gastrin

gastrin is a hormone produced in the stomach which stimulates gastric acid secretion after a meal. It was discovered in 1905 by John Sydney Edkins (1863–1940), working in St Bartholomew's Hospital, London. Edkins reasoned that gastric acid secretion might be regulated by a mechanism analogous to the control of pancreatic secretion by the intestinal hormone secretin which had been discovered by W. M. Bayliss and E. H. Starling three years earlier. He then showed that when extracts of the lowest part of the stomach were injected into the jugular vein they stimulated gastric acid secretion, and he called the active factor ‘gastrin’. Gastrin is a polypeptide. It occurs in several different molecular forms, the most important of which are molecules of 17 and 34 amino acid residues.

In 1919 the Russian physiologist L. Popielski showed that histamine was a powerful stimulant of gastric acid secretion and for some years thereafter it was widely thought that Edkins' ‘gastrin’ was in fact histamine. The issue was clarified by S. A. Komarov, who established that histamine-free extracts of gastric mucosa stimulated acid secretion when injected into the blood. However, the low concentrations of gastrin in stomach tissue frustrated early attempts to obtain the hormone in a pure form. Success was finally achieved by Rod Gregory and Hilda Tracy at the University of Liverpool, who in the early 1960s purified from pig stomach the 17 amino acid form of the hormone. Their work required the routine processing of many hundreds of pig stomachs obtained each week from a local abattoir. Together with their colleague, the chemist George Kenner, they established the structure of gastrin and noted that a sequence of 4 amino acid residues was sufficient to produce the full range of actions of the molecule they had purified. A synthetic compound based on this sequence, pentagastrin, is used clinically for tests of gastric acid secretion. A closely related sequence occurs in the brain–gut peptide cholecystokinin, and a similar peptide is also found in high concentrations in skin glands of certain amphibians, for example the South African clawed toad, Xenopus leavis.

Gastrin is released from specialized cells in the mucosa of the final part of the stomach. Secretion into the bloodstream is increased by the presence of food, particularly protein, in the stomach, and is also stimulated by neural reflexes. Gastrin is then carried by the blood throughout the body, but it exerts its action by virtue of specific receptors on cells of the acid-secreting (middle and upper) part of the stomach. Gastric acid, in turn, passes to the lower part of the stomach and there inhibits the release of gastrin, providing a mechanism to limit acid secretion during digestion. In the absence of acid due either to loss of the parietal cells that secrete it (pernicious anaemia) or to administration of drugs that block the proton pump in parietal cells, e.g. omeprazole, the concentration of gastrin in the blood becomes elevated. It also becomes elevated in the blood of patients with the rare condition of Zollinger–Ellison syndrome, due to a gastrin-producing tumour typically sited in the pancreas.

Gastrin increases acid secretion both by direct stimulation of the acid-producing parietal cells, and by increasing the release of histamine from specialized cells, known as enterochromaffin-like cells, in the mucosa adjacent to parietal cells. Histamine then diffuses through the mucosa to parietal cells, acting as a local regulator. Gastrin is also a stimulant of the growth of the gastric mucosa, and in particular of the enterochromaffin-like cells. In extreme cases, elevated concentrations of gastrin in blood may be associated with the development of nodules of enterochromaffin-like cells, known as gastric carcinoid tumours.

The actions of gastrin are mediated by receptors on the surface of parietal and enterochromaffin-like cells, activation of which leads to increased intracellular calcium. The same receptor responds to cholecystokinin, and is known as the gastrin/cholecystokinin-B receptor. Cholecystokinin is normally present in blood in concentrations about ten times lower than those of gastrin and so its actions on these receptors in the stomach are relatively unimportant. Cholecystokinin also acts at a different type of receptor (the cholecystokinin-A receptor) which responds weakly to gastrin. Actions at cholecystokinin-A receptors account for the capacity of gastrin to stimulate pancreatic enzyme secretion and gall bladder contraction when given in high doses. The gastrin/cholecystokinin-B receptor is abundant in the central nervous system. Gastrin is not normally present in the brain and does not normally penetrate from the circulation; however, cholecystokinin does occur in the brain and so is the natural stimulant of this receptor in the central nervous system.

G. J. Dockray

See also alimentary system.