Cholecystokinin-From Local Gut Hormone to Ubiquitous Messenger

Abstract

Cholecystokinin (CCK) was discovered in 1928 in jejunal extracts as a gallbladder contraction factor. It was later shown to be member of a peptide family, which are all ligands for the CCK₁ and CCK₂ receptors. CCK peptides are known to be synthetized in small intestinal endocrine I-cells and cerebral neurons. But in addition, CCK is expressed in several endocrine glands (pituitary cells, thyroid C-cells, pancreatic islets, the adrenals, and the testes); in peripheral nerves; in cortical and medullary kidney cells; in cardial myocytes; and in cells of the immune system. CCK peptides stimulate pancreatic enzyme secretion and growth, gallbladder contraction, and gut motility, satiety and inhibit acid secretion from the stomach. Moreover, they are major neurotransmitters in the brain and the periphery. CCK peptides also stimulate calcitonin, insulin, and glucagon secretion, and they may act as natriuretic peptides in the kidneys. CCK peptides are derived from proCCK with a C-terminal bioactive YMGWMDFamide sequence, in which the Y-residue is partly O-sulfated. The plasma forms are CCK-58, -33, -22, and -8, whereas the small CCK-8 and -5 are potent neurotransmitters. Over the last decades, CCK expression has also been encountered in tumors (neuroendocrine tumors, cerebral astrocytomas, gliomas, acoustic neuromas, and specific pediatric tumors). Recently, a metastastic islet cell tumor was found to cause a specific CCKoma syndrome, suggesting that circulating CCK may be a useful tumor marker.

Keywords: cholecystokinin; gastrointestinal hormones; neuroendocrine tumors; neuropeptides; tumor markers.

Figure 1

The homologous bioactive sequences of peptide systems belonging to the cholecystokinin (CCK) family (upper panel). CCK and the antral hormone, gastrin, are the only mammalian members of the family. Caerulein and phyllocaerulein are identified from frogskin extracts. Cionin is a neuropeptide isolated from the central ganglion of the protochord, ciona intestinalis. Note the unique disulfated sequence, which might suggest that cionin may resemble a common ancestor of CCK and gastrin. The core of the bioactive sequences, the common C-terminal tetrapeptide amide, is boxed. The lower panel shows the bioactive sequences of the insect peptides, the sulfakinins, which display some homology with vertebrate and protochordian members of the CCK family (4, 5). Also their C-terminal tetrapeptide amide sequence is boxed.