Gastric endocrine cells: Gene expression, processing, and targeting of active products

Endocrine cells of the gastric epithelium secrete biologically active peptides and small messenger molecules such as histamine, serotonin, and gamma-aminobutyric acid. The secretory products may act locally (paracrine or autocrine effects) or at distant targets after delivery in the circulation (hormonal effects). The contents of the gastric lumen control both secretion by gastric endocrine cells and the expression of genes involved in the synthesis of their active secretory products; in some cases, gene regulation may occur over periods as short as that required for digestion of a single meal. The conversion of inactive peptide precursors to their active forms takes place during transit along the secretory pathway and is only completed after sequestration in secretory granules. The processing of the gastrin precursor provides a useful model for studying prohormone processing. Generation of the well-known amidated gastrins requires prohormone cleavage and COOH-terminal amidation; the products stimulate acid secretion and mucosal growth. However, recent work indicates that biosynthetic intermediates that do not stimulate acid secretion may nevertheless act at a novel receptor to stimulate growth, so that control of prohormone processing determines which of two alternative types of biologically active peptide is released by gastrin cells. Gastric endocrine cells also have the capacity to accumulate small messenger molecules in secretory vesicles, via proton exchangers. Recent work indicates physiological regulation of the expression of genes encoding cytosolic enzymes such as histidine decarboxylase, which converts histidine to histamine, and of secretory granule transporters such as vesicular monoamine transporter type 2, which concentrates amines in secretory vesicles. Together these findings suggest that modulation of regulatory peptide and amine biosynthesis in gastric endocrine cells constitutes a primary response of the stomach to the arrival of a meal.