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[[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, reduces of gastric acid secretion, increases bile acid production in the liver, delays gastric emptying, and induces digestive enzyme production in the pancreas.]]
'''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, previously 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 [[digestive enzymes]] and [[bile]] from the [[pancreas]] and [[gallbladder]], respectively, and also acts as a [[appetite suppressant|hunger suppressant]].<ref name = "Johnson_2014">{{cite book | last1 = Johnson | first1 = Leonard R. | name-list-format = vanc | 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 | accessdate = 6 November 2015 | deadurl = yes | archiveurl = https://web.archive.org/web/20160317024952/http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html | archivedate = 17 March 2016 | df = dmy-all }} </ref>


==Structure==
The existence of CCK was first suggested in 1905 by the British physiologist Joy Simcha Cohen. 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 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 = 1187–209 | 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., CCK58, CCK33, CCK22 and CCK8. 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 = G860-8 | date = May 1996 | pmid = 8967499 }}</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.<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-A receptor.<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 = 424–31 | date = August 2014 | pmid = 24734780 | doi = 10.3109/00365513.2014.900695 }}</ref>
== Function ==
CCK plays important physiologic 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  }}</ref> It participates in a number of [[Physiology|physiological]] processes such as digestion, [[Hunger (motivational state)|satiety]] and [[anxiety]].<nowiki/>
=== 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]]<nowiki/>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]]), [[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 = 320–35 | date = 2001-01-01 | pmid = 12120211  }}</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 = 977–82 | date = December 2013 | pmid = 24091195 | doi = 10.1016/j.coph.2013.09.004  }}</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 = G319-27 | date = September 1995 | pmid = 7573441 }}</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" />


==== 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 = R353-60 | date = February 1987 | pmid = 3812772 | url = http://ajpregu.physiology.org/cgi/content/abstract/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 Pt 1 | pages = G8-13 | date = July 1998 | pmid = 9655678 | doi =  | url = http://ajpgi.physiology.org/content/275/1/G8.full#cited-by }}</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 = R751-8 | date = March 2005 | pmid = 15550621 | doi = 10.1152/ajpregu.00094.2004 }}</ref>


==Overview==
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 }}</ref>
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{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Cholecystokinin
| HGNCid = 1569
| Symbol = CCK
| AltSymbols =; MGC117187
| OMIM = 118440
| ECnumber = 
| Homologene = 583
| MGIid = 88297
| GeneAtlas_image1 = PBB_GE_CCK_205827_at_tn.png
| Function = {{GNF_GO|id=GO:0005184 |text = neuropeptide hormone activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}} {{GNF_GO|id=GO:0005625 |text = soluble fraction}} {{GNF_GO|id=GO:0030424 |text = axon}}
| Process = {{GNF_GO|id=GO:0001764 |text = neuron migration}} {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007409 |text = axonogenesis}} {{GNF_GO|id=GO:0042755 |text = eating behavior}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 885
    | Hs_Ensembl = ENSG00000187094
    | Hs_RefseqProtein = NP_000720
    | Hs_RefseqmRNA = NM_000729
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 42274322
    | Hs_GenLoc_end = 42281399
    | Hs_Uniprot = P06307
    | Mm_EntrezGene = 12424
    | Mm_Ensembl = ENSMUSG00000032532
    | Mm_RefseqmRNA = NM_031161
    | Mm_RefseqProtein = NP_112438
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 9
    | Mm_GenLoc_start = 121338523
    | Mm_GenLoc_end = 121344360
    | Mm_Uniprot = Q53WS9
  }}
}}
{{Protein
|Name=Cholecystokinin
  |image=Control-of-stomach-acid-sec.png
  |caption=CCK identified at bottom right.
  |Symbol=CCK
  |AltSymbols=
  |HGNCid=1569
  |Chromosome=3
  |Arm=
  |Band=
  |LocusSupplementaryData=pter-p21
  |ECnumber=
  |OMIM=118440
  |EntrezGene=885
  |RefSeq=NM_000729
  |UniProt=P06307
  |PDB=
}}
{{SI}}
__NOTOC__
'''Cholecystokinin''' ('''CCK'''; 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, previously called '''''pancreozymin''''', is synthesised by I-cells in the mucosal epithelium of the small intestine and secreted in the [[duodenum]], the first segment of the [[small intestine]], and causes the release of digestive [[enzyme]]s and [[bile]] from the [[pancreas]] and [[gallbladder]], respectively. It also acts as a [[appetite suppressant|hunger suppressant]]. Recent evidence has suggested that it also plays a major role in inducing drug [[tolerance]] to [[opioids]] like [[morphine]] and [[heroin]], and is partly implicated in experiences of pain hypersensitivity during opioid [[withdrawal]].<ref name="pmid10866896">{{cite journal | author = Kissin I, Bright CA, Bradley EL | title = Acute tolerance to continuously infused alfentanil: the role of cholecystokinin and N-methyl-D-aspartate-nitric oxide systems | journal = Anesth. Analg. | volume = 91 | issue = 1 | pages = 110–6 | year = 2000 | pmid = 10866896 | doi = | issn = | url = http://www.anesthesia-analgesia.org/cgi/content/abstract/91/1/110  | doi = 10.1097/00000539-200007000-00021}}</ref><ref name="pmid17558184">{{cite journal | author = Fukazawa Y, Maeda T, Kiguchi N, Tohya K, Kimura M, Kishioka S | title = Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats | journal = J. Pharmacol. Sci. | volume = 104 | issue = 2 | pages = 159–66 | year = 2007 | pmid = 17558184 | doi = 10.1254/jphs.FP0070475 | issn = }}</ref>


==Structure==
=== Neurological ===
CCK is composed of varying numbers of [[amino acid]]s (e.g., CCK58, CCK33, CCK8) depending on [[protein synthesis|post-translational]] modification of the CCK gene product, preprocholecystokinin. CCK is very similar in structure to [[gastrin]], another of the [[gastrointestinal hormone]]s, so much so that the last five C-terminal amino acids are same as those of gastrin.  CCK58 comprises a helix-turn-helix configuration.
 
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 | doi = 10.1016/j.physbeh.2012.03.004 | pmc = 3532931 }}</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|peraqueductal 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 = 762–74 | date = September 2012 | pmid = 22553078 | doi = 10.1002/da.21919 }}</ref>


==Release and Function==
==== Panicogenic ====
CCK mediates a number of [[physiology|physiological]] processes, including [[digestion]] and [[satiety]].
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 for this purpose of 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 = 178–88 | date = July 1993 | pmid = 8104032 | pmc = 1188527 | doi =  }}</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" />


===Digestion===
==== Hallucinogenic ====
Secretion of CCK by the duodenal and intestinal mucosa is stimulated by fat- or protein-rich [[chyme]] entering the [[duodenum]]. It then inhibits gastric emptying and [[gastric acid]] secretion and mediates digestion in the duodenum. It acts on the [[pancreas]] to stimulate the secretion of a juice rich in pancreatic [[digestive enzymes]]. Together these  enzymes catalyze the digestion of fat, protein, and carbohydrates. Thus the levels of the substances which stimulated the release of CCK drop and the concentration of the hormone drops as well. The release of CCK is also inhibited by [[somatostatin]].  
Several studies have implicated CCK as a cause of [[Hallucination|visual hallucinations]] in [[Parkinson's disease|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" />


CCK also causes the increased production of hepatic bile, and stimulates the contraction of the [[gallbladder]] 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 salt]]s form amphipathic [[micelle]]s that [[emulsification|emulsify]] fats, aiding in their digestion and absorption.
== Interactions ==


===Neurobiology===
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 = 1044–50 | date = January 2005 | pmid = 15520004 | doi = 10.1074/jbc.M409480200 }}</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 = 485–94 | date = March 2004 | pmid = 15001692 | doi =  }}</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 = 973–82 | date = May 2003 | pmid = 12695525 | doi = 10.1124/mol.63.5.973 }}</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 = 7459–69 | date = August 2005 | pmid = 16093397 | doi = 10.1523/JNEUROSCI.1193-05.2005 }}</ref> CCK can have indirect effects on sleep regulation.<ref>{{cite thesis |degree=PhD |first=Levente |last=Kapas | name-list-format = vanc | 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>
As a [[neuropeptide]], CCK mediates satiety by acting on the [[CCK receptor]]s distributed widely throughout the [[central nervous system]]. In humans, it has been suggested that CCK administration causes [[nausea]] and [[anxiety]], and weakly decreases the desire to eat is the reason for CCK administration to induce a satiating effect.  Some studies have given a strong correlation for the satiating effect, but have not proven or disproven that CCK administration causes nauseau or anxiety Benoit et al (2003).<ref name="pmid9855480">{{cite journal | author = Greenough A, Cole G, Lewis J, Lockton A, Blundell J | title = Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion | journal = Physiol. Behav. | volume = 65 | issue = 2 | pages = 303–10 | year = 1998 | pmid = 9855480 | doi = 10.1016/S0031-9384(98)00169-3 | issn = }}</ref> The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.<ref name="pmid3812772">{{cite journal | author = Shillabeer G, Davison JS | title = Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats | journal = Am. J. Physiol. | volume = 252 | issue = 2 Pt 2 | pages = R353–60 | year = 1987 | pmid = 3812772 | doi = | issn = | url = http://ajpregu.physiology.org/cgi/content/abstract/252/2/R353 }}</ref>


The effects of CCK vary between individuals. For example, in [[rat]]s, CCK administration significantly reduces hunger in young males, but is slightly less effective in older 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 | author = Fink H, Rex A, Voits M, Voigt JP | title = Major biological actions of CCK--a critical evaluation of research findings | journal = Exp Brain Res | volume = 123 | issue = 1-2 | pages = 77–83 | year = 1998 | pmid = 9835394 | doi = 10.1007/s002210050546 | issn = }}</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==
== See also ==
* [[Antianalgesia]]
* [[Antianalgesia]]
* [[Cholecystokinin antagonist]]
* [[Cholecystokinin antagonist]]
* [[Proglumide]]
* [[Proglumide]]


==References==
== References ==
<references/>
{{Reflist|33em}}


==External links==
== External links ==
* {{MeshName|Cholecystokinin}}
* {{MeshName|Cholecystokinin}}
* {{GeorgiaPhysiology|6/6ch2/s6ch2_14}}


{{Hormones}}
{{Hormones}}
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{{Neuropeptides}}
{{Neuropeptides}}
{{Gastrointestinal hormones}}
{{Gastrointestinal hormones}}
{{Neuropeptidergics}}


[[Category:Anxiogenics]]
[[Category:Hepatology]]
[[Category:Hepatology]]
[[Category:Intestinal hormones]]
[[Category:Intestinal hormones]]
[[Category:Neuropeptides]]
[[Category:Neuropeptides]]
[[Category:Endocrinology]]
[[Category:Cholecystokinin]]
 
 
 
[[de:Cholecystokinin]]
[[fr:Cholécystokinine]]
[[it:Colecistochinina]]
[[nl:Cholecystokinine]]
[[pl:Cholecystokinina]]
[[pt:Colecistocinina]]
[[sr:Холецистокинин]]
[[fi:Kolekystokiniini]]
[[sv:Cholecystokinin]]
 
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Latest revision as of 23:15, 25 October 2017

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File:Effects of CCK on the gastrointestinal tract.svg
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.

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, previously 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.[1][2]

Structure

The existence of CCK was first suggested in 1905 by the British physiologist Joy Simcha Cohen. 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.[3] 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.[4] 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.[3] 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.[5]

Function

CCK plays important physiologic roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut.[6] It participates in a number of physiological 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.[1] 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.[3] 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).[7]

Once in the circulatory system, CCK has a relatively short half-life.[8]

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.[9]

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.[1][2] Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption.[1]

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.[10] CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin.[11] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.[12]

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.[13]

Neurological

CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system.[14] CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms.[14] The predominant form of CCK in the central nervous system is the sulfated octapeptide, CCK-8S.[14]

Anxiogenic

In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety.[8] The site of the anxiety-inducing effects of CCK seems to be central with specific targets being the basolateral amygdala, hippocampus, hypothalamus, peraqueductal grey, and cortical regions.[8][15]

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.[15][16] 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.[14]

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.[6]

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.[17][18][19] 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.[20] CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep).[21] CCK can have indirect effects on sleep regulation.[22]

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

References

  1. ↑ 1.0 1.1 1.2 1.3 Johnson LR (2013). Gastrointestinal Physiology (Eighth ed.). Philadelphia: Elsevier/Mosby. ISBN 978-0-323-10085-4.
  2. ↑ 2.0 2.1 Bowen R (28 January 2001). "Cholecystokinin". Colorado State University. Archived from the original on 17 March 2016. Retrieved 6 November 2015.
  3. ↑ 3.0 3.1 3.2 Chaudhri O, Small C, Bloom S (July 2006). "Gastrointestinal hormones regulating appetite". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 361 (1471): 1187–209. doi:10.1098/rstb.2006.1856. PMC 1642697. PMID 16815798.
  4. ↑ Reeve JR, Eysselein VE, Rosenquist G, Zeeh J, Regner U, Ho FJ, Chew P, Davis MT, Lee TD, Shively JE, Brazer SR, Liddle RA (May 1996). "Evidence that CCK-58 has structure that influences its biological activity". The American Journal of Physiology. 270 (5 Pt 1): G860–8. PMID 8967499.
  5. ↑ Agersnap M, Rehfeld JF (August 2014). "Measurement of nonsulfated cholecystokinins". Scandinavian Journal of Clinical and Laboratory Investigation. 74 (5): 424–31. doi:10.3109/00365513.2014.900695. PMID 24734780.
  6. ↑ 6.0 6.1 Lenka A, Arumugham SS, Christopher R, Pal PK (May 2016). "Genetic substrates of psychosis in patients with Parkinson's disease: A critical review". Journal of the Neurological Sciences. 364: 33–41. doi:10.1016/j.jns.2016.03.005. PMID 27084212.
  7. ↑ Chey WY, Chang T (2001-01-01). "Neural hormonal regulation of exocrine pancreatic secretion". Pancreatology. 1 (4): 320–35. PMID 12120211.
  8. ↑ 8.0 8.1 8.2 Skibicka KP, Dickson SL (December 2013). "Enteroendocrine hormones - central effects on behavior". Current Opinion in Pharmacology. 13 (6): 977–82. doi:10.1016/j.coph.2013.09.004. PMID 24091195.
  9. ↑ Liddle RA (September 1995). "Regulation of cholecystokinin secretion by intraluminal releasing factors". The American Journal of Physiology. 269 (3 Pt 1): G319–27. PMID 7573441.
  10. ↑ Shillabeer G, Davison JS (February 1987). "Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats". The American Journal of Physiology. 252 (2 Pt 2): R353–60. PMID 3812772.
  11. ↑ Holzer P (July 1998). "Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve". The American Journal of Physiology. 275 (1 Pt 1): G8–13. PMID 9655678.
  12. ↑ 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 (March 2005). "CCK inhibits the orexigenic effect of peripheral ghrelin". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 288 (3): R751–8. doi:10.1152/ajpregu.00094.2004. PMID 15550621.
  13. ↑ Fink H, Rex A, Voits M, Voigt JP (November 1998). "Major biological actions of CCK--a critical evaluation of research findings". Experimental Brain Research. 123 (1–2): 77–83. doi:10.1007/s002210050546. PMID 9835394.
  14. ↑ 14.0 14.1 14.2 14.3 Bowers ME, Choi DC, Ressler KJ (December 2012). "Neuropeptide regulation of fear and anxiety: Implications of cholecystokinin, endogenous opioids, and neuropeptide Y". Physiology & Behavior. 107 (5): 699–710. doi:10.1016/j.physbeh.2012.03.004. PMC 3532931. PMID 22429904.
  15. ↑ 15.0 15.1 Zwanzger P, Domschke K, Bradwejn J (September 2012). "Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin". Depression and Anxiety. 29 (9): 762–74. doi:10.1002/da.21919. PMID 22553078.
  16. ↑ Bradwejn J (July 1993). "Neurobiological investigations into the role of cholecystokinin in panic disorder". Journal of Psychiatry & Neuroscience. 18 (4): 178–88. PMC 1188527. PMID 8104032.
  17. ↑ Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ (January 2005). "Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy". The Journal of Biological Chemistry. 280 (2): 1044–50. doi:10.1074/jbc.M409480200. PMID 15520004.
  18. ↑ Aloj L, Caracò C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, De Luca S, Arra C, Pedone C, Morelli G, Salvatore M (March 2004). "In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging". Journal of Nuclear Medicine. 45 (3): 485–94. PMID 15001692.
  19. ↑ Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S (May 2003). "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". Molecular Pharmacology. 63 (5): 973–82. doi:10.1124/mol.63.5.973. PMID 12695525.
  20. ↑ Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA (January 2008). "Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo". Molecular Biology of the Cell. 19 (1): 198–206. doi:10.1091/mbc.E07-05-0430. PMC 2174201. PMID 17978097.
  21. ↑ Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T (August 2005). "Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor". The Journal of Neuroscience. 25 (32): 7459–69. doi:10.1523/JNEUROSCI.1193-05.2005. PMID 16093397.
  22. ↑ Kapas L (2010). Metabolic signals in sleep regulation: the role of cholecystokinin (PDF). The Journal of Neuroscience (PhD thesis). University of Szeged.

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