Cholecystokinin Explained

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..[1] [2]

History

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.[3] [4] In 1903, the French physiologist showed that this reflex was not mediated by the nervous system.[5] In 1904, the French physiologist Charles Fleig showed that the discharge of bile was mediated by a substance that was conveyed by the blood.[6] 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".[7] 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";[8] however, pancreozymin was subsequently found to be cholecystokinin.[9] [10] [11] 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.[12]

Structure

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.[13] 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.[14] 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.[15]

Function

CCK plays important physiological roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut.[16] It is the most abundant neuropeptide in the central nervous system.[17] [18] CCK has been researched thoroughly for its role in digestion[19] and it participates in a number of processes such as digestion, satiety and anxiety.

Gastrointestinal

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. It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of fatty acids and/or certain amino acids in the chyme entering the duodenum. In addition, release of CCK is stimulated by monitor peptide (released by pancreatic acinar cells), CCK-releasing protein (via paracrine signalling mediated by enterocytes in the gastric and intestinal mucosa), and acetylcholine (released by the parasympathetic nerve fibers of the vagus nerve).[20]

Once in the circulatory system, CCK has a relatively short half-life.[21]

Digestion

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.[22]

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. Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption.

Satiety

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.[23] CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin.[24] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.[25]

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.[26]

Neurological

CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system.[27] CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms. The predominant form of CCK in the central nervous system is the sulfated octapeptide, CCK-8S.

Anxiogenic

In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety. The site of the anxiety-inducing effects of CCK seems to be central with specific targets being the basolateral amygdala, hippocampus, hypothalamus, periaqueductal grey, and cortical regions.[28]

Panicogenic

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.[29] 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.

Hallucinogenic

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.

Interactions

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.[30] [31] [32] 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.[33] CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep).[34] CCK can have indirect effects on sleep regulation.[35]

CCK in the body cannot cross the blood–brain barrier, but certain parts of the hypothalamus and brainstem are not protected by the barrier.

See also

Notes and References

  1. Book: Johnson LR . Gastrointestinal Physiology . 2013 . 978-0-323-10085-4 . Eighth . Elsevier/Mosby . Philadelphia .
  2. Web site: Cholecystokinin . 28 January 2001 . Colorado State University . Bowen R . 6 November 2015 . dead . https://web.archive.org/web/20160317024952/http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html . 17 March 2016 .
  3. Book: Bernard . Claude . Leçons de physiologie expérimentale appliquée à la médecine . 1856 . J.B. Baillière et fils . Paris, France . 2 . 430 . French. From p. 430: "En effet, si l'on ouvre le duodenum sur un animal vivant et que l'on touche l'orifice du conduit cholédoque avec une baguette de verre imprégnée d'acide acétique faible, on voit immédiatement un flot de bile lancé dans l'intestin; ce qui ne se fait pas si, au lieu de toucher l'orifice du conduit cholédoque avec un liquide acide, on le touche avec un liquide lègérement alcalin, comme du carbonate de soude par example." (Indeed, if one opens the duodenum on a living animal and touches the orifice of the bile duct with a glass rod impregnated with weak acetic acid, one immediately sees a stream of bile squirted into the intestine; which is not done if, instead of touching the orifice of the bile duct with an acidic liquid, it is touched with a slightly alkaline liquid, such as sodium carbonate for example.)
  4. Rehfeld . Jens F. . Cholecystokinin and the hormone concept . Endocrine Connections . March 2021 . 10 . 3 . R139–R150 . 10.1530/EC-21-0025 . 33640870 . 8052576 .
  5. Wertheimer . E. . De l'action des acides et du chloral sur la sécrétion biliaire (d'après les expériences de M. Ch. Dubois) . Compte Rendus Hebdomadaires des Séances et Mémoires de la Société Biologie . 1903 . 55 . 286–287 . On the action of acids and chloral on bile secretion (according to the experiments of Mr. Charles Dubois) . French. From p. 287: "Ces expériences furent ensuite répétées après section préalable des pneumogastriques au cou et des sympathiques dans le thorax: cinq sur douze ont encore donné des résultats positifs." (These experiments [namely, introducing dilute acid into the duodenum in order to determine whether the acid then stimulated the secretion of bile] were then repeated after prior section [i.e., cutting] of the pneumogastric [i.e., vagus nerves] in the neck and the sympathetic [nerves] in the thorax: five out of twelve [experiments] again gave positive results.)
  6. Fleig . Charles . Du mode d'action des excitants chimiques des glandes digestives . Archives Internationales de Physiologie et de Biochimie . 1904 . 1 . 286–346 . On the mode of action of the chemical stimulants of the digestive glands . French. From pp. 316-317: "Expérience. — Chien 13 k. chloralosé. On isole une anse de duodéno-jejunum, … C'est là pour le moment une question non résolue et qui ne m'a donné aucun résultat." (Experiment: A dog of 13 kg. was anaesthetized with chloral hydrate. One isolates a section of the duodenum-jejunum; one introduces into it a solution of 0.5% HCl, and one collects the venous blood from the section as usual. Infusion of the [venous] blood which is administered during 30 minutes (about 100 cc.) to a dog of 7 kg. having a canula in the bile duct and [having] the cystic duct bound. The flow of bile is increased to double ([see] fig. 44). But is this humoral action due to the same secretin that acts on the pancrease or [is it due to the action of] a special "crinine" [i.e., a hypothetical hormone that's involved in digestion, like Fleig's "sapocrinine" (see p. 293)] on the liver? For the moment it's an unresolved question and [one] that has given me no result.)
  7. Ivy AC, Oldberg E . A hormone mechanism for gall-bladder contraction and evacuation . American Journal of Physiology . 86. 3 . 599–613 . October 1928 . 10.1152/ajplegacy.1928.86.3.599. free .
  8. Harper . A. A. . Raper . H. S. . Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine . The Journal of Physiology . 30 June 1943 . 102 . 1 . 115–125 . 10.1113/jphysiol.1943.sp004021 . 16991584 . 1393423 .
  9. Jorpes . E. . Mutt . V. . Cholecystokinin and pancreozymin, one single hormone? . Acta Physiologica Scandinavica . Jan–Feb 1966 . 66 . 1 . 196–202. 10.1111/j.1748-1716.1966.tb03185.x . 5935672 .
  10. Konturek PC, Konturek SJ . The history of gastrointestinal hormones and the Polish contribution to elucidation of their biology and relation to nervous system . Journal of Physiology and Pharmacology . 54 . 83–98 . December 2003 . Suppl 3 . 15075466 .
  11. Broden B . Experiments with cholecystokinin in cholecystography . Acta Radiologica . 49 . 1 . 25–30 . January 1958 . 13508336 . 10.3109/00016925809170975 . free .
  12. Mutt . V. . Jorpes . J.E. . Structure of porcine cholecystokinin-pancreozymin. I. Cleavage with thrombin and with trypsin . European Journal of Biochemistry . 1968 . 6 . 1 . 156–162. 10.1111/j.1432-1033.1968.tb00433.x . 5725809 . free .
  13. Chaudhri O, Small C, Bloom S . Gastrointestinal hormones regulating appetite . Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences . 361 . 1471 . 1187–209 . July 2006 . 16815798 . 1642697 . 10.1098/rstb.2006.1856 .
  14. Reeve JR, Eysselein VE, Rosenquist G, Zeeh J, Regner U, Ho FJ, Chew P, Davis MT, Lee TD, Shively JE, Brazer SR, Liddle RA . 6 . Evidence that CCK-58 has structure that influences its biological activity . The American Journal of Physiology . 270 . 5 Pt 1 . G860-8 . May 1996 . 8967499 . 10.1152/ajpgi.1996.270.5.G860 .
  15. Agersnap M, Rehfeld JF . Measurement of nonsulfated cholecystokinins . Scandinavian Journal of Clinical and Laboratory Investigation . 74 . 5 . 424–31 . August 2014 . 24734780 . 10.3109/00365513.2014.900695 . 207421432 .
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