion. Caboclo et al., using methodology that allows collection of gastric juice in rats in their habitual conditions (without restraining), paired sound as the conditioning stimulus with food as the unconditioning stimulus. After 10 days of conditioning, noise significantly increased acid secretion. The work confirms that interprandial secretion may be elicited physiologically by cortical factors such as memory-dependent learning behavior. Such secretion could conceivably play a role in peptic ulcer disease.
Peripheral regulation of gastric acid secretion
A variety of neurocrine, paracrine, and endocrine signals as well as luminal chemicals regulate gastric acid secretion such as gastrin, histamine, ghrelin, glutamate, coffee, somatostatin, and ethanol [10,11].
The major stimulants of acid secretion are histamine, gastrin, and acetylcholine . Histamine, released from neighboring ECL cells, stimulates the parietal cell directly via H-2 receptors. Gastrin, released from antral G cells, stimulates the parietal cell mainly indirectly via cholecystokinin-2 (CCK-2) receptors on ECL cells coupled to histamine release. Acetylcholine, released from postganglionic neurons, stimulates the parietal cell directly via M3 receptors and indirectly via M2 and M4 receptors coupled to inhibition of somatostatin secretion. Other stimulants include ghrelin, glutamate, and coffee.
Histamine, like gastrin, may act not only as a secretagogue but also as a mucosal growth factor. Histidine decarboxylase-deficient mice, which lack endogenous histamine synthesis, exhibit alterations in chief cell differentiation . The effect of histamine loss is, in part, mediated by the reciprocal increase in gastrin secretion induced by the decrease in luminal acidity since breeding of histidine decarboxylase-deficient mice onto the gastrin-null background ameliorates the premature chief cell differentiation phenotype. On the other hand, knockout of the H-2 receptor produces a different phenotype without alteration in chief cell lineages, despite an increase in gastrin secretion, suggesting that histamine may exert some of its influence via another histamine receptor, perhaps the H-3 receptor .
Gastrin, a hormone released from antral G cells, stimulates gastric acid secretion and mucosal cell growth. Its actions are mediated primarily through the CCK-2 receptor, a G protein-coupled receptor previously termed the CCKB or gastrin receptor. It is currently believed that gastrin stimulates the ECL cells to release histamine, which, in turn, binds to H-2 receptors on parietal cells to stimulate acid secretion .
Gastrin is secreted in response to chemical (e.g., elevated pH and protein) and mechanical (e.g., distension) stimuli that act directly on the G cell and/or indirectly via adjacent neuroendocrine cells and neurons. Capsaicin, the pungent ingredient in hot chilli peppers, is known to excite sensory neurons by binding the vanilloid receptor-1 (VR1). Ericson et al.[15•], using isolated human antral glands, localized VR1 to G cells and showed that capsaicin stimulates gastrin secretion. Similar results were reported by Kidd et al. using isolated rodent G cells. Gastrin release was also stimulated by pituitary adenylate cyclase-activating protein, bombesin, sucralose, glucose, caffeine, and bacterial lipopolysaccharide. Whether luminal substances, in intact organisms, can actually reach and interact with specific gastrin cell surface receptors, however, has not been proven.
Hypergastrinemia, defined as a fasting serum gastrin concentration of >100 pg/ml or >47.7 pM, is frequently encountered in patients. Causes include gastrinoma, antral predominant H. pylori gastritis, gastric outlet obstruction, renal failure, retained antrum, atrophic gastritis, and antisecretory therapy .
Acute infection with H. pylori is associated with hypochlorhydria. The mechanisms by which H. pylori inhibits acid secretion are multifactorial and include production of the proinflammatory cytokine interleukin 1β. In gastric carcinoma cells, interleukin 1β inhibits gastrin secretion at the transcriptional level, in part via activation of NFκB .
Although ghrelin has been reported to be present in A-like or Gr cells located in the basal portion of oxyntic glands, a recent study reports its presence abundantly in pyloric glands, as well . Gr cells account for 20–30% of all gastric endocrine cells and the mammalian stomach produces 60–80% of the body's ghrelin. Alternate splicing of the preproghrelin yields ghrelin, des-acyl ghrelin, and obestatin . The major active form of human ghrelin is a 28-amino acid peptide modified by octanoyl esterification of a serine residue at position three of the peptide chain. The acyl transferase enzyme responsible for this modification is ghrelin O-acyltransferase (GOAT) . Using a custom-made anti-GOAT antibody, Stengel et al. report that 95% of GOAT-immunoreactive cells in mice co-labeled with ghrelin whereas in rats only 56% of GOAT-positive cells showed co-expression of ghrelin; the remainder, in rat, co-expressed histidine decarboxylase. Similar findings in mice were reported by Sakata et al..
In the gastrointestinal tract, ghrelin increases appetite and stimulates motility and gastric emptying . Following bariatric surgery, in particular procedures that involve gastric resection or bypass, ghrelin levels are reduced . In rat weanling pups, vitamin B12 deficiency is associated with decreased plasma ghrelin levels and lowered body weights . In piglets, zinc supplementation increased plasma concentration of ghrelin as well as food intake and growth .
Iwakura et al. have established a ghrelin-producing cell line, MGN3-1, from a mouse gastric ghrelin-producing tumor. This cell line, which contains GOAT and responds appropriately to somatostatin, may prove useful for studying the production and secretion of ghrelin.
It has been postulated that certain gastric epithelial cells may sense luminal nutrients and function similar to taste receptor cells. Hass et al.[29•] have identified taste receptors of the subtype T1R3, which detect sugar and amino acids, on closed type ghrelin cells and adjacent open type brush cells in mice. This is interesting since ghrelin secretion is decreased by food intake, in particular proteins and carbohydrates. Whether food constituents regulate ghrelin secretion indirectly via paracrine signals emanating from adjacent brush cells or from serum concentrations of amino acids and glucose remains to be investigated.
Using elutriation and gradient centrifugation to enrich various cell fractions from isolated rat gastric mucosa, Nakamura et al. show that parietal cells express the metabotropic glutamate receptors mGluR1, mGluR2, mGluR3, mGluR4, mGluR6, and mGluR7. Smaller endocrine cells, possibly somatostatin-containing D cells, expressed mGluR2, 3, 4, and 7, although expression was low. A decrease in somatostatin secretion may be one mechanism whereby glutamate stimulates acid secretion in dogs equipped with vagally innervated or vagally denervated gastric pouches .
As coffee stimulates gastric acid secretion and is associated with peptic ulcer and gastroesophageal reflux disease, work has been directed to developing a ‘stomach-friendly’ coffee. Weiss et al. at the German Research Center for Food Chemistry developed a flow cytometric method for measuring the intracellular pH of the human parietal cell line HGT-1 using the pH sensitive dye, 1,5-carboxyseminaphtorhodafluor acetoxymethyl ester (SNARF-AM). Treatment with histamine resulted in an 8% decrease in intracellular proton concentration, indicating increased proton efflux whereas treatment with omeprazole resulted in a 22% increase in intracellular protons. Steam treatment prior to roasting reduced the ability of both caffeinated and decaffeinated coffee to stimulate acid secretion in this preparation.
Inhibitors include somatostatin, ethanol, and cadmium.
Somatostatin is present in D cells of the gastric oxyntic and pyloric mucosa. It inhibits acid secretion in a paracrine fashion directly by inhibiting secretion from the parietal cell as well as indirectly by inhibiting histamine secretion from the ECL cell and gastrin secretion from the G cell.
The biological actions of somatostatin are mediated via six G protein-coupled receptors encoded by five different genes, termed sst1–sst5. The sst2 somatostatin receptor exists in two splice variants sst2A and sst2B . The sst2 receptor is the most widely distributed somatostatin receptor subtype and is the subtype involved in the regulation of gastric acid secretion. In isolated vascularly perfused mouse stomach, exogenous adenosine, >1 μM, stimulates somatostatin secretion via the A2A receptor whereas at lower concentrations it inhibits somatostatin secretion via the A1 receptor .
Alcoholic beverages stimulate acid secretion but the effect of pure alcohol is controversial with most, but not all, studies showing inhibition. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is activated by an increase in the AMP/ATP-ratio and functions as a cellular energy sensory that prevents ATP-depletion of the cell by down-regulating energy consuming key enzymes and inducing pathways that generate ATP. An increase in AMPK inhibits acid secretion in mouse stomach . In isolated rat gastric glands loaded with the pH-sensitive dye BCECF, low-dose (2%) ethanol inhibits secretagogue-dependent acid secretion by activation of the AMPK pathway [36•].
Cadmium, ingested through contaminated food and water, is a highly toxic nonessential heavy metal. In amphibian oxyntic mucosa mounted in Ussing chamber, addition of cadmium to the serosal, but not luminal side, inhibits histamine-stimulated acid secretion . The precise mechanism, however, is not known.
Intracellular regulation of gastric acid secretion
During acid secretion, there is a morphological transformation of the parietal cell with translocation of cytoplasmic tubulovesicles containing the acid-secreting pump (H+K+-ATPase) to the apical membrane where it transports protons out of the cell in exchange for luminal potassium at the expense of a molecule of ATP. Although H+K+-ATPase is often considered the most important contributor for HCl secretion into the lumen, chloride secretion and potassium recycling are equally necessary.
The parietal cell secretes isotonic HCl against a huge gradient (greater than 106-fold) by ATP-driven exchange of one H+ for one K+ at the apical plasma membrane via the enzyme known as H+K+-ATPase [38••]. The H+K+-ATPase is composed of a catalytic α-subunit and an accessory β-subunit . In the resting state, the bulk of H+K+-ATPase is sequestered within cytoplasmic tubulovesicles and is inactive (Fig. 1). Stimulation of acid secretion effects a recruitment and fusion of the tubulovesicles with the apical membrane and electrogenic H+ transport. A number of proteins have been implicated in parietal cell membrane targeting, docking, and fusion including soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) such as VAMP, syntaxins 1 and 3, and SNAP25 as well as Rab GTPases such as rab11. Other participating proteins include dynamin, F-actin, and ezrin.
PPIs are prodrugs that become locally activated within the acid environment of the apical canaliculus and covalently bind extracellular cysteine residues of the H+K+-ATPase that are accessible from the gastric lumen. Thus, only the proton pumps inserted into the apical membrane are susceptible to blockade by PPIs and the covalent binding mechanism permits PPIs to continue to act long after their plasma concentrations have dropped [40••].
Clotrimazole, an imidazole derivative antimycotic drug, has been shown to inhibit gastric H+K+-ATPase derived from hog gastric mucosa . As there is a loss of polarity in this preparation, it would be useful to repeat the studies in intact stomach.
Channels and transporters
Acid secretion by the parietal cell requires a functional H+K+-ATPase as well as apical chloride and potassium channels [40••] (Fig. 1). Chloride enters the cell via the basolateral membrane chloride channel, SLC26A7, as well as the Cl−/HCO3− exchanger, SLC4A2, and the Na+-2Cl−K+ cotransporter, NKCCl (Fig. 1) . Chloride is thought to exit the apical membrane via the cystic fibrosis transmembrane regulator (CFTR). The CFTR is present in parietal cells and small-molecule CFTR inhibitors as well as mutations in the CFTR decrease gastric acid secretion. An additional route for chloride secretion may involve the Cl−/HCO3− exchanger, SLC26A9; it, too, has been localized to the apical membrane of parietal cells and knockout of this exchanger impairs acid secretion.
Potassium secretion into the gastric lumen provides substrate for reciprocal proton secretion and is necessary for maintaining sustained H+K+-ATPase activity. The main apical potassium channel is KCNQ1  (Fig. 1). KCNQ1 assembles with its β-subunit KCNE2 to function as a constitutively open, voltage-insensitive, and acid-resistant luminal potassium channel. Other luminal potassium channels may include members of the Kir family (e.g., Kir4.1) which are trafficked together with H+K+-ATPase to the apical membrane upon stimulation.
Two parietal cell intracellular signaling pathways key to acid secretion are the cAMP-mediated protein kinase activation (PKA) pathway induced by histaminergic activation of the H-2 receptor and the intracellular calcium pathway induced by cholinergic activation of the M3 receptor and gastrin activation of the CCK2 receptor. Intracellular levels of cAMP are, in part, also regulated by phosphodiesterase-4 which hydrolyzes cAMP into inactive metabolites  and phosphoinositol-3-kinase (P13K) which activates protein kinase B/Akt and inhibits cAMP formation .
Acid secretion is highly energy dependent. The parietal cell is packed with abundant mitochondria to ensure an adequate supply of ATP. A recent study suggests that AMPK may function as a metabolic energy regulator to switch off acid secretion as cellular ATP levels fall . As AMPK is a known modulator of the CFTR in other tissue, it is conceivable that it inhibits acid secretion by inhibiting the function of the apical chloride channel, CFTR. As discussed above, low-dose ethanol inhibits acid secretion via activation of the AMPK pathway [36•].
Risks of profound acid suppression
PPIs are the second most prescribed class of drugs in the United States and, although remarkably well tolerated, concerns have been raised recently regarding potential serious clinical adverse effects. The physiological consequence of acid suppression is hypergastrinemia. Gastrin is not only a secretagogue but also exerts growth promoting effects in normal and neoplastic tissues. In the stomach, hypergastrinemia results in parietal and ECL cell hyperplasia which persists for 2–3 months after stopping the PPI [46••]. The clinical consequence is rebound acid secretion after discontinuation of PPIs which may induce dyspeptic symptoms in healthy individuals, exacerbate reflux symptoms in patients with gastroesophageal reflux disease, and provoke symptoms in patients with duodenal ulcer disease [47••].
Gastrin, acting via the CCK-2 receptor, suppresses apoptosis in a variety of tumors in and outside the gastrointestinal tract [48,49]. A recent study suggests that hypochlorhydria (and hence hypergastrinemia) is a strong independent risk factor for esophageal squamous cell carcinoma .
Other purported adverse effects of acid suppression by proton pump inhibitors include infections, bacterial overgrowth, osteoporosis, and drug–drug interactions; these are discussed in Denis McCarthy's article.
Too much acid and too little acid secretion are both important pathogenic factors for a variety of common upper gastrointestinal disorders. We continue to make progress in our understanding of gastric acid secretion in health and disease. In particular, much progress has being made in elucidating the mechanisms and pathways regulating H+K+-ATPase trafficking as well as ion transport in the parietal cell. It is anticipated that this knowledge will lead to the development of new drugs to treat acid-peptic disorders. In addition, we are beginning to take stock of potential adverse effects related to prolonged and profound inhibition of acid secretion.
The author is grateful to Mary Beatty-Brooks for the artwork.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 663–665).
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