Холецистокинин: гормон пищеварительной системы

Hormone of the gastrointestinal system

Cholecystokinin (CCK or CCK PZ; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile sac (gallbladder)) is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, formerly called pancreozymin, is synthesized and secreted by enteroendocrine cells in the duodenum, the first segment of the small intestine. Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant.

Evidence that the small intestine controls the release of bile was uncovered as early as 1856, when French physiologist Claude Bernard showed that when dilute acetic acid was applied to the orifice of the bile duct, the duct released bile into the duodenum. In 1903, the French physiologist fr showed that this reflex was not mediated by the nervous system. In 1904, the French physiologist Charles Fleig showed that the discharge of bile was mediated by a substance that was conveyed by the blood. There remained the possibility that the increased flow of bile in response to the presence of acid in the duodenum might be due to secretin, which had been discovered in 1902. The problem was finally resolved in 1928 by Andrew Conway Ivy and his colleague Eric Oldberg of the Northwestern University Medical School, who found a new hormone that caused contraction of the gall bladder and that they called "cholecystokinin". In 1943, Alan A. Harper and Henry S. Raper of the University of Manchester discovered a hormone that stimulated pancreatic enzyme secretion and that they named "pancreozymin"; however, pancreozymin was subsequently found to be cholecystokinin. Swedish biochemists Johannes Erik Jorpes and Viktor Mutt undertook the monumental task of isolating and purifying porcine cholecystokinin and then determining its amino acid sequence. They finally presented porcine cholecystokinin's amino acid sequence in 1968.

Cholecystokinin 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., CCK 58, CCK 33, CCK 22 and CCK 8. 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). It is the most abundant neuropeptide in the central nervous system. CCK has been researched thoroughly for its role in digestion and it participates in a number of processes such as digestion, satiety and anxiety.

CCK is synthesized and released by enteroendocrine cells in the mucosal lining of the small intestine (mostly in the duodenum and jejunum), called I cells, neurons of the enteric nervous system, and neurons in the brain. 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. CCK also causes the increased production of hepatic bile, and stimulates the contraction of the gall bladder and the relaxation of the sphincter of Oddi (Glisson's sphincter), resulting in the delivery of bile into the duodenal part of the small intestine. 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.

CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system. CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms.

The CCK tetrapeptide fragment CCK 4 (Trp Met Asp Phe NH2) reliably causes anxiety and panic attacks (panicogenic effect) when administered to humans and is commonly used in scientific research for this purpose of in order to test new anxiolytic drugs. Positron emission tomography visualization of regional cerebral blood flow in patients undergoing CCK 4 induced panic attacks show changes in the anterior cingulate gyrus, the claustrum insular amygdala region, and cerebellar vermis. 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. CCK in the body cannot cross the blood–brain barrier, but certain parts of the hypothalamus and brainstem are not protected by the barrier.