Cholecystokinin (CCK or CCK-PZ; from

Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...

''chole'', "bile"; ''cysto'', "sac"; ''kinin'', "move"; hence, ''move the bile-sac (

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow Organ (anatomy), organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath t ...

)'') is a

peptide hormone Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...

of the

gastrointestinal system The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

responsible for stimulating the

digestion 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 th ...

fat In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food. The term often refers specif ...

and

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

. Cholecystokinin, formerly called pancreozymin, is synthesized and secreted by

enteroendocrine cell 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 e ...

s in the

duodenum The duodenum is the first section of the small intestine in most vertebrates, including mammals, reptiles, and birds. In mammals, it may be the principal site for iron absorption. The duodenum precedes the jejunum and ileum and is the shortest p ...

, the first segment of the

small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from food takes place. It lies between the stomach and large intes ...

. Its presence causes the release of

pancreatic juice 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 th ...

from the

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

and

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

from the

History

Evidence that the small intestine controls the release of bile was uncovered as early as 1856, when French physiologist

Claude Bernard Claude Bernard (; 12 July 1813 – 10 February 1878) was a French physiologist. I. Bernard Cohen of Harvard University called Bernard "one of the greatest of all men of science". He originated the term ''milieu intérieur'' and the associated c ...

showed that when dilute acetic acid was applied to the orifice of the bile duct, the duct released bile into the duodenum. In 1903, the French physiologist showed that this reflex was not mediated by the nervous system. In 1904, the French physiologist Charles Fleig showed that the discharge of bile was mediated by a substance that was conveyed by the blood. 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 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 had been discovered in 1902. The problem was finally resolved in 1928 by

Andrew Conway Ivy Andrew Conway Ivy (February 25, 1893 – February 7, 1978) was an American physician. He was appointed by the American Medical Association as its representative at the Doctors' Trial, and later fell into disrepute for advocating the fraudulent drug ...

and his colleague Eric Oldberg of the

Northwestern University Medical School Northwestern or North-western or North western may refer to: * Northwest, a direction * Northwestern University, a private research university in Evanston, Illinois ** The Northwestern Wildcats, this school's intercollegiate athletic program ** No ...

, who found a new hormone that caused contraction of the gall bladder and that they called "cholecystokinin". In 1943, Alan A. Harper and Henry S. Raper of the

University of Manchester The University of Manchester is a public university, public research university in Manchester, England. The main campus is south of Manchester city centre, Manchester City Centre on Wilmslow Road, Oxford Road. The University of Manchester is c ...

discovered a hormone that stimulated pancreatic

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

secretion and that they named "pancreozymin"; however, pancreozymin was subsequently found to be cholecystokinin. 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 Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthe ...

. They finally presented porcine cholecystokinin's amino acid sequence in 1968.

Structure

Cholecystokinin is a member of the gastrin/cholecystokinin family of peptide hormones and is very similar in structure to

gastrin 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. ...

, another

gastrointestinal hormone The gastrointestinal hormones (or gut hormones) constitute a group of hormones secreted by enteroendocrine cells in the stomach, pancreas, and small intestine that control various functions of the digestive organs. Later studies showed that most ...

. CCK and gastrin share the same five C-terminal amino acids. CCK is composed of varying numbers of

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s depending on

post-translational modification In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translation (biolog ...

of the 150-amino acid precursor, preprocholecystokinin. 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 Helix-turn-helix is a DNA-binding domain (DBD). The helix-turn-helix (HTH) is a major structural motif capable of binding DNA. Each monomer incorporates two alpha helix, α helices, joined by a short strand of amino acids, that bind to the majo ...

configuration. Biological activity resides in the C-terminus of the peptide. Most CCK peptides have a

sulfate The sulfate or sulphate ion is a polyatomic anion with the empirical formula . Salts, acid derivatives, and peroxides of sulfate are widely used in industry. Sulfates occur widely in everyday life. Sulfates are salts of sulfuric acid and many ...

group attached to a

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...

located seven residues from the C-terminus (see

tyrosine sulfation In biochemistry, tyrosine sulfation is a posttranslational modification where a sulfate group () is added to a tyrosine residue of a protein molecule. Secreted proteins and extracellular parts of membrane proteins that pass through the Golgi appar ...

). This modification is crucial for the ability of CCK to activate the

cholecystokinin A receptor The Cholecystokinin A receptor is a human protein, also known as CCKAR or CCK1, with CCK1 now being the IUPHAR-recommended name. Function This gene encodes a G-protein coupled receptor that binds sulfated members of the cholecystokinin (CCK) ...

. Nonsulfated CCK peptides also occur, which consequently cannot activate the CCK-A receptor, but their biological role remains unclear.

Function

CCK plays important

physiological Physiology (; ) is the science, scientific study of function (biology), functions and mechanism (biology), mechanisms in a life, living system. As a branches of science, subdiscipline of biology, physiology focuses on how organisms, organ syst ...

roles both as a

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

and as a

in the gut. It is the most abundant neuropeptide in the central nervous system. CCK has been researched thoroughly for its role in digestion In addition to its role in digestion, CCK is involved in regulating various behavioral phenomena, including

satiety Satiety ( /səˈtaɪ.ə.ti/ ''sə-TYE-ə-tee'') is a state or condition of fullness gratified beyond the point of satisfaction, the opposite of hunger. Following satiation (meal termination), satiety is a feeling of fullness lasting until the next ...

appetite Appetite is the desire to eat food items, usually due to hunger. Appealing foods can stimulate appetite even when hunger is absent, although appetite can be greatly reduced by satiety. Appetite exists in all higher life-forms, and serves to reg ...

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

thermoregulation Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...

, sexual behavior, memory, and the response to drugs of abuse, particularly within the

cortex Cortex or cortical may refer to: Biology * Cortex (anatomy), the outermost layer of an organ ** Cerebral cortex, the outer layer of the vertebrate cerebrum, part of which is the ''forebrain'' *** Motor cortex, the regions of the cerebral cortex i ...

and

limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''P ...

regions of the brain.

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 The enteric nervous system (ENS) is one of the three divisions of the autonomic nervous system (ANS), the others being the sympathetic nervous system (SNS) and parasympathetic nervous system (PSNS). It consists of a mesh-like system of neurons th ...

, and neurons in the brain. It is released rapidly into the circulation in response to a meal. The greatest stimulator of CCK release is the presence of

fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...

s and/or certain

s in the

chyme Chyme or chymus (; ) is the semi-fluid mass of partly digested food that is expelled by the stomach, through the pyloric valve, into the duodenum (the beginning of the small intestine). Chyme results from the mechanical and chemical breakdown ...

entering the

. In addition, release of CCK is stimulated by

monitor peptide 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 ...

(released by pancreatic

acinar cells Centroacinar cells are spindle-shaped cells in the exocrine pancreas. They are small and have microvilli on the apical surface. They work with organs such as the kidney, lungs, stomach, brain, intestine. The exocrine pancreas is one of two co ...

), Diazepam binding inhibitor, CCK-releasing protein (via paracrine signalling mediated by enterocytes 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). Once in the circulatory system, CCK has a relatively short half-life.

Digestion

CCK mediates digestion in the small intestine by inhibiting gastric emptying. It stimulates the Centroacinar cells, acinar cells of the

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. 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

into the duodenal part of the small intestine. Bile salts form amphiphile, amphipathic lipids, micelles that emulsification, emulsify fats, aiding in their digestion and absorption. Effects of CCK on the gastrointestinal tract

Effects of CCK on the gastrointestinal tract

Satiety

As a peptide hormone, CCK mediates satiety by acting on the CCK receptors distributed widely throughout the

. The mechanism for hunger suppression is thought to be a decrease in the rate of gastric emptying. CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin. The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve. 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.

Neurological

CCK is found extensively throughout the

, with high concentrations found in the limbic system. CCK is synthesized as a 115 amino acid preprohormone, that is then converted into multiple Protein isoform, isoforms. The predominant form of CCK in the central nervous system is the Tyrosine sulfation, sulfated Peptide, octapeptide, CCK-8S.

Anxiogenic

In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased

. 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.

Panicogenic

The CCK tetrapeptide fragment CCK-4 (Tryptophan, Trp-Methionine, Met-Aspartate, Asp-Phenylalanine, 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. 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.

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.

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_B receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa. 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. CCK has been shown to interact with orexin neurons, which control appetite and wakefulness (sleep). CCK can have indirect effects on sleep regulation. CCK in the body cannot cross the blood–brain barrier, but certain parts of the hypothalamus and brainstem are not protected by the barrier.

References

External links

* * {{Gastrointestinal hormones Cholecystokinin, Anxiogenics Hepatology Intestinal hormones Neuropeptides Cholecystokinin agonists