GASTRIN AND THE ENTEROCHROMAFFIN-LIKE CELL - AN ACID UPDATE

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-a lpha (TGF-alpha) and inhibited by somatostatin (SST). The inactive pre cursor form is converted to the active molecule by several posttransla tion processing steps which include cleavage, C-terminal amidation, gl ycosylation, phosphorylation and sulfation. Aberrations in processing steps generate incompletely processed forms, particularly glycosylated progastrin, which may act as autocrine growth factors for gastrointes tinal neoplasms. Gastrin release is stimulated by luminal aromatic ami no acids and inhibited by a decrease in luminal pH. Other gastrin agon ists include beta-adrenergic agents, acetylcholine, gastrin-releasing peptide (bombesin), TGF-alpha, and possibly the gastric pathogen, Heli cobacter 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 pr oliferation. The fundic enterochromaffin-like (ECL) cell is the princi pal cellular transducer of the gastrin-acid signal. Activation of its gastrin/CCKB receptor results in histamine synthesis and release with consequent activation of the fundic parietal cell H-2 receptor. An inc rease in luminal pH caused by acid inhibitory pharmacotherapy agents ( particularly proton pump inhibitors) results in hypergastrinemia and E CL cell hyperplasia. Gastric carcinoids however appear occur in patien ts with multiple endocrine neoplasia type I syndrome, suggesting that an associated genomic defect is necessary. Gastrin is thus both a pote nt gastrointestinal trophic and histamine secretory agent. As a hormon e it is a paradigm in the elucidation of both cellular secretory and g rowth factor induced cell proliferation.