Cholecystokinin

Cholecystokinin (CCK or CCK-PZ; from Greek chole, "bile"; cysto, "sac"; kinin, "move"; hence, move the bile-sac (is_associated_with::gallbladder)) is a is_associated_with::peptide hormone of the is_associated_with::gastrointestinal system responsible for stimulating the is_associated_with::digestion of is_associated_with::fat and is_associated_with::protein. Cholecystokinin, previously called pancreozymin, is synthesized by I-cells in the mucosal epithelium of the small intestine and secreted in the is_associated_with::duodenum, the first segment of the is_associated_with::small intestine, and causes the release of is_associated_with::digestive enzymes and is_associated_with::bile from the is_associated_with::pancreas and is_associated_with::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 is_associated_with::opioids like is_associated_with::morphine and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid withdrawal.

Structure
CCK is composed of varying numbers of is_associated_with::amino acids depending on is_associated_with::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 is_associated_with::helix-turn-helix configuration. Its existence was first suggested in 1905 by the British physiologist Joy Simcha Cohen. CCK is very similar in structure to is_associated_with::gastrin, another of the is_associated_with::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 is_associated_with::cholecystokinin A receptor. Nonsulfated CCK peptides also occur, which consequently cannot activate the CCK-A receptor.

Functions
CCK mediates a number of physiological processes, including digestion and satiety. It is released by I cells located in the mucosal epithelium of the small intestine (mostly in the duodenum and jejunum), 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 is_associated_with::chyme entering the is_associated_with::duodenum is the greatest stimulator of CCK release.

CCK mediates digestion in the small intestine by inhibiting gastric emptying and decreasing is_associated_with::gastric acid secretion. It stimulates the acinar cells of the is_associated_with::pancreas to release digestive enzymes and stimulates the secretion of a juice rich in pancreatic is_associated_with::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 is_associated_with::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 is_associated_with::gall bladder and the relaxation of the is_associated_with::Sphincter of Oddi (Glisson's sphincter), resulting in the delivery of is_associated_with::bile into the duodenal part of the small intestine. is_associated_with::Bile salts form amphipathic is_associated_with::lipids, is_associated_with::micelles that emulsify fats, aiding in their digestion and absorption.

Neurobiology
As a peptide hormone, CCK mediates satiety by acting on the is_associated_with::CCK receptors distributed widely throughout the is_associated_with::central nervous system. In humans, it has been suggested that CCK administration causes is_associated_with::nausea and is_associated_with::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. The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.

CCK also has stimulatory effects on the is_associated_with::vagus nerve, effects that can be inhibited by is_associated_with::capsaicin. The stimulatory effects of CCK oppose those of is_associated_with::ghrelin, which has been shown to inhibit the vagus nerve. The CCK tetrapeptide fragment is_associated_with::CCK-4 (Trp-Met-Asp-Phe-NH2) reliably causes anxiety when administered to humans, and is commonly used in scientific research to induce is_associated_with::panic attacks for the purpose of testing new is_associated_with::anxiolytic drugs. 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.

The effects of CCK vary between individuals. For example, in is_associated_with::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.

Interactions
Cholecystokinin has been shown to interact with the Cholecystokinin A receptor located mainly on pancreatic acinar cells and is_associated_with::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.

CCK has also been shown to interact with is_associated_with::calcineurin in the pancreas. Calcineurin will go on to activate the transcription factors is_associated_with::NFAT 1–3, which will stimulate is_associated_with::hypertrophy and growth of the pancreas. CCK can be stimulated by a diet high in protein, or by is_associated_with::protease inhibitors.

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

Cholecystokinin in the body cannot cross the is_associated_with::blood-brain barrier, but certain parts of the is_associated_with::hypothalamus and brainstem are not protected by the barrier.