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Cholecystokinin

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Cholecystokinin (CCK) is a peptide hormone discovered in the small intestine. Together with secretin and gastrin, CCK constitutes the classical gut hormone triad. In addition to gallbladder contraction, CCK also regulates pancreatic enzyme secretion and growth, intestinal motility, satiety signalling and the inhibition of gastric acid secretion. CCK is, however, also a transmitter in central and intestinal neurons. Notably, CCK is the most abundant neuropeptide in the human brain. Owing to difficulties in developing accurate assays, knowledge about CCK secretion in disease is limited. Available data indicate, however, that proCCK is expressed in certain neuroendocrine tumours and sarcomas, whereas the secretion of CCK is impaired in celiac disease and bulimia nervosa. Stimulation with exogenous CCK has proved useful in diagnostic tests of gallbladder and pancreatic diseases, as well as medullary thyroid carcinomas.

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Definition of CCK as a gut hormone

CCK controls the emptying of the gallbladder and the release of enzymes from the pancreas. Other factors also influence these functions, but CCK is the single most potent one. Although CCK is involved in other functions as well, its role in these is less settled. Therefore, in functional terms, CCK is still defined best by its cholecystokinetic and pancreozymic actions.

It is possible also to define CCK in structural terms. The CCK gene, mRNA, preproCCK and most naturally occurring products of

The digestive juice era

The mechanisms of bile secretion have been studied for one and a half centuries. Thus, in 1856, Claude Bernard noted that hydrochloric acid in the duodenum stimulated bile flow. Subsequently, Wertheimer in 1903 reported that the response persisted after cutting the vagal and thoracic sympathetic nerves. Hence a year after the discovery of secretin, French physiologists might have suggested the existence of a bile-releasing hormone. Similarly, Okada almost predicted CCK when he noted that

The CCK gene and mRNA

In man, the CCK gene is located on chromosome 3.17 The transcription unit is 7 kilobases interrupted by two introns, the second being the larger. The first of the three exons is small and non-coding (Figure 1). The coding region for the CCK-33 sequence is confined to exon 3. Except for the homology with the gastrin gene in the coding region and in the 5′-untranscribed regulatory region, the structure of the CCK gene has no remarkable features.

Only one CCK mRNA molecule has been found. Thus, the

Endocrine cells in the gut

In the small intestine, CCK peptides are released from endocrine I-cells29, whose apical membrane is in direct contact with the intestinal lumen and whose basal region contains medium-sized, round or slightly irregular dense secretory granules containing CCK peptides.

Endocrine cells outside the gut

CCK is also synthesized in pituitary corticotrophs and melanotrophs, as well as a few adrenal medullary cells.30., 31. In the pituitary cells, CCK constitutes a small fraction of the hormones present, and its function is unknown.

Release from endocrine cells

It was not possible to examine the release of CCK into the bloodstream until specific assays were developed.12., 14., 42., 43. The specific plasma assays have confirmed most classic concepts about CCK. Thus, food—particularly protein- and fat-rich food—is the most important stimulus to release.14., 43. Of the constituents, protein and l-amino acids as well as digested fat cause a significant release of CCK43., 44., whereas carbohydrates release only small amounts of CCK.43 Finally, hydrochloric

Plasma assays

Until it has been demonstrated that a peptide in plasma occurs in a concentration appropriate for regulating its target, a peptide cannot be considered to be a hormone: it might act via nerves or paracrine cells. Moreover, hormones may circulate in different molecular forms. Gut hormone assays have to be sensitive because gut peptides often circulate at or below concentrations of 1 pmol/l.49 The measurement of CCK in plasma has been particular difficult.12., 42., 49. Thus, one might argue that

CCK receptors

Two CCK receptors have been identified.60., 61. The ‘alimentary’ CCK-A receptor60 mediates gallbladder contraction, relaxation of the sphincter of Oddi, pancreatic growth and enzyme secretion, delay of gastric emptying, and inhibition of gastric acid secretion.62 CCK-A receptors have also been found in the anterior pituitary, the myenteric plexus and areas of the midbrain63., 64., in which CCK-containing dopaminergic neurons have been implicated in the pathogenesis of schizophrenia.41 The CCK-A

Diagnostic use

The effect of CCK on the pancreas and the gallbladder has been exploited diagnostically. In the secretin-CCK test, CCK is added to an intravenous infusion of secretin, secretion being collected from the duodenum to measure volume, bicarbonate and various pancreatic enzymes.93 The test is widely used to measure exocrine function in pancreatic disease. CCK is less widely used in cholecystographic examinations of acalculous biliary disease.94 In addition, CCK has also been found to be of value in

Summary

CCK is a classical hormone and an important member of the gastrin-CCK family of peptides. Although discovered as a gut hormone that controls gallbladder emptying and pancreatic enzyme secretion, its major biological significance may well be as a transmitter in the central and peripheral nervous systems. Hence, evolutionary studies indicate that CCK peptides occurred in the neurons of protochordates millions of years before CCK became a hormone.

In mammals, the CCK gene is expressed in endocrine

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