The parietal cell is stimulated by acetylcholine, gastrin, and histamine. Neural, hormonal, and paracrine pathways regulate the parietal cell. Vagal parasympathetic preganglionic outflow to the stomach activates the parietal cell in three ways. Acetylcholine is released from enteric neurons, which acts on the parietal cell via muscarinic receptors. Histamine is released from the ECL cell, which stimulates the parietal cell through a paracrine pathway. Gastrin-releasing peptide (GRP) from enteric neurons activates G cells in gastric glands, leading to the release of gastrin. Gastrin then stimulates the parietal cell through a humoral pathway.

The exact mechanism of chemosensors is unclear, but it may involve endocrine cells releasing their contents to activate nerve endings. This topic will be further discussed in Chapter 30.

There is a negative feedback mechanism that inhibits the parietal cell when there is acid present in the distal part of the stomach (antrum). When the luminal concentration of H+ reaches a certain threshold (<pH 3), somatostatin is released from endocrine cells in the antral mucosa. Somatostatin acts on neighboring G cells to decrease the release of gastrin and subsequently reduce gastric acid secretion.

The receptors on the parietal cell membrane for acetylcholine, gastrin, and histamine, as well as the intracellular second messengers involved, are depicted in Figure 29.9. Histamine is the strongest stimulator of H+ secretion, while gastrin and acetylcholine are weaker agonists. However, these secretagogues potentiate each other's actions on the parietal cell. Antagonists of H2 histamine receptors (e.g., cimetidine [Tagamet]) block acid secretion stimulated by secretagogues. Thus, much of the response to gastrin is mediated by histamine release induced by gastrin. Gastrin also has trophic effects, causing an increase in the size and number of ECL cells.

Activation of H2 receptors on the parietal cell plasma membranes by histamine stimulates adenylyl cyclase and increases the cytosolic concentration of cAMP. This results in H+ secretion by activating basolateral K+ channels and apical Cl− channels, as well as by increasing the insertion of H+,K+-ATPase molecules and Cl− channels into the apical plasma membrane.
ACETYLCHOLINE, GASTRIN, AND HISTAMINE STIMULATE THE PARIETAL CELL • Fig.29.7The parietal cell is regulated by neural, hormonal, and paracrine pathways. Activation of vagal parasympathetic preganglionic outflow to the stomach acts in three ways to stimulate gastric acid secretion. There is direct neural innervation and activation of the parietal cell via release of acetylcholine (A) from enteric neurons, which acts on the parietal cell via muscarinic receptors. In addition, neural activation of the ECL cell stimulates release of histamine (H), which acts via a paracrine pathway to stimulate the parietal cell. Finally, G cells located in gastric glands in the gastric antrum are activated by release of gastrin-releasing peptide (GRP) from enteric neurons, which acts on the G cell to stimulate release of gastrin (G). Gastrin thereafter acts via a humoral pathway to stimulate the parietal cell.
chemosensors is not clear but may involve endocrine cells that release their contents to activate nerve endings. This topic will be discussed in more detail in
Chapter 30.
There is also an important negative feedback mechanism whereby the presence of acid in the distal part of the stomach (antrum) induces a feedback loop to inhibit the parietal cell such that meal-stimulated H+ secretion does not go unchecked. When the concentration of H+ in the lumen reaches a certain threshold (<pH 3), somatostatin is released from endocrine cells in the antral mucosa. Somatostatin has a paracrine action on neighboring G cells to decrease the release of gastrin and thereby decrease gastric acid secretion (Fig. 29.8
The receptors on the parietal cell membrane for acetylcholine, gastrin, and histamine, as well as the intracellular second messengers by which these secretagogues act, are shown in
Fig. 29.9 . Histamine is the strongest agonist of H+ secretion, whereas gastrin and acetylcholine are much • Fig.29.8Feedback regulation of gastric acid secretion by release of somatostatin and its action on G cells in the gastric antrum. Endocrine cells in the mucosa of the gastric antrum sense the presence of H+and secrete somatostatin. This in turn acts on specific receptors on G cells to inhibit release of gastrin and thus bring about inhibition of gastric acid secretion. Circulation G cell – + D cell Antral lumen GastrinSomatostatin weaker agonists. However, histamine, acetylcholine, and gastrin potentiate one another’s actions on the parietal cell. Antagonists of H2 histamine receptors (e.g., cimetidine [Tagamet]) block secretagogue-stimulated acid secretion. Thus much of the response to gastrin results from gastrinstimulated release of histamine. Gastrin also has important trophic effects; elevation of gastrin levels causes ECL cells to increase in size and number. Binding of histamine to H2 receptors on parietal cell plasma membranes activates adenylyl cyclase and elevates the cytosolic concentration of cAMP. These events stimulate H+ secretion by activating basolateral K+ channels and apical Cl− channels and by causing more H+,K+-ATPase molecules and Cl− channels to be inserted into the apical plasma membrane (see