The gastrins: Their production and biological activities

Gastric epithelial organization and function are controlled and maintained by a variety of endocrine and paracrine mediators. Peptides encoded by the gastrin gene are an important part of this system because targeted deletion of the gene, or of the gastrin-CCKB receptor gene, leads to decreased numb ers of parietal cells and decreased gastric acid secretion. Recent studies indicate that the gastrin precursor, preprogastrin, gives rise to a variety of products, each with a distinctive spectrum of biological activity. The conversion of progastrin to smaller peptides is regulated by multiple mecha nisms including prohormone phosphorylation and secretory vesicle pH, Progas trin itself stimulates colonic epithelial proliferation; biosynthetic inter mediates (Gly-gastrins) stimulate colonic epithelial proliferation and gast ric epithelial differentiation; and C-terminally amidated gastrins stimulat e colonic proliferation, gastric epithelial proliferation and differentiati on, and acid secretion. The effects of progastrin-derived peptides on gastr ic epithelial function are mediated in part by release of paracrine factors that include histamine, epidermal growth factor (EGF)-receptor ligands, an d Reg. The importance of the appropriate regulation of this system is shown by the observation that prolonged moderate hypergastrinemia in transgenic mice leads to remodelling of the gastric epithelium, and in the presence of Helicobacter. to gastric cancer.