Cellular and Molecular Targets of Gastrin

Gastrin was recognized as a hormone that stimulates gastric secretion almost 60 yr ago. Its existence was proved by Komarov (1) in 1938. It was first isolated and characterized by Gregory and Tracy (2,3) in 1961, and since then became a subject of intensive study. It is one of the most well studied peptide hormones (4). Nevertheless, in spite of an enormous amount of research that was already conducted on gastrin, it might be just a beginning of an exciting story. New findings suggest that gastrin has many more important functions than had been recognized in the past, and that it has additional, until recently, unknown cellular and molecular targets that yet need to be characterized. Gastrin is produced mainly by G-cells of antral mucosa and duodenum (5). Low levels of gastrin expression were detected in the pancreas of adult mammals (high in fetal and neonatal rats), in anterior and intermediate pituitary lobes, human spermatogenic cells, bronchial mucosa, vagal neurons, hypothalamo-hypophyseal neurons, and some endocrine cells of the small intestine (6). Gastrin is synthesized in a form of a 101 amino acid residues precursor (7). The major forms of gastrin in circulation are the heptadecapeptide (G-17) and the tetratriaconpeptide (G-34) (8). They are formed from the precursor as a result of removal of the signal peptide, C- and N-terminal extensions and processing of glycine extended intermediates to amidated forms of the hormone (9). Gastrin in mature form shares the same carboxiamidated C-terminus, -Trp-Met-Asp-Phe-NH2 with cholecystokinin (CCK), which is expressed predominantly in duodenal and jejunal mucosa and in the cerebral cortex. This sequence constitutes the active site of both hormones and is highly preserved during evolution (10). Gastrin and CCK have many overlapping activities, because their structures are similar. Though a major role of gastrin is still considered to be in the stimulation of gastric secretion, recent data suggest that the hormone is indeed multifunctional. It was shown to increase blood flow through the stomach mucosa (11), it is involved in contraction of the stomach muscle (12), it has trophic effects on gastric and duodenal mucosa and the pancreas (13–18), it stimulates fractional sodium excretion in kidneys, and increases renal plasma flow (19), and may play a role in regulation of pancreatic secretion (20).