Topical review. Gastrin and gastric epithelial physiology

Abstract

Transepithelial transducing cells, particularly the gastrin (G) cell, co-ordinate gastric acid secretion with the arrival of food in the stomach. Recent work suggests that multiple active products are generated from the gastrin precursor, and that there are multiple control points in gastrin biosynthesis. Biosynthetic precursors and intermediates (progastrin and Gly-gastrins) are putative growth factors; their products, the amidated gastrins, regulate epithelial cell proliferation, the differentiation of acid-producing parietal cells and histamine-secreting enterochromaffin-like (ECL) cells, and the expression of genes associated with histamine synthesis and storage in ECL cells, as well as acutely stimulating acid secretion. Gastrin also stimulates the production of members of the epidermal growth factor (EGF) family, which in turn inhibit parietal cell function but stimulate the growth of surface epithelial cells. Plasma gastrin concentrations are elevated in subjects with Helicobacter pylori, who are known to have increased risk of duodenal ulcer disease and gastric cancer. Studies of the physiology of gastrin may therefore contribute to an understanding of the mechanisms relevant to major upper gastrointestinal tract disease.

Figure 1. Progastrin processing

A, schematic of the main products of preprogastrin processing. The signal sequence (green) of preprogastrin is cleaved in the endoplasmic reticulum and progastrin then passes through the Golgi complex to secretory vesicles where it is cleaved (dashed arrows) and the COOH-terminus amidated; processing enzymes are indicated in the boxes. B, the pathways of post-translational processing of rat preprogastrin as revealed by pulse-chase kinetic studies are shown together with a summary of the main biological properties of the various progastrin-derived peptides. C, putative mechanisms regulating progastrin processing are shown: selected cleavages are inhibited by raising intravesicular pH and by phosphorylation by physiological casein kinase. The inset shows the primary sequence of the cleavage/phosphorylation site in the single-letter notation. Cleavage sites (Arg^57,58, Lys^74,75, Arg^94,95) are also identified in the single-letter notation.

Figure 2. Schematic representation of a secretory vesicle containing progastrin and processing enzymes indicating the major steps and requirements for processing

Internal pH is approximately 5·5 due to the activity of the vacuolar proton pump (vH⁺-ATPase), but proton extrusion via vesicular monoamine transporters (VMAT) may raise intragranular pH and inhibit cleavage. Biogenic amines transported by VMATs are generated from their precursors by aromatic amino acid decarboxylase (AADC). The bifunctional enzyme peptidyl α-amidating mono-oxygenase (PAM) converts peptides with COOH-terminal -Gly into the corresponding amide in a 2-step reaction; the peptidyl α-hydroxylating mono-oxygenase (PHM) domain of PAM generates a hydroxy-Gly intermediate that is the substrate for the peptidyl α-hydroxyglycine α-amidating lyase (PAL) domain of the enzyme.

Figure 3. Cellular interactions in the gastric epithelium

A, schematic representation of an acid-secreting gastric gland, showing the main classes of epithelial cell and sites of action of gastrin. Proliferation in the isthmus region followed by cell migration gives rise to mucus-secreting neck and surface cells (blue), and the main glandular cell types, i.e. parietal (green), chief (yellow) and enterochromaffin-like (ECL) cells (red). Gastrin stimulates proliferation and the differentiation of parietal and ECL cells; it also stimulates acid secretion from parietal cells, at least in part by increasing histamine synthesis and release in ECL cells. B, cellular interactions in the gastric epithelium. Gastrin stimulates histamine release from ECL cells which acts on parietal cells. Various neurohumoral agents (noradrenaline, cholecystokinin (CCK), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP) stimulate somatostatin release from D-cells, which inhibits ECL and parietal cells. By an unknown mechanism, the latter also regulate chief cell numbers. C, remodelling of gastric glands with prolonged stimulation by gastrin. Hypergastrinaemia increases the expression of EGF family members such as heparin-binding EGF (HB-EGF), amphiregulin and transforming growth factor (TGF)-α in parietal cells, and Reg-1α in chief and ECL cells. EGF-related peptides inhibit acid secretion and depress parietal cell numbers, but increase surface epithelial cell numbers. Inactivating mutations of Reg-1α occur in ECL cell tumours, suggesting that this peptide also has autocrine growth inhibitory effects, although it is a stimulant of the growth of surface mucus cells.