Physiology of gastrin

INTRODUCTION

Gastrin is the major hormonal regulator of gastric acid secretion [1]. Its discovery at the turn of the century was based upon its profound effect on meal-stimulated acid secretion, making it one of the first hormones to be described [1]. The study of gastrin accelerated with the isolation and characterization of the peptide in 1964 after which it was found to promote growth of the gastric antrum and have a proliferative effect, which has implicated it as having a possible role in cancer [2,3]. The cloning and characterization of the gastrin receptor in 1992 has provided a valuable tool in the study of gastrointestinal hormones [4]

MOLECULAR FORMS

Human gastrin is the product of a single gene located on chromosome 17. The active hormone is generated from a precursor peptide "pre-pro-gastrin" (graph 1). Human preprogastrin contains 101 amino acids (AA) including a signal peptide (21 AA), spacer sequence (37 AA), gastrin component (34 AA) and a 9 AA extension segment at the carboxyl terminus. The enzymatic processing of preprogastrin produces all of the known physiologically active forms of gastrin.

Preprogastrin is processed into progastrin and gastrin peptide fragments of various sizes by sequential enzymatic cleavage (graph 1). Like other hormones, gastrin is synthesized on rough endoplasmic reticulum, processed in the Golgi apparatus and packaged in secretory granules, where final modifications occur [5]. In endocrine cells, the glycine residue at the carboxyl terminus is cleaved and the terminus is amidated to form the mature gastrin peptide.

Two major forms of gastrin are secreted (G-34 and G-17), although a larger G-71 and smaller forms exist (table 1). The common feature of all gastrins is an amidated tetrapeptide (Try-Met-Asp-Phe-NH2) at the carboxyl terminus, which imparts full biological activity. Modification by sulfation at tyrosine residues produces alternative gastrin forms. The circulating half-life of gastrin is affected by the size of the various molecular forms. The full physiologic response is determined by the presence of the biologically active moiety and the time available for receptor interaction. (See "Synthesis, secretion, and regulation of gastrointestinal peptides".)

Gastrin can be ectopically expressed in non-endocrine cells, such as tumors. However, because these cells lack secretory vesicles, prohormone convertases and amidating enzymes, the main forms of gastrin secreted are progastrins including glycine-extended gastrin. These forms of gastrin may have growth promoting effects on certain tumors.