Gastrin and the Enterochromaffin-Like Cell: An Acid Update

Abstract

Gastrin is synthesized and secreted mostly in a heptadecapeptide form from neurocrine G cells located in the antrum. The biologically active sequence of the molecule is a C-terminal pentapeptide, which has been conserved across many species. Transcriptional regulation of gastrin mRNA synthesis is positively regulated by transforming growth factor-α (TGF-α) and inhibited by somatostatin (SST). The inactive precursor form is converted to the active molecule by several posttranslation processing steps which include cleavage, C-terminal amidation, glycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointestinal neoplasms. Gastrin release is stimulated by luminal aromatic amino acids and inhibited by a decrease in luminal pH. Other gastrin agonists include β-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-α, and possibly the gastric pathogen, Helicobacter pylori. The principal peptide inhibitor of gastrin release is SST. The major physiological roles of gastrin include stimulation of acid secretion, regulation of mucosal cell lineage and mucosal cell proliferation. The fundic enterochromaffin-like (ECL) cell is the principal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCK_B receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H₂ receptor. An increase in luminal pH caused by acid inhibitory pharmacotherapy agents (particularly proton pump inhibitors) results in hypergastrinemia and ECL cell hyperplasia. Gastric carcinoids however appear occur in patients with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a potent gastrointestinal trophic and histamine secretory agent. As a hormone it is a paradigm in the elucidation of both cellular secretory and growth factor induced cell proliferation.

Simultaneous detection of gastric acid and histamine release to unravel the regulation of acid secretion from the guinea pig stomach

“…Histamine production is diminished by ϳ10% in the presence of the CCK2 blocker proglumide, suggesting that gastrin is active along this pathway. This finding is different than other studies, where in various species histamine is believed to be predominately mediated by gastrin to elevate acid secretion (11,15,19,20). Although we show that this pathway is active in the guinea pig, no other studies have monitored both the direct and indirect gastrin pathways leading to the activation of the parietal cell in one experiment on any species.…”

“…Although we show that this pathway is active in the guinea pig, no other studies have monitored both the direct and indirect gastrin pathways leading to the activation of the parietal cell in one experiment on any species. However, other studies have shown that when acid secretion is monitored, inhibitors of the gastrin pathway diminish acid secretion (16,20) or when histamine is monitored, gastrin elevates levels of histamine (15,19,23,29). Our data are supportive of both these studies, but provide further information in the degree gastrin plays in both pathways.…”

“…shown that gastrin stimulation induces histidine decarboxylase to synthesize histamine (11,15,30). ACh is released from postganglionic neurons and stimulates the parietal cells directly via M3 receptors and indirectly via M2 and M4 inhibition of somatostatin secretion (34,35).…”

The Epstein-Barr Virus Protein BMRF1 Activates Gastrin Transcription

“…This negative result may reflect the fact that the gastrin gene product is extensively posttranslationally modified in G cells (21,44,48) to produce the various different forms of gastrin. The preprogastrin protein is converted to multiple different forms of gastrin, including progastrin, glycine-extended gastrin and amidated gastrins.…”

“…The microarray analysis indicated that cells infected with AdBMRF1 expressed the cellular gastrin gene at a 34-fold-higher level than the mock-infected cells or the AdLacZ-infected cells (data not shown). Since gastrin expression is normally limited to specialized neuroendocrine-like cells in the stomach (the G cells) (21), the finding that BMRF1 (Fig. 1a).…”