Cholecystokinin

Cholecystokinin
Identifiers
Symbols CCK ; MGC117187
External IDs OMIM: 118440 MGI: 88297 HomoloGene: 583 ChEMBL: 1649050 GeneCards: CCK Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 885 12424
Ensembl ENSG00000187094 ENSMUSG00000032532
UniProt P06307 P09240
RefSeq (mRNA) NM_000729 NM_001284508
RefSeq (protein) NP_000720 NP_001271437
Location (UCSC) Chr 3:
42.26 – 42.27 Mb		 Chr 9:
121.49 – 121.5 Mb
PubMed search
CCK identified at bottom right.

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,[1] the first segment of the small intestine, and causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively. It also acts as a 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.[2][3]

Structure

CCK is composed of varying numbers of amino acids depending on post-translational modification of the CCK gene product, preprocholecystokinin. Thus CCK is actually a family of hormones identified by number of amino acids, e.g., CCK58, CCK33, CCK22 and CCK8. CCK58 assumes a helix-turn-helix configuration.[4] Its existence was first suggested in 1905 by the British physiologist Joy Simcha Cohen. CCK is very similar in structure to gastrin, another of the gastrointestinal hormones. CCK and gastrin share the same five amino acids at their C-termini. Most CCK peptides have a sulfate-group attached to the tyrosine in position 7 in the C-terminus. 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]

Functions

CCK mediates a number of physiological processes, including digestion and satiety. It 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. Release of CCK is stimulated by monitor peptide released by pancreatic acinar cells as well as CCK-releasing protein, a paracrine factor secreted by enterocytes in the gastrointestinal mucosa. In addition, release of acetylcholine by the parasympathetic nerve fibers of the vagus nerve also stimulate its secretion. The presence of fatty acids and/or certain amino acids in the chyme entering the duodenum is the greatest stimulator of CCK release.

CCK mediates digestion in the small intestine by inhibiting gastric emptying and decreasing gastric acid secretion. It stimulates the acinar cells of the pancreas to release a juice rich in pancreatic digestive enzymes, hence the old name pancreozymin. Together these enzymes 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. Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption.

Neurobiology

As a peptide hormone, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the central nervous system. In humans, it has been suggested that CCK administration causes nausea and anxiety, and induces a satiating effect. CCK-4 is routinely used to induce anxiety in humans though certainly different forms of CCK are being shown to have highly variable effects.[6] The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.[7]

CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin.[8] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.[9] The CCK tetrapeptide fragment CCK-4 (Trp-Met-Asp-Phe-NH2) reliably causes anxiety when administered to humans, and is commonly used in scientific research to induce panic attacks for the purpose of testing new anxiolytic drugs.[10] One study shows that visual hallucinations in Parkinson's disease are associated with cholecystokinin −45C>T polymorphism, and this association is still observed in the presence of the cholecystokinin-A receptor TC/CC genotype, indicating a possible interaction of these two genes in the visual hallucinogenesis in Parkinson's disease.[11]

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.[12]

Interactions

Cholecystokinin 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.[13][14][15]

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.[16]

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

Cholecystokinin 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. ↑ "Cholecystokinin". http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/gi/cck.html. External link in |website= (help);
  2. ↑ Kissin I, Bright CA, Bradley EL (2000). "Acute tolerance to continuously infused alfentanil: the role of cholecystokinin and N-methyl-D-aspartate-nitric oxide systems". Anesth. Analg. 91 (1): 110–6. doi:10.1097/00000539-200007000-00021. PMID 10866896.
  3. ↑ Fukazawa Y, Maeda T, Kiguchi N, Tohya K, Kimura M, Kishioka S (2007). "Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats". J. Pharmacol. Sci. 104 (2): 159–66. doi:10.1254/jphs.FP0070475. PMID 17558184.
  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 (1996). "Evidence that CCK-58 has structure that influences its biological activity". Am. J. Physiol. 270 (5 Pt 1): G860–8. PMID 8967499.
  5. ↑ Agersnap M, Rehfeld JF (2014). "Measurement of nonsulfated cholecystokinins". Scand. J. Clin. Lab. Invest. 74 (5): 424–31. doi:10.3109/00365513.2014.900695. PMID 24734780.
  6. ↑ Greenough A, Cole G, Lewis J, Lockton A, Blundell J (1998). "Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion". Physiol. Behav. 65 (2): 303–10. doi:10.1016/S0031-9384(98)00169-3. PMID 9855480.
  7. ↑ Shillabeer G, Davison JS (1987). "Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats". Am. J. Physiol. 252 (2 Pt 2): R353–60. PMID 3812772.
  8. ↑ Holzer P (July 1998). "Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve". Am. J. Physiol. 275 (1 Pt 1): G8–13. PMID 9655678.
  9. ↑ 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". Am. J. Physiol. Regul. Integr. Comp. Physiol. 288 (3): R751–8. doi:10.1152/ajpregu.00094.2004. PMID 15550621.
  10. ↑ Bradwejn J (July 1993). "Neurobiological investigations into the role of cholecystokinin in panic disorder". J Psychiatry Neurosci 18 (4): 178–88. PMC 1188527. PMID 8104032.
  11. ↑ Wang J, Si YM, Liu ZL, Yu L. (June 2003). "Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease.". Pharmacogenetics 13 (6): 365–9. doi:10.1097/00008571-200306000-00008. PMID 12777967.
  12. ↑ Fink H, Rex A, Voits M, Voigt JP (1998). "Major biological actions of CCK--a critical evaluation of research findings". Exp Brain Res 123 (1-2): 77–83. doi:10.1007/s002210050546. PMID 9835394.
  13. ↑ 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". J. Biol. Chem. 280 (2): 1044–50. doi:10.1074/jbc.M409480200. PMID 15520004.
  14. ↑ 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". J. Nucl. Med. 45 (3): 485–94. PMID 15001692.
  15. ↑ 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". Mol. Pharmacol. 63 (5): 973–82. doi:10.1124/mol.63.5.973. PMID 12695525.
  16. ↑ Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA (January 2008). "Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo". Mol. Biol. Cell 19 (1): 198–206. doi:10.1091/mbc.E07-05-0430. PMC 2174201. PMID 17978097.
  17. ↑ 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". J. Neurosci. 25 (32): 7459–69. doi:10.1523/JNEUROSCI.1193-05.2005. PMID 16093397.
  18. ↑ Kapas, Levente (2010). Metabolic signals in sleep regulation: the role of cholecystokinin (PDF). The Journal of Neuroscience (PhD thesis) (University of Szeged).

External links

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