Cholecystokinin

gastrointestinal hormones

1. CHOLECYSTOKININ Bhagya Siripalli , Pharmacology dept, SVIPS

2. INTRODUCTION Cholecystokinin is a peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Cholecystokinin, officially 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.

3. STRUCTURE  It was discovered in 1943 by A.C. Ivy and E. Olberg . 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 .  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.  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 ). This modification is crucial for the ability of CCK to activate the  cholecystokinin A receptor.

4. FUNCTION CCK plays important physiological roles both as a neuropeptide in the central nervous system and as a peptide hormone in the gut.  It participates in a number of processes such as  Digestion,  Satiety and  Anxiety.

5. FUNCTION… 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.  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.  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).

6. 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. 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. FUNCTION…

7. 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.  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. FUNCTION…

8. Anxiogenic In both humans and rodents, studies clearly indicate that elevated CCK levels causes increased anxiety.  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. Panicogenic The CCK tetrapeptide fragment CCK-4 ( Trp - Met - Asp - Phe -NH 2 ) 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.  FUNCTION…

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

10. 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. 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. 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. INTERACTIONS

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