Cholecystokinin

Last updated

CCK
Identifiers
Aliases CCK , cholecystokinin
External IDs OMIM: 118440 MGI: 88297 HomoloGene: 583 GeneCards: CCK
Orthologs
SpeciesHumanMouse
Entrez

885

12424

Ensembl

ENSG00000187094

ENSMUSG00000032532

UniProt

P06307

P09240

RefSeq (mRNA)

NM_000729
NM_001174138

NM_031161
NM_001284508

RefSeq (protein)

NP_000720
NP_001167609

NP_001271437
NP_112438

Location (UCSC) Chr 3: 42.26 – 42.27 Mb Chr 9: 121.32 – 121.32 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6]

Contents

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. [7] [8] In 1903, the French physiologist Émile Wertheimer  [ fr ] showed that this reflex was not mediated by the nervous system. [9] In 1904, the French physiologist Charles Fleig showed that the discharge of bile was mediated by a substance that was conveyed by the blood. [10] 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". [11] 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"; [12] however, pancreozymin was subsequently found to be cholecystokinin. [13] [14] [15] 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. [16]

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. [17] 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. [18] 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). [17] 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. [19] [17]

Function

CCK plays important physiological roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut. [20] It is the most abundant neuropeptide in the central nervous system. [21] [22] CCK has been researched thoroughly for its role in digestion [23] and it participates in a number of processes such as digestion, satiety and anxiety.[ citation needed ]

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. [5] 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. [17] 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). [24]

Once in the circulatory system, CCK has a relatively short half-life. [25]

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. [26]

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. [5] [6] Bile salts form amphipathic lipids, micelles that emulsify fats, aiding in their digestion and absorption. [5]

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. 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, 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 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. [27] CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. [28] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve. [29]

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. [30]

Neurological

CCK is found extensively throughout the central nervous system, with high concentrations found in the limbic system. [31] CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple isoforms. [31] The predominant form of CCK in the central nervous system is the sulfated octapeptide, CCK-8S. [31]

Anxiogenic

In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety. [25] 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. [25] [32]

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. [32] [33] 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. [31]

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. [20]

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. [34] [35] [36] 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. [37] CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep). [38] CCK can have indirect effects on sleep regulation. [39]

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

Related Research Articles

<span class="mw-page-title-main">Digestion</span> Biological process of breaking down food

Digestion is the breakdown of large insoluble food compounds into small water-soluble components so that they can be absorbed into the blood plasma. In certain organisms, these smaller substances are absorbed through the small intestine into the blood stream. Digestion is a form of catabolism that is often divided into two processes based on how food is broken down: mechanical and chemical digestion. The term mechanical digestion refers to the physical breakdown of large pieces of food into smaller pieces which can subsequently be accessed by digestive enzymes. Mechanical digestion takes place in the mouth through mastication and in the small intestine through segmentation contractions. In chemical digestion, enzymes break down food into the small compounds that the body can use.

<span class="mw-page-title-main">Secretin</span> Hormone involved in stomach, pancreas and liver secretions

Secretin is a hormone that regulates water homeostasis throughout the body and influences the environment of the duodenum by regulating secretions in the stomach, pancreas, and liver. It is a peptide hormone produced in the S cells of the duodenum, which are located in the intestinal glands. In humans, the secretin peptide is encoded by the SCT gene.

Chyme or chymus is the semi-fluid mass of partly digested food that is expelled by a person's or another animal's stomach, through the pyloric valve, into the duodenum.

<span class="mw-page-title-main">Gastrin</span> Mammalian protein found in Homo sapiens

Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.

<span class="mw-page-title-main">Gastric acid</span> Digestive fluid formed in the stomach

Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the long chains of amino acids of proteins. Gastric acid is regulated in feedback systems to increase production when needed, such as after a meal. Other cells in the stomach produce bicarbonate, a base, to buffer the fluid, ensuring a regulated pH. These cells also produce mucus – a viscous barrier to prevent gastric acid from damaging the stomach. The pancreas further produces large amounts of bicarbonate and secretes bicarbonate through the pancreatic duct to the duodenum to neutralize gastric acid passing into the digestive tract.

<span class="mw-page-title-main">Digestive enzyme</span> Class of enzymes

Digestive enzymes are a group of enzymes that break down polymeric macromolecules into their smaller building blocks, in order to facilitate their absorption into the cells of the body. Digestive enzymes are found in the digestive tracts of animals and in the tracts of carnivorous plants, where they aid in the digestion of food, as well as inside cells, especially in their lysosomes, where they function to maintain cellular survival. Digestive enzymes of diverse specificities are found in the saliva secreted by the salivary glands, in the secretions of cells lining the stomach, in the pancreatic juice secreted by pancreatic exocrine cells, and in the secretions of cells lining the small and large intestines.

<span class="mw-page-title-main">Glucose-dependent insulinotropic polypeptide</span> Mammalian protein found in Homo sapiens

Glucose-dependent insulinotropic polypeptide, abbreviated as GIP, is an inhibiting hormone of the secretin family of hormones. While it is a weak inhibitor of gastric acid secretion, its main role, being an incretin, is to stimulate insulin secretion.

<span class="mw-page-title-main">Motilin</span>

Motilin is a 22-amino acid polypeptide hormone in the motilin family that, in humans, is encoded by the MLN gene.

Pancreatic juice is a liquid secreted by the pancreas, which contains a number of digestive enzymes, including trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, nucleases and amylase. The pancreas is located in the visceral region, and is a major part of the digestive system required for proper digestion and subsequent assimilation of macronutrient substances required for living.

<span class="mw-page-title-main">Pancreatic polypeptide</span> Protein produced by the endocrine pancreas

Pancreatic polypeptide (PP) is a polypeptide secreted by PP cells in the endocrine pancreas. It regulates pancreatic secretion activities, and also impacts liver glycogen storage and gastrointestinal secretion. Its secretion may be impacted by certain endocrine tumours.

<span class="mw-page-title-main">Peptide YY</span> Peptide released from cells in the ileum and colon in response to feeding

Peptide YY (PYY) also known as peptide tyrosine tyrosine is a peptide that in humans is encoded by the PYY gene. Peptide YY is a short peptide released from cells in the ileum and colon in response to feeding. In the blood, gut, and other elements of periphery, PYY acts to reduce appetite; similarly, when injected directly into the central nervous system, PYY is also anorexigenic, i.e., it reduces appetite.

Somatostatinomas are a tumor of the delta cells of the endocrine pancreas that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Thus, somatostatinomas are associated with mild diabetes mellitus, steatorrhoea and gallstones, and achlorhydria. Somatostatinomas are commonly found in the head of pancreas. Only ten percent of somatostatinomas are functional tumours [9], and 60–70% of tumours are malignant. Nearly two-thirds of patients with malignant somatostatinomas will present with metastatic disease.

<span class="mw-page-title-main">Enteroendocrine cell</span>

Enteroendocrine cells are specialized cells of the gastrointestinal tract and pancreas with endocrine function. They produce gastrointestinal hormones or peptides in response to various stimuli and release them into the bloodstream for systemic effect, diffuse them as local messengers, or transmit them to the enteric nervous system to activate nervous responses. Enteroendocrine cells of the intestine are the most numerous endocrine cells of the body. They constitute an enteric endocrine system as a subset of the endocrine system just as the enteric nervous system is a subset of the nervous system. In a sense they are known to act as chemoreceptors, initiating digestive actions and detecting harmful substances and initiating protective responses. Enteroendocrine cells are located in the stomach, in the intestine and in the pancreas. Microbiota play key roles in the intestinal immune and metabolic responses in these enteroendocrine cells via their fermentation product, acetate.

Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and excrete waste products. The GI tract is composed of the alimentary canal, that runs from the mouth to the anus, as well as the associated glands, chemicals, hormones, and enzymes that assist in digestion. The major processes that occur in the GI tract are: motility, secretion, regulation, digestion and circulation. The proper function and coordination of these processes are vital for maintaining good health by providing for the effective digestion and uptake of nutrients.

<span class="mw-page-title-main">Cholecystokinin A receptor</span> Protein-coding gene in the species Homo sapiens

The Cholecystokinin A receptor is a human protein, also known as CCKAR or CCK1, with CCK1 now being the IUPHAR-recommended name.

The secretin-cholecystokinin test is a combination of the secretin test and the cholecystokinin test and is used to assess the function of both the pancreas and gall bladder.

The nervous system, and endocrine system collaborate in the digestive system to control gastric secretions, and motility associated with the movement of food throughout the gastrointestinal tract, including peristalsis, and segmentation contractions.

The gastrin family of proteins is defined by the peptide hormones gastrin and cholecystokinin. Gastrin and cholecystokinin (CCK) are structurally and functionally related peptide hormones that serve as regulators of various digestive processes and feeding behaviors. Additional structurally related members of this family include the amphibian caerulein skin peptide, the cockroach leukosulphakinin I and II (LSK) peptides, Drosophila melanogaster putative CCK-homologs Drosulphakinins I and II, cionin, a chicken gastrin/cholecystokinin-like peptide and cionin, a neuropeptide from the protochordate Ciona intestinalis.

<span class="mw-page-title-main">Human digestive system</span> Digestive system in humans

The human digestive system consists of the gastrointestinal tract plus the accessory organs of digestion. Digestion involves the breakdown of food into smaller and smaller components, until they can be absorbed and assimilated into the body. The process of digestion has three stages: the cephalic phase, the gastric phase, and the intestinal phase.

<span class="mw-page-title-main">Monitor peptide</span>

Monitor peptide, also known as pancreatic secretory trypsin inhibitor I (PSTI-I) or pancreatic secretory trypsin inhibitor 61 (PSTI-61), is a peptide that plays an important role in the regulation of the digestive system, specifically the release of cholecystokinin (CCK).

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032532 - Ensembl, May 2017
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  9. ↑ Wertheimer, E. (1903). "De l'action des acides et du chloral sur la sécrétion biliaire (d'après les expériences de M. Ch. Dubois)" [On the action of acids and chloral on bile secretion (according to the experiments of Mr. Charles Dubois)]. Compte Rendus Hebdomadaires des Séances et Mémoires de la Société Biologie (in French). 55: 286–287. 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.)
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  35. ↑ 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. ProQuest   219229095.
  36. ↑ 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. S2CID   38395309.
  37. ↑ 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.
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  39. ↑ 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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