Effects of cholecystokinin on the gastrointestinal tract. Cholecystokinin is secreted by I-cells in the small intestine and induces contraction of the gallbladder, relaxes the sphincter of Oddi, reduces of gastric acid secretion, increases bile acid production in the liver, delays gastric emptying, and induces digestive enzyme production in the pancreas.
The existence of CCK was first suggested in 1905 by the British physiologist Joy Simcha Cohen. It was discovered in 1943 by A.C. Ivy and E. Olberg. It is a member of the gastrin/cholecystokinin family of peptide hormones and is very similar in structure to gastrin, another gastrointestinal hormone. CCK and gastrin share the same five C-terminal amino acids. CCK is composed of varying numbers of amino acids depending on post-translational modification of the 150-amino acid precursor, preprocholecystokinin. Thus, the CCK peptide hormone exists in several forms, each identified by the number of amino acids it contains, e.g., CCK58, CCK33, CCK22 and CCK8. CCK58 assumes a helix-turn-helix configuration. Biological activity resides in the C-terminus of the peptide. Most CCK peptides have a sulfate group attached to a tyrosine located seven residues from the C-terminus (see tyrosine sulfation). This modification is crucial for the ability of CCK to activate the cholecystokinin A receptor. Nonsulfated CCK peptides also occur, which consequently cannot activate the CCK-A receptor, but their biological role remains unclear.
Once in the circulatory system, CCK has a relatively short half-life.
CCK mediates digestion in the small intestine by inhibiting gastric emptying. It stimulates the acinar cells of the pancreas to release a juice rich in pancreatic digestive enzymes (hence an alternate name, pancreozymin) that catalyze the digestion of fat, protein, and carbohydrates. Thus, as the levels of the substances that stimulated the release of CCK drop, the concentration of the hormone drops as well. The release of CCK is also inhibited by somatostatin and pancreatic peptide. Trypsin, a protease released by pancreatic acinar cells, hydrolyzes CCK-releasing peptide and monitor peptide, in effect turning off the additional signals to secrete CCK.
As a peptide hormone, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. The mechanism for hunger suppression is thought to be a decrease in the rate of gastric emptying. CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.
The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in adult males, but is slightly less effective in younger subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats.
Several studies have implicated CCK as a cause of visual hallucinations in Parkinson’s disease. Mutations in CCK receptors in combination with mutated CCK genes potentiate this association. These studies also uncovered potential racial/ethnic differences in the distribution of mutated CCK genes.
CCK has been shown to interact with the Cholecystokinin A receptor located mainly on pancreatic acinar cells and Cholecystokinin B receptor mostly in the brain and stomach. CCKB receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa. CCK has also been shown to interact with calcineurin in the pancreas. Calcineurin will go on to activate the transcription factors NFAT 1–3, which will stimulate hypertrophy and growth of the pancreas. CCK can be stimulated by a diet high in protein, or by protease inhibitors. CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep). CCK can have indirect effects on sleep regulation.
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