View source for Cholecystokinin

{{short description|Hormone of the gastrointestinal system}}
{{Use dmy dates|date=May 2021}}
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{{Infobox_gene}}
'''Cholecystokinin''' ('''CCK''' or '''CCK-PZ'''; from [[Greek language|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 cell]]s in the [[duodenum]], the first segment of the [[small intestine]]. Its presence causes the release of [[pancreatic juice]] from the [[pancreas]] and [[bile]] from the [[gallbladder]].<ref name="Johnson_2014">{{cite book | vauthors = Johnson LR | title = Gastrointestinal Physiology | date = 2013 | isbn = 978-0-323-10085-4 | edition = Eighth | publisher = Elsevier/Mosby | location = Philadelphia }}</ref><ref name="urlCholecystokinin">{{cite web | url = http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html | title = Cholecystokinin | date = 28 January 2001 | publisher = Colorado State University | vauthors = Bowen R | access-date = 6 November 2015 | url-status = dead | archive-url = https://web.archive.org/web/20160317024952/http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html | archive-date = 17 March 2016 }}</ref>

==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.<ref>{{cite book | vauthors = Bernard C |title=Leçons de physiologie expérimentale appliquée à la médecine |date=1856 |publisher=J.B. Baillière et fils |location=Paris, France |volume=2 |page=430 |url=https://www.biodiversitylibrary.org/item/16939#page/442/mode/1up |language=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.)</ref><ref>{{cite journal | vauthors = Rehfeld JF | title = Cholecystokinin and the hormone concept | journal = Endocrine Connections | volume = 10 | issue = 3 | pages = R139–R150 | date = March 2021 | pmid = 33640870 | pmc = 8052576 | doi = 10.1530/EC-21-0025 }}</ref>  In 1903, the French physiologist {{ill|Émile Wertheimer|fr}} showed that this reflex was not mediated by the nervous system.<ref>{{cite journal | vauthors = Wertheimer E |title=De l'action des acides et du chloral sur la sécrétion biliaire (d'après les expériences de M. Ch. Dubois) |journal=Compte Rendus Hebdomadaires des Séances et Mémoires de la Société Biologie |date=1903 |volume=55 |pages=286–287 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b4020783&view=1up&seq=310&skin=2021 |trans-title=On the action of acids and chloral on bile secretion (according to the experiments of Mr. Charles Dubois) |language=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.)</ref>  In 1904, the French physiologist Charles Fleig showed that the discharge of bile was mediated by a substance that was conveyed by the blood.<ref>{{cite journal | vauthors = Fleig C |title=Du mode d'action des excitants chimiques des glandes digestives |journal=Archives Internationales de Physiologie et de Biochimie |date=1904 |volume=1 |pages=286–346 |url=https://babel.hathitrust.org/cgi/pt?id=uc1.b3888268&view=1up&seq=326&skin=2021 |trans-title=On the mode of action of the chemical stimulants of the digestive glands |language=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.)</ref>  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".<ref>{{cite journal | vauthors = Ivy AC, Oldberg E | title = A hormone mechanism for gall-bladder contraction and evacuation | journal = American Journal of Physiology | volume = 86| issue = 3 | pages = 599–613 | date = October 1928 | doi = 10.1152/ajplegacy.1928.86.3.599| doi-access = free }}</ref> 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";<ref>{{cite journal | vauthors = Harper AA, Raper HS | title = Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine | journal = The Journal of Physiology | volume = 102 | issue = 1 | pages = 115–125 | date = June 1943 | pmid = 16991584 | pmc = 1393423 | doi = 10.1113/jphysiol.1943.sp004021 }}</ref> however, pancreozymin was subsequently found to be cholecystokinin.<ref>{{cite journal | vauthors = Jorpes E, Mutt V | title = Cholecystokinin and pancreozymin, one single hormone? | journal = Acta Physiologica Scandinavica | volume = 66 | issue = 1 | pages = 196–202 | date = Jan–Feb 1966 | pmid = 5935672 | doi = 10.1111/j.1748-1716.1966.tb03185.x }}</ref><ref>{{cite journal | vauthors = Konturek PC, Konturek SJ | title = The history of gastrointestinal hormones and the Polish contribution to elucidation of their biology and relation to nervous system | journal = Journal of Physiology and Pharmacology | volume = 54 | issue = Suppl 3 | pages = 83–98 | date = December 2003 | pmid = 15075466 | url = https://www.jpp.krakow.pl/journal/archive/12_03_s3/pdf/83_12_03_s3_article.pdf }}</ref><ref>{{cite journal | vauthors = Broden B | title = Experiments with cholecystokinin in cholecystography | journal = Acta Radiologica | volume = 49 | issue = 1 | pages = 25–30 | date = January 1958 | pmid = 13508336 | doi = 10.3109/00016925809170975 | doi-access = free }}</ref>  Swedish biochemists [[Erik Jorpes|Johannes Erik Jorpes]] and Viktor Mutt undertook the monumental task of isolating and purifying porcine cholecystokinin and then determining its [[Protein primary structure|amino acid sequence]].  They finally presented porcine cholecystokinin's amino acid sequence in 1968.<ref>{{cite journal | vauthors = Mutt V, Jorpes JE | title = Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage with thrombin and with trypsin | journal = European Journal of Biochemistry | volume = 6 | issue = 1 | pages = 156–162 | date = October 1968 | pmid = 5725809 | doi = 10.1111/j.1432-1033.1968.tb00433.x | doi-access = free }}</ref>

== 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 acid]]s depending on [[post-translational modification]] of the 150-amino acid precursor, preprocholecystokinin.<ref name=":0">{{cite journal | vauthors = Chaudhri O, Small C, Bloom S | title = Gastrointestinal hormones regulating appetite | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 361 | issue = 1471 | pages = 1187–1209 | date = July 2006 | pmid = 16815798 | pmc = 1642697 | doi = 10.1098/rstb.2006.1856 }}</ref> 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 [[Sincalide|CCK-8]]. CCK58 assumes a [[helix-turn-helix]] configuration.<ref name="pmid8967499">{{cite journal | vauthors = Reeve JR, Eysselein VE, Rosenquist G, Zeeh J, Regner U, Ho FJ, Chew P, Davis MT, Lee TD, Shively JE, Brazer SR, Liddle RA | title = Evidence that CCK-58 has structure that influences its biological activity | journal = The American Journal of Physiology | volume = 270 | issue = 5 Pt 1 | pages = G860–G868 | date = May 1996 | pmid = 8967499 | doi = 10.1152/ajpgi.1996.270.5.G860 }}</ref> 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]]).<ref name=":0" /> 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 receptor|CCK-A receptor]], but their biological role remains unclear.<ref name=":0" /><ref name="PMID 24734780">{{cite journal | vauthors = Agersnap M, Rehfeld JF | title = Measurement of nonsulfated cholecystokinins | journal = Scandinavian Journal of Clinical and Laboratory Investigation | volume = 74 | issue = 5 | pages = 424–431 | date = August 2014 | pmid = 24734780 | doi = 10.3109/00365513.2014.900695 | s2cid = 207421432 }}</ref>

== Function ==
CCK plays important [[Physiology|physiological]] roles both as a [[neuropeptide]] in the [[central nervous system]] and as a [[peptide hormone]] in the gut.<ref name="Lenka_2016">{{cite journal | vauthors = Lenka A, Arumugham SS, Christopher R, Pal PK | title = Genetic substrates of psychosis in patients with Parkinson's disease: A critical review | journal = Journal of the Neurological Sciences | volume = 364 | pages = 33–41 | date = May 2016 | pmid = 27084212 | doi = 10.1016/j.jns.2016.03.005 | s2cid = 31298855 }}</ref> It is the most abundant neuropeptide in the central nervous system.<ref>{{cite journal | vauthors = Ma Y, Giardino WJ | title = Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction | journal = Addiction Neuroscience | volume = 3 | article-number = 100024 | date = September 2022 | pmid = 35983578 | pmc = 9380858 | doi = 10.1016/j.addicn.2022.100024 }}</ref><ref>{{cite journal | vauthors = Moran TH, Schwartz GJ | title = Neurobiology of cholecystokinin | journal = Critical Reviews in Neurobiology | volume = 9 | issue = 1 | pages = 1–28 | date = 1994 | pmid = 8828002 }}</ref> CCK has been researched thoroughly for its role in digestion<ref>{{cite journal | vauthors = Ma Y, Giardino WJ | title = Neural circuit mechanisms of the cholecystokinin (CCK) neuropeptide system in addiction | journal = Addiction Neuroscience | volume = 3 | article-number = 100024 | date = September 2022 | pmid = 35983578 | pmc = 9380858 | doi = 10.1016/j.addicn.2022.100024 }}</ref> In addition to its role in digestion, CCK is involved in regulating various behavioral phenomena, including [[Hunger (physiology)|satiety]], [[appetite]], [[anxiety]], [[thermoregulation]], sexual behavior, memory, and the response to drugs of abuse, particularly within the [[Cortex (anatomy)|cortex]] and [[Limbic system|limbic]] regions of the brain.<ref>{{cite journal | vauthors = Rotzinger S, Vaccarino FJ | title = Cholecystokinin receptor subtypes: role in the modulation of anxiety-related and reward-related behaviours in animal models | journal = Journal of Psychiatry & Neuroscience | volume = 28 | issue = 3 | pages = 171–181 | date = May 2003 | pmid = 12790157 | pmc = 161741 }}</ref>

=== Gastrointestinal ===

CCK is synthesized and released by enteroendocrine cells in the mucosal lining of the small intestine (mostly in the duodenum and jejunum), called [[Enteroendocrine cell#Intestinal enteroendocrine cells|I cells]], neurons of the [[enteric nervous system]], and neurons in the brain.<ref name="Johnson_2014" /> It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of [[fatty acid]]s and/or certain [[amino acid]]s in the [[chyme]] entering the [[duodenum]].<ref name=":0" /> In addition, release of CCK is stimulated by [[monitor peptide]] (released by pancreatic [[Centroacinar cell|acinar cells]]), [[Diazepam binding inhibitor|CCK-releasing protein]] (via [[paracrine signalling]] mediated by [[enterocyte]]s in the [[Gastric mucosa|gastric]] and [[Human gastrointestinal tract#Mucosa|intestinal mucosa]]), and [[acetylcholine]] (released by the [[Parasympathetic nervous system|parasympathetic nerve]] fibers of the [[vagus nerve]]).<ref>{{cite journal | vauthors = Chey WY, Chang T | title = Neural hormonal regulation of exocrine pancreatic secretion | journal = Pancreatology | volume = 1 | issue = 4 | pages = 320–335 | date = 2001-01-01 | pmid = 12120211 | doi = 10.1159/000055831 | s2cid = 22629842 }}</ref>

Once in the circulatory system, CCK has a relatively short half-life.<ref name="Skibicka_2013">{{cite journal | vauthors = Skibicka KP, Dickson SL | title = Enteroendocrine hormones - central effects on behavior | journal = Current Opinion in Pharmacology | volume = 13 | issue = 6 | pages = 977–982 | date = December 2013 | pmid = 24091195 | doi = 10.1016/j.coph.2013.09.004 | doi-access = free }}</ref>

==== Digestion ====
CCK mediates digestion in the small intestine by inhibiting gastric emptying.  It stimulates the [[Centroacinar cells|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.<ref>{{cite journal | vauthors = Liddle RA | title = Regulation of cholecystokinin secretion by intraluminal releasing factors | journal = The American Journal of Physiology | volume = 269 | issue = 3 Pt 1 | pages = G319–G327 | date = September 1995 | pmid = 7573441 | doi = 10.1152/ajpgi.1995.269.3.G319 }}</ref>

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.<ref name="Johnson_2014" /><ref name="urlCholecystokinin" /> [[Bile salt]]s form [[amphiphile|amphipathic]] [[lipids]], [[micelle]]s that [[emulsification|emulsify]] fats, aiding in their digestion and absorption.<ref name="Johnson_2014" />[[File:Effects of CCK on the gastrointestinal tract.svg|thumb|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, increases bile acid production in the liver, delays gastric emptying, and induces digestive enzyme production in the pancreas.]]

==== Satiety ====
As a peptide hormone, CCK mediates satiety by acting on the [[CCK receptor]]s distributed widely throughout the [[central nervous system]]. The mechanism for hunger suppression is thought to be a decrease in the rate of gastric emptying.<ref name="pmid3812772">{{cite journal | vauthors = Shillabeer G, Davison JS | title = Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats | journal = The American Journal of Physiology | volume = 252 | issue = 2 Pt 2 | pages = R353–R360 | date = February 1987 | pmid = 3812772 | doi = 10.1152/ajpregu.1987.252.2.R353 }}</ref> CCK also has stimulatory effects on the [[vagus nerve]], effects that can be inhibited by [[capsaicin]].<ref name="pmid9655678">{{cite journal | vauthors = Holzer P | title = Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve | journal = The American Journal of Physiology | volume = 275 | issue = 1 | pages = G8-13 | date = July 1998 | pmid = 9655678 | doi = 10.1152/ajpgi.1998.275.1.G8 | doi-access =  }}</ref> The stimulatory effects of CCK oppose those of [[ghrelin]], which has been shown to inhibit the vagus nerve.<ref name="pmid15550621">{{cite journal | vauthors = Kobelt P, Tebbe JJ, Tjandra I, Stengel A, Bae HG, Andresen V, van der Voort IR, Veh RW, Werner CR, Klapp BF, Wiedenmann B, Wang L, Taché Y, Mönnikes H | title = CCK inhibits the orexigenic effect of peripheral ghrelin | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 288 | issue = 3 | pages = R751–R758 | date = March 2005 | pmid = 15550621 | doi = 10.1152/ajpregu.00094.2004 }}</ref>

The effects of CCK vary between individuals. For example, in [[rat]]s, 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.<ref name="pmid9835394">{{cite journal | vauthors = Fink H, Rex A, Voits M, Voigt JP | title = Major biological actions of CCK--a critical evaluation of research findings | journal = Experimental Brain Research | volume = 123 | issue = 1–2 | pages = 77–83 | date = November 1998 | pmid = 9835394 | doi = 10.1007/s002210050546 | s2cid = 11251325 }}</ref>

=== Neurological ===

CCK is found extensively throughout the [[central nervous system]], with high concentrations found in the [[limbic system]].<ref name="Bowers_2012">{{cite journal | vauthors = Bowers ME, Choi DC, Ressler KJ | title = Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y | journal = Physiology & Behavior | volume = 107 | issue = 5 | pages = 699–710 | date = December 2012 | pmid = 22429904 | pmc = 3532931 | doi = 10.1016/j.physbeh.2012.03.004 }}</ref> CCK is synthesized as a 115 amino acid [[preprohormone]], that is then converted into multiple [[Protein isoform|isoforms]].<ref name="Bowers_2012" /> The predominant form of CCK in the central nervous system is the [[Tyrosine sulfation|sulfated]] [[Peptide|octapeptide]], CCK-8S.<ref name="Bowers_2012" />

==== Anxiogenic ====
In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased [[anxiety]].<ref name="Skibicka_2013" /> The site of the anxiety-inducing effects of CCK seems to be central with specific targets being the [[basolateral amygdala]], [[hippocampus]], [[hypothalamus]], [[Periaqueductal gray|periaqueductal grey]], and [[Cerebral cortex|cortical regions]].<ref name="Skibicka_2013" /><ref name="Zwanzger_2012">{{cite journal | vauthors = Zwanzger P, Domschke K, Bradwejn J | title = Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin | journal = Depression and Anxiety | volume = 29 | issue = 9 | pages = 762–774 | date = September 2012 | pmid = 22553078 | doi = 10.1002/da.21919 | s2cid = 24581213 | doi-access = free }}</ref>

==== Panicogenic ====
The CCK tetrapeptide fragment [[CCK-4]] ([[Tryptophan|Trp]]-[[Methionine|Met]]-[[Aspartate|Asp]]-[[Phenylalanine|Phe]]-NH<sub>2</sub>) reliably causes anxiety and [[panic attack]]s (panicogenic effect) when administered to humans and is commonly used in scientific research in order to test new [[anxiolytic]] drugs.<ref name="Zwanzger_2012" /><ref name="pmid8104032">{{cite journal | vauthors = Bradwejn J | title = Neurobiological investigations into the role of cholecystokinin in panic disorder | journal = Journal of Psychiatry & Neuroscience | volume = 18 | issue = 4 | pages = 178–188 | date = July 1993 | pmid = 8104032 | pmc = 1188527 }}</ref> [[Positron emission tomography]] visualization of regional cerebral blood flow in patients undergoing CCK-4 induced panic attacks show changes in the [[Anterior cingulate cortex|anterior cingulate gyrus]], the [[claustrum]]-[[Insular cortex|insular]]-[[amygdala]] region, and [[cerebellar vermis]].<ref name="Bowers_2012" />

==== Hallucinogenic ====
Several studies have implicated CCK as a cause of [[Hallucination|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.<ref name="Lenka_2016" />

== Interactions ==

CCK has been shown to [[Protein-protein interaction|interact]] with the cholecystokinin A receptor located mainly on pancreatic acinar cells and [[cholecystokinin B receptor]] mostly in the brain and stomach.  CCK<sub>B</sub> receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa.<ref name="pmid15520004">{{cite journal | vauthors = Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ | title = Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy | journal = The Journal of Biological Chemistry | volume = 280 | issue = 2 | pages = 1044–1050 | date = January 2005 | pmid = 15520004 | doi = 10.1074/jbc.M409480200 | doi-access = free }}</ref><ref name="pmid15001692">{{cite journal | vauthors = Aloj L, Caracò C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, De Luca S, Arra C, Pedone C, Morelli G, Salvatore M | title = In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging | journal = Journal of Nuclear Medicine | volume = 45 | issue = 3 | pages = 485–494 | date = March 2004 | pmid = 15001692 | url = http://jnm.snmjournals.org/cgi/pmidlookup?view=long&pmid=15001692 | id = {{ProQuest|219229095}} }}</ref><ref name="pmid12695525">{{cite journal | vauthors = Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S | title = Identification of tyrosine 189 and asparagine 358 of the cholecystokinin 2 receptor in direct interaction with the crucial C-terminal amide of cholecystokinin by molecular modeling, site-directed mutagenesis, and structure/affinity studies | journal = Molecular Pharmacology | volume = 63 | issue = 5 | pages = 973–982 | date = May 2003 | pmid = 12695525 | doi = 10.1124/mol.63.5.973 | s2cid = 38395309 }}</ref> 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]].<ref name="pmid17978097">{{cite journal | vauthors = Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA | title = Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo | journal = Molecular Biology of the Cell | volume = 19 | issue = 1 | pages = 198–206 | date = January 2008 | pmid = 17978097 | pmc = 2174201 | doi = 10.1091/mbc.E07-05-0430 }}</ref> CCK has been shown to interact with [[orexin]] neurons, which control appetite and wakefulness ([[sleep]]).<ref name="pmid16093397">{{cite journal | vauthors = Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = The Journal of Neuroscience | volume = 25 | issue = 32 | pages = 7459–7469 | date = August 2005 | pmid = 16093397 | pmc = 6725310 | doi = 10.1523/JNEUROSCI.1193-05.2005 | doi-access = free }}</ref> CCK can have indirect effects on sleep regulation.<ref>{{cite thesis |degree=PhD | vauthors = Kapas L | date=2010 |title=Metabolic signals in sleep regulation: the role of cholecystokinin |journal=The Journal of Neuroscience |publisher=University of Szeged | url=http://www.phd.szote.u-szeged.hu/Elmeleti_DI/Disszertaciok/2010/de_Levente_Kapas.pdf }}</ref>

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 ==
* [[Antianalgesia]]
* [[Cholecystokinin antagonist]]
* [[Proglumide]]
{{clear}}

== References ==
{{Reflist|33em}}

== External links ==
* {{Commons category-inline}}
* {{MeshName|Cholecystokinin}}

{{Gastrointestinal physiology}}
{{Neuropeptides}}
{{Gastrointestinal hormones}}

[[Category:Cholecystokinin| ]]
[[Category:Anxiogenics]]
[[Category:Hepatology]]
[[Category:Intestinal hormones]]
[[Category:Neuropeptides]]
[[Category:Cholecystokinin agonists]]