Big Chemical Encyclopedia

Chemical substances, components, reactions, process design ...

Articles Figures Tables About

Parietal cells secretory canaliculus

MOA PPIs are substituted benzimidazoles that irreversibly inhibit gastric parietal cell release of acid. PPIs are prodrugs that must be activated in the acidic environment of the secretory canaliculus located in the parietal cell. PPIs inhibit the ATPase pump and can inhibit nearly 100% of the gastric acid secretion Promotility agents increase LES tone and accelerate gastric emptying. [Pg.100]

Hydrochloric acid is secreted by parietal cells via H, K -ATPase pumps (proton pumps), of which there are more than one million per cell. The H, K -ATPase pumps utilize the phosphorylation of ATP to exchange water-solvated protons (protonated water, hydroxonium ion, H30 ) for potassium ions. In conjunction with parallel potassium and chloride ion conductances, this ATPase is responsible for the secretion of hydrochloric acid into the secretory canaliculus of the parietal cell, the enclosed space reaching a pH of near 1.0 (Rabon Reuben 1990). In the resting parietal cell, these pumps reside within the membranes of vesicles in the cell cytoplasm. When activated by histamine and gastrin, the parietal cells alter their shape and the vesicles merge with the outer cell membrane to form secretory canaliculi. [Pg.97]

When the resting parietal cell is stimulated by acid secretagogues, the tubulovesicles are transformed into the secretory canaliculus. The parietal cell has the largest mitochondrial content of any mammalian cell (—34% of cell volume) and the ATP generated by this is mainly used for acid secretion. Hydrolysis of ATP results in a conformational change in the protein that mediates the electroneutral exchange of intracellular and extracellular K+. The pump is activated only when it is associated with a potassium chloride pathway in the canalicular membrane (Fig. 3.6). This allows potassium chloride efflux into the extra-cytoplasmic space and thus results in the secretion of HCl at the expense of ATP... [Pg.104]

Schematic representation of the resting (left side) and stimulated (right side) state of the parietal cell. Basolateral membrane contains three major receptor classes gastrin (G), acetylcholine (ACh), and histamine (H). Their actions are mediated by cAMP responses, Ca changes, or both. In addition, there are a number of ion transport pathways. In the stimulated state, the apical membrane acquires H", K -ATPase contained in the tubulovesicles (tv) as well as the property of K+ and CI conductance, both of which are essential in the secretion of HCl. A change in cytoskeletal arrangement is also associated with stimulation. CaM = calmodulin SC -secretory canaliculus mf = microfilaments. [Reproduced with permission from D. H. Malinowska and G. Sachs, Cellular mechanisms of acid secretion, Clin. Gastroenterol. 13, 322 (1984).]... Schematic representation of the resting (left side) and stimulated (right side) state of the parietal cell. Basolateral membrane contains three major receptor classes gastrin (G), acetylcholine (ACh), and histamine (H). Their actions are mediated by cAMP responses, Ca changes, or both. In addition, there are a number of ion transport pathways. In the stimulated state, the apical membrane acquires H", K -ATPase contained in the tubulovesicles (tv) as well as the property of K+ and CI conductance, both of which are essential in the secretion of HCl. A change in cytoskeletal arrangement is also associated with stimulation. CaM = calmodulin SC -secretory canaliculus mf = microfilaments. [Reproduced with permission from D. H. Malinowska and G. Sachs, Cellular mechanisms of acid secretion, Clin. Gastroenterol. 13, 322 (1984).]...
Electron micrographs of a resting and stimulated parietal cell showing the conversion of the cytoplasmic tubulovesicles to the microvilli of the secretory canaliculus. [Pg.108]

Acid secretion is a regulated process whose rate is determined by its necessity after a meal. Consequently, the eventual result of the complex mechanisms for regulation of secretion described in previous sections is to activate the H,K ATPase. In contrast to the regulation of many other enzymes, there is no evidence for any chemical factors that directly influence the activity of the H,K ATPase, other than the availability of the necessary substrates MgATP, H, and K. Because within the parietal cell the availability of protons and AAgATP is not likely to be rate limiting, it follows that the major, if not the only, factor that controls proton transport is the availability of K at the extracytosolic surface of the H,K ATPase. Substantial evidence has accumulated to indicate that this is indeed the case, and that activation of the proton pump results from association of the H,K ATPase with a K and Cl" permeability in the membrane of the secretory canaliculus. [Pg.119]

ATPase with an endogenous K permeability is necessary and sufficient for activation of the proton pump in the parietal cell. However, for K to efflux by itself would result in a large membrane potential hindering acid secretion thus, the exit of K through a K channel is accompanied by the efflux of Cl" through a Cl" channel. Several different channels have been claimed to be associated with the secretory canaliculus, but the means whereby they are activated along with translocation of the ATPase remain unknown. [Pg.120]

A model of activation of acid secretion by the parietal cell. On the left is the resting cell, with most of the pumps (in red) present in the cytoplasmic tubules. On the right, after stimulation either by histamine or acetylcholine (ACh), the pump is now associated with the microvilli of the expanded secretory canaliculus that also contains conductances for K and Cl". Both Ca and cAAAP signaling systems are involved. [Pg.120]

Activity of the H,K ATPase results In a primary secretion of 160 mM of HCl Into the secretory canaliculus. Because the H,K ATPase Is electroneutral. It Is necessary that the KCl permeability pathway assodated with the canaliculus transfer a minimum of 160 mmol of KCl for each liter of acidic fluid secreted. This Is true whether the KCl pathway consists of conductive or electroneutral transporters. It Is likely. In fact, that the KCl pathway allows transfer of a slight excess of KCl over the minimum required for the production of HCl. This Is suggested both by the observation that gastric secretions contain a low but significant concentration of KCl and by the likelihood that the H,K ATPase Is not fully efficient at recovering K from the canalicular fluid. In the absence of other mechanisms, the combined activity of the transporters at the apical pole of the parietal cell would lead to alkallnizatlon of the cell and depletion of cellular Cl" and K. The potential disturbances In electrolyte balance are prevented by the activity of transporters at the basolateral membrane. These Include an anion exchanger (AE, HCOj /Cl"), a sodlum/proton exchanger (NHE), and the Na,K ATPase. [Pg.123]

The PPIs have a unique mode of action, being add-activated prodrugs. They covalently inhibit the gastric H,K ATPase. First, as weak bases, they accumulate in the acid space generated in the secretory canaliculus of the stimulated parietal cell. This accumulation is followed by acid-dependent conversion to the active compound, a cationic thiophilic reagent. The active spedes binds covalently to one or more cysteines accessible from the luminal face of the pump hence, there is covalent inhibition of the proton pump by these PPIs. Their inhibitory effect is prolonged as compared to their dwell time in the blood. [Pg.136]

A high-resolution micrograph of a stimulated parietal cell after inhibition by radioactive omeprazole, showing the localization of the binding of this PPI exclusively to the active secretory canaliculus. The dark grains indicate the covalent binding of acid-activated omeprazole to the pump in the secretory canaliculus. [Pg.151]

An illustration of the essential steps in inhibition of acid secretion by PPIs with pantoprazole as an example. The drug is administered in a gastroprotected formulation and is absorbed in the duodenum or is administered in a reconstituted IV formulation. The acidic, membrane-enclosed space of the active parietal cell s secretory canaliculus accumulates the PPI approximately 1,000-fold (pH 1.0, pKa of drug approximately 4.0) due to protonation of the pyridine. After intramolecular transfer to the N of the benzimidazole, rearrangement of the molecule occurs to form first the cationic thiophilic sulfenic acid and then the sulfonamide, either of which reacts rapidly with cysteines on the luminal face of the pump. [Pg.310]

Figure 2. This illustrates the general mechanism of acid secretion catalyzed by H,K ATPase. It secretes acid only when present in the canalicular membrane. There is activation of a KVCl pathway that enables efflux of KCl and H2O from the cytoplasm of the parietal cell. The K secreted into the lumen of the secretory canaliculus of the parietal cell is transported inward in exchange for by the cycle of phosphorylation/dephosphorylation on the catalytic subunit of the H,K ATPase, leaving HCl in the canalicular lumen. Figure 2. This illustrates the general mechanism of acid secretion catalyzed by H,K ATPase. It secretes acid only when present in the canalicular membrane. There is activation of a KVCl pathway that enables efflux of KCl and H2O from the cytoplasm of the parietal cell. The K secreted into the lumen of the secretory canaliculus of the parietal cell is transported inward in exchange for by the cycle of phosphorylation/dephosphorylation on the catalytic subunit of the H,K ATPase, leaving HCl in the canalicular lumen.
Figure 5. A model of the receptors present on the basolateral surface of the parietal cell and their intracellular effects, which lead to movement of the H,K ATPase from the cytoplasmic tubule to the microvillus of the secretory canaliculus. The cholinergic receptor is of the M3 sub-type and increases intracellular calcium. The gastrin receptor is the CCK-B receptor and also generates calcium signaling, although it appears that elevation of cAMP is required for this signaling cascade. The histamine 2 (H2) receptor is coupled mainly to adenylate cyclase and is the major regulatory receptor for acid secretion. The substrates for the A kinase are not known. Figure 5. A model of the receptors present on the basolateral surface of the parietal cell and their intracellular effects, which lead to movement of the H,K ATPase from the cytoplasmic tubule to the microvillus of the secretory canaliculus. The cholinergic receptor is of the M3 sub-type and increases intracellular calcium. The gastrin receptor is the CCK-B receptor and also generates calcium signaling, although it appears that elevation of cAMP is required for this signaling cascade. The histamine 2 (H2) receptor is coupled mainly to adenylate cyclase and is the major regulatory receptor for acid secretion. The substrates for the A kinase are not known.
Figure 6. A model of the cycling of the H,K ATPase between the cytoplasmic tubule and the microvillus of the secretory canaliculus of the parietal cell. Figure 6. A model of the cycling of the H,K ATPase between the cytoplasmic tubule and the microvillus of the secretory canaliculus of the parietal cell.

See other pages where Parietal cells secretory canaliculus is mentioned: [Pg.116]    [Pg.626]    [Pg.107]    [Pg.107]    [Pg.108]    [Pg.120]    [Pg.143]    [Pg.144]    [Pg.147]    [Pg.151]    [Pg.308]    [Pg.309]    [Pg.63]    [Pg.66]   
See also in sourсe #XX -- [ Pg.108 ]




SEARCH



Canaliculi

Parietal cells

Secretory

© 2024 chempedia.info