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Abstract: Background: The ECL cells are histamine-producing endocrine cells in the oxyntic mucosa that synthesize and secrete proteins and peptides. They are the primary target for gastrin and mediate the control of gastrin on acid secretion and oxyntic mucosal growth. Knowledge of the molecular biology of the ECL cell is therefore important for understanding gastric physiology. Accordingly, we wanted to identify genes that are characteristically expressed in the ECL cells and controlled by gastrin. Methods: Using Affymetrix GeneChips®, RNA expression profiles were generated from ECL cells isolated by counterflow elutriation from hyper- or hypogastrinemic rats. Contamination from non-endocrine cells was eliminated by subtraction of the expression profiles of the fundic and antral mucosa. Results: The expression of 365 genes was ECL cell characteristic. Gastrin was found to control the expression of 120 which could be divided into two major groups depending on the known or anticipated biological function of the encoded protein: genes encoding proteins involved in the secretory process and genes encoding proteins needed to generate energy for secretion. Interestingly, gastrin stimulation also increased ECL cells expression of anti-apoptotic genes. Conclusion: The ECL cell specific expression profile is reminiscent of that of neurons and other endocrine cells exhibiting high expression of genes encoding proteins involved in the synthesis, storage and secretion of neuropeptides or peptide hormones. Gastrin regulated the expression of one third of these genes and is thus involved in the control of secretion from the ECL cells. [Copyright &y& Elsevier]

Abstract: The gastrointestinal hormone, gastrin, was discovered a century ago as the second hormone in history. Subsequently, gastrin peptides have been identified and the genes encoding the hormone as well as its receptor have been cloned in several mammalian species including the mouse. This has facilitated the development of gastrin and gastrin receptor deficient mice as models for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with the development of intestinal metaplasia and bacterial overgrowth, which ultimately lead to development of gastric tumors. Outside the stomach, gastrin deficiency alters pancreatic islet physiology and is associated with a moderate fasting hypoglycemia in the fasting state. But lack of gastrin does not impair islet regeneration. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies still remains to be proven. While others have focused on models of increased gastrin production, the present review will describe the lessons learned from the gastrin deficient mice. These mice help understand how dysregulation of gastrin secretion may be implicated in human disease. [Copyright &y& Elsevier]

Background & Aims: Gastrin deficiency and proton pump inhibitor treatment cause achlorhydria, which predisposes to disease. To elucidate the underlying molecular biology, we examined the changes in gastric gene expression in both types of achlorhydria. We also explored the associated changes in the gastric microflora and the long-term consequences of gastrin-deficient achlorhydria. Methods: Expression profiles were generated from gastric RNA from wild-type mice, gastrin knockout (KO) mice, gastrin KO mice after 1 week of gastrin infusion, and wild-type mice treated for 1 month with a proton pump inhibitor. The results were confirmed using real-time polymerase chain reaction and immunohistochemistry. Selective media were used to characterize the gastric microflora. Results: The number of gastric bacteria was increased in both gastrin KO and PPI-treated mice. The expression profiles revealed activation of immune defense genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. In young gastrin-deficient mice, gastrin infusions reversed the changes. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development. Finally, the study showed that gastrin regulated the expression of genes encoding extracellular matrix proteins. Conclusions: Independently of gastrin, achlorhydria is associated with gastric bacterial overgrowth and intestinal gene expression patterns and is associated with predisposition to disease. Gastrin is therefore essential for prevention of gastric disease, mainly through control of acid secretion but to a lesser extent also through control of gastric gene expression. The gastrin-deficient mouse serves as a useful new model for gastric metaplasia and neoplasia. [Copyright &y& Elsevier]

Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three pathways, the gastrin–histamine pathway, the CCK–somatostatin pathway and the neural pathway. Genetically-engineered mice, subjected to targeted gene disruption (i.e., knockout mice), have been used to dissect the signaling pathways that are responsible for the complexity of the regulation of acid secretion in vivo. Both gastrin knockout and gastrin/CCK2 receptor knockout mice displayed greatly impaired acid secretion, presumably because of the loss of the gastrin–histamine pathway. Gastrin/CCK double-knockout mice had a relatively high percentage of active parietal cells with a maintained ability to respond with copious acid secretion to pylorus ligation-evoked vagal stimulation and to a histamine challenge. The low acid secretion in gastrin knockout mice and gastrin/CCK2 receptor knockout mice and the restoration of acid secretion in gastrin/CCK doubleknockout mice suggest that CCK plays an important role as inhibitor of the parietal cells via the CCK–somatostatin pathway by stimulating the CCK1 receptor of the D cell. In the absence of both the gastrin–histamine and the CCK–somatostatin pathway (as in gastrin/CCK2 receptor double-knockout mice), the control of acid secretion is probably taken over by neural pathways, explaining the high acid output. The observations illustrate the complexity and plasticity of the acid regulatory mechanisms. It seems that one pathway may be suppressed or allowed to dominate over the others depending on the circumstances. [ABSTRACT FROM AUTHOR]

The gastric hormone gastrin was the 2nd hormone to be identified and was initially recognized for its ability to induce acid secretion. Following the purification and subsequent development of specific radioimmunoassays for gastrin, it was also shown to be a regulator of oxyntic mucosal growth. To explore the importance of gastrin or its receptors for gastric development and gastric physiology both have been knocked out. The knock-out mice are viable, develop with any gross abnormalities, and are fertile. Even though gastrin acts as a growth factor during hypergastrinaemia there was no general atrophy of the gastrin mucosa in the knock-out mice. But the maturation of both parietal and ECL cells were disturbed and the number of parietal cells reduced. Furthermore, lack of gastrin impaired basal acid secretion and rendered the parietal cells unresponsive to histamine and acetylcholine, the other two major stimulators of gastric acid secretion. Despite the major changes in gastric physiology, the number of genes down-regulated in the gastrin knock-out mice is modest. The achlorhydria due to lack of gastrin also leads to bacterial overgrowth of the stomachs of the gastrin knockout mice, which could facilitate the development of gastric ulcer disease and cancer. [ABSTRACT FROM AUTHOR]

Cellular synthesis of neuroendocrine peptides requires prohormone convertases (PCs). In order to determine the role of PC2 for gastrin synthesis, we examined antral extracts from mice lacking PC2 or its chaperone, 7B2. The overall concentrations of precursors and α-amidated gastrins were similar in all mice. Chromatography, however, revealed that while the K53-K54 site was almost fully cleaved in controls and half cleaved in PC2 null mice, only 23% was cleaved in 7B2 null mice. The results show that PC2 and 7B2 both are required for synthesis of the main form of gastrin (gastrin-17), and that 7B2 exhibits effects beyond PC2-mediated cleavages. [ABSTRACT FROM AUTHOR]

The gastric hormone gastrin was first recognized for its ability to induce acid secretion. Following the purification and subsequent development of specific radioimmunoassays for gastrin, it was also shown to be a regulator of oxyntic mucosal growth. To examine the importance of gastrin or its receptors during development in general and for gastric physiology specifically both have been knocked out. Gastrin and gastrin receptor knockout mice are viable, develop without any gross abnormalities, and are fertile. Even though gastrin acts as a growth factor during hypergastrinemia there was no general atrophy of the gastric mucosa in the knockout mice. However, the maturation of both parietal and ECL cells was disturbed and the number of parietal cells was reduced. Basal acid secretion was impaired and rendered the parietal cells unresponsive to secretagogues. Outside the stomach the mice had no apparent phenotype. However, studies have suggested that progastrin and glycine-extended proforms of gastrin may have biological importance, but these results are still circumstantial and identification of the implicated receptors will be crucial for further studies. [ABSTRACT FROM AUTHOR]

Studies the impairment of gastric acid secretion in gastrin-deficient mice. Reduction of the number of parietal cells with the accumulation of immature cells lacking H+K+-ATPase; Inability of histamine, carbachol and gastrin to induce basal gastric acid secretion; Expression of histidine decarboxylase.

Presents a study which focuses on the role of the peptide hormone gastrin in the devolvement of and function of the stomach. Methods and materials used in the study; What influences gastric acid secretions; Information on the process of gene targeting and generation of mice.

The antral hormone gastrin continues to be in focus, because its hormonal and growth promoting effects are essential both for the function of the normal stomach and for the pathogenesis of major dyspeptic and neoplastic diseases. Deduction of the progastrin structure has improved the insight in the cellular synthesis of gastrin, but has also revealed that the biosynthetic machinery is complex, and, accordingly, that progastrin is processed to a multitude of more or less bioactive fragments. The naming of these fragments has, however, become inconsistent and confusing. Therefore, we propose a systematic nomenclature for progastrin-derived peptides of which there are three classes: (I) The gastrins with the evolutionary preserved tetrapeptide amide (Trp-Met-Asp-PheNH2) at the C-terminus, which ensures high-affinity binding to the gastrin (CCK-B) receptor. Among the gastrins, gastrin-34 and gastrin-17 constitute the primary forms. (II) Processing intermediates, which are early products of progastrin that contain the structure of the primary gastrins within their sequence, but still cannot bind the gastrin receptor due to insufficient processing at their C-terminus. (III) Flanking fragments from the N- and C-termini of progastrin that do not contain any primary gastrin in their sequence, but nevertheless may undergo posttranslational processing. Each fragment can be specified with suffixes corresponding to the derived sequence in progastrin. [Copyright &y& Elsevier]