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'''Cholecystokinin''' ('''CCK''' or '''CCK-PZ'''; from [[Greek language|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 by I-cells in the mucosal epithelium of the small intestine and secreted in the [[duodenum]], the first segment of the [[small intestine]], and causes the release of digestive [[enzyme]]s and [[bile]] from the [[pancreas]] and [[gallbladder]], respectively. It also acts as a [[appetite suppressant|hunger suppressant]]. Recent evidence has suggested that it also plays a major role in inducing drug [[Drug tolerance|tolerance]] to [[opioids]] like [[morphine]] and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid [[withdrawal]].<ref name="pmid10866896">{{cite journal | author=Kissin I, Bright CA, Bradley EL | title = Acute tolerance to continuously infused alfentanil: the role of cholecystokinin and N-methyl-D-aspartate-nitric oxide systems | journal=Anesth. Analg. | volume = 91 | issue = 1 | pages = 110–6 | year = 2000 | pmid = 10866896 | doi = 10.1097/00000539-200007000-00021| url = http://www.anesthesia-analgesia.org/cgi/content/abstract/91/1/110}}</ref><ref name="pmid17558184">{{cite journal | author=Fukazawa Y, Maeda T, Kiguchi N, Tohya K, Kimura M, Kishioka S | title = Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats | journal=J. Pharmacol. Sci. | volume = 104 | issue = 2 | pages = 159–66 | year = 2007 | pmid = 17558184 | doi = 10.1254/jphs.FP0070475 }}</ref>
+
'''Cholecystokinin''' ('''CCK''' or '''CCK-PZ'''; from [[Greek language|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 by I-cells in the mucosal epithelium of the small intestine and secreted in the [[duodenum]], the first segment of the [[small intestine]], and causes the release of digestive [[enzyme]]s and [[bile]] from the [[pancreas]] and [[gallbladder]], respectively. It also acts as a [[appetite suppressant|hunger suppressant]].
   
 
==Structure==
 
==Structure==
Line 25: Line 25:
   
 
==Functions==
 
==Functions==
CCK mediates a number of [[physiology|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 [[chyme]] entering the [[duodenum]] is the greatest stimulator of CCK release.
+
CCK mediates [[digestion]] in the small intestine by inhibiting gastric emptying and [[gastric acid]] secretion. It stimulates the [[acinar cells]] of the [[pancreas]] to release digestive enzymes and stimulates the secretion of 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]]. Trypsin, a protease released by pancreatic acinar cells hydrolyzes CCK-releasing peptide and monitor peptide effectively turning off the additional signals to secrete CCK.
   
CCK mediates digestion in the small intestine by inhibiting gastric emptying and [[gastric acid]] secretion. It stimulates the [[acinar cells]] of the [[pancreas]] to release digestive enzymes and stimulates the secretion of 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]]. Trypsin, a protease released by pancreatic acinar cells hydrolyzes CCK-releasing peptide and monitor peptide effectively turning off the additional signals to secrete CCK.
+
Cholecystokinin in the body cannot cross the [[blood brain barrier]], but certain parts of the [[hypothalamus]] and [[brainstem]] aren't protected by the barrier.
   
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 salt]]s form [[Amphipathic lipids|amphipathic]] [[micelle]]s that [[emulsification|emulsify]] fats, aiding in their digestion and absorption.
+
==Interactions==
  +
Cholecystokinin 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<sub>B</sub> receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa.<ref name="pmid15520004">{{cite journal | author = Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ | title = Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy | journal = J. Biol. Chem. | volume = 280 | issue = 2 | pages = 1044–50 | year = 2005 | month = January | pmid = 15520004 | doi = 10.1074/jbc.M409480200 }}</ref><ref name="pmid15001692">{{cite journal | author = Aloj L, Caracò C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, De Luca S, Arra C, Pedone C, Morelli G, Salvatore M | title = In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging | journal = J. Nucl. Med. | volume = 45 | issue = 3 | pages = 485–94 | year = 2004 | month = March | pmid = 15001692 | doi = }}</ref><ref name="pmid12695525">{{cite journal | author = Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S | title = 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 | journal = Mol. Pharmacol. | volume = 63 | issue = 5 | pages = 973–82 | year = 2003 | month = May | pmid = 12695525 | doi = 10.1124/mol.63.5.973 }}</ref>
  +
  +
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]].<ref name="pmid17978097">{{cite journal | author = Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA | title = Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo | journal = Mol. Biol. Cell | volume = 19 | issue = 1 | pages = 198–206 | year = 2008 | month = January | pmid = 17978097 | pmc = 2174201 | doi = 10.1091/mbc.E07-05-0430 }}</ref>
  +
  +
===Role in appetite and satiety===
  +
CCK mediates a number of [[physiology|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 [[chyme]] entering the [[duodenum]] is the greatest stimulator of CCK release.
   
===Neurobiology===
 
 
As a [[neuropeptide]], CCK mediates satiety by acting on the [[CCK receptor]]s 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.<ref name="pmid9855480">{{cite journal | author=Greenough A, Cole G, Lewis J, Lockton A, Blundell J | title = Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion | journal=Physiol. Behav. | volume = 65 | issue = 2 | pages = 303–10 | year = 1998 | pmid = 9855480 | doi = 10.1016/S0031-9384(98)00169-3 }}</ref> The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.<ref name="pmid3812772">{{cite journal | author=Shillabeer G, Davison JS | title = Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats | journal=Am. J. Physiol. | volume = 252 | issue = 2 Pt 2 | pages = R353–60 | year = 1987 | pmid = 3812772 | url = http://ajpregu.physiology.org/cgi/content/abstract/252/2/R353 }}</ref>
 
As a [[neuropeptide]], CCK mediates satiety by acting on the [[CCK receptor]]s 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.<ref name="pmid9855480">{{cite journal | author=Greenough A, Cole G, Lewis J, Lockton A, Blundell J | title = Untangling the effects of hunger, anxiety, and nausea on energy intake during intravenous cholecystokinin octapeptide (CCK-8) infusion | journal=Physiol. Behav. | volume = 65 | issue = 2 | pages = 303–10 | year = 1998 | pmid = 9855480 | doi = 10.1016/S0031-9384(98)00169-3 }}</ref> The mechanism for this hunger suppression is thought to be a decrease in the rate of gastric emptying.<ref name="pmid3812772">{{cite journal | author=Shillabeer G, Davison JS | title = Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats | journal=Am. J. Physiol. | volume = 252 | issue = 2 Pt 2 | pages = R353–60 | year = 1987 | pmid = 3812772 | url = http://ajpregu.physiology.org/cgi/content/abstract/252/2/R353 }}</ref>
   
CCK also has stimulatory effects on the [[vagus nerve]], effects that can be inhibited by [[capsaicin]].<ref name="pmid9655678">{{cite journal | author = Holzer P | title = Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve | journal = Am. J. Physiol. | volume = 275 | issue = 1 Pt 1 | pages = G8–13 | year = 1998 | month = July | pmid = 9655678 | doi = | url = http://ajpgi.physiology.org/content/275/1/G8.full#cited-by }}</ref> The stimulatory effects of CCK oppose those of [[ghrelin]], which has been shown to inhibit the vagus nerve.{{Citation needed|date=October 2008}} The CCK tetrapeptide fragment [[CCK-4]] ([[Tryptophan|Trp]]-[[Methionine|Met]]-[[Aspartate|Asp]]-[[Phenylalanine|Phe]]-NH<sub>2</sub>) reliably causes anxiety when administered to humans, and is commonly used in scientific research to induce [[panic attack]]s for the purpose of testing new [[anxiolytic]] drugs.<ref name="pmid8104032">{{cite journal | author = Bradwejn J | title = Neurobiological investigations into the role of cholecystokinin in panic disorder | journal = J Psychiatry Neurosci | volume = 18 | issue = 4 | pages = 178–88 | year = 1993 | month = July | pmid = 8104032 | pmc = 1188527 | doi = }}</ref>
+
Cholecystokinin has been shown to interact with [[orexin]] neurons which control appetite and wakefulness ([[sleep]]).<ref name="pmid16093397">{{cite journal | author = Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = J. Neurosci. | volume = 25 | issue = 32 | pages = 7459–69 | year = 2005 | month = August | pmid = 16093397 | doi = 10.1523/JNEUROSCI.1193-05.2005 }}</ref> Cholecystokinin can have indirect effects on sleep regulation.<ref>{{cite thesis |degree=PhD |first=Levente |last=Kapas |date=2010 |title=Metabolic signals in sleep regulation: the role of cholecystokinin |journal=The Journal of Neuroscience |publisher=University of Szeged | url=http://www.phd.szote.u-szeged.hu/Elmeleti_DI/Disszertaciok/2010/de_Levente_Kapas.pdf }}</ref>
   
 
The effects of CCK vary between individuals. For example, in [[rat]]s, CCK administration significantly reduces hunger in young males, but is slightly less effective in older subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats.<ref name="pmid9835394">{{cite journal | author=Fink H, Rex A, Voits M, Voigt JP | title = Major biological actions of CCK—a critical evaluation of research findings | journal=Exp Brain Res | volume = 123 | issue = 1–2 | pages = 77–83 | year = 1998 | pmid = 9835394 | doi = 10.1007/s002210050546 }}</ref>
 
The effects of CCK vary between individuals. For example, in [[rat]]s, CCK administration significantly reduces hunger in young males, but is slightly less effective in older subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats.<ref name="pmid9835394">{{cite journal | author=Fink H, Rex A, Voits M, Voigt JP | title = Major biological actions of CCK—a critical evaluation of research findings | journal=Exp Brain Res | volume = 123 | issue = 1–2 | pages = 77–83 | year = 1998 | pmid = 9835394 | doi = 10.1007/s002210050546 }}</ref>
   
==Interactions==
+
==Role in anxiety==
Cholecystokinin 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<sub>B</sub> receptor also binds gastrin, a gastrointestinal hormone involved in stimulating gastric acid release and growth of the gastric mucosa.<ref name="pmid15520004">{{cite journal | author = Harikumar KG, Clain J, Pinon DI, Dong M, Miller LJ | title = Distinct molecular mechanisms for agonist peptide binding to types A and B cholecystokinin receptors demonstrated using fluorescence spectroscopy | journal = J. Biol. Chem. | volume = 280 | issue = 2 | pages = 1044–50 | year = 2005 | month = January | pmid = 15520004 | doi = 10.1074/jbc.M409480200 }}</ref><ref name="pmid15001692">{{cite journal | author = Aloj L, Caracò C, Panico M, Zannetti A, Del Vecchio S, Tesauro D, De Luca S, Arra C, Pedone C, Morelli G, Salvatore M | title = In vitro and in vivo evaluation of 111In-DTPAGlu-G-CCK8 for cholecystokinin-B receptor imaging | journal = J. Nucl. Med. | volume = 45 | issue = 3 | pages = 485–94 | year = 2004 | month = March | pmid = 15001692 | doi = }}</ref><ref name="pmid12695525">{{cite journal | author = Galés C, Poirot M, Taillefer J, Maigret B, Martinez J, Moroder L, Escrieut C, Pradayrol L, Fourmy D, Silvente-Poirot S | title = 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 | journal = Mol. Pharmacol. | volume = 63 | issue = 5 | pages = 973–82 | year = 2003 | month = May | pmid = 12695525 | doi = 10.1124/mol.63.5.973 }}</ref>
+
CCK also has stimulatory effects on the [[vagus nerve]], effects that can be inhibited by [[capsaicin]].<ref name="pmid9655678">{{cite journal | author = Holzer P | title = Neural injury, repair, and adaptation in the GI tract. II. The elusive action of capsaicin on the vagus nerve | journal = Am. J. Physiol. | volume = 275 | issue = 1 Pt 1 | pages = G8–13 | year = 1998 | month = July | pmid = 9655678 | doi = | url = http://ajpgi.physiology.org/content/275/1/G8.full#cited-by }}</ref> The stimulatory effects of CCK oppose those of [[ghrelin]], which has been shown to inhibit the vagus nerve.{{Citation needed|date=October 2008}} The CCK tetrapeptide fragment [[CCK-4]] ([[Tryptophan|Trp]]-[[Methionine|Met]]-[[Aspartate|Asp]]-[[Phenylalanine|Phe]]-NH<sub>2</sub>) reliably causes anxiety when administered to humans, and is commonly used in scientific research to induce [[panic attack]]s for the purpose of testing new [[anxiolytic]] drugs.<ref name="pmid8104032">{{cite journal | author = Bradwejn J | title = Neurobiological investigations into the role of cholecystokinin in panic disorder | journal = J Psychiatry Neurosci | volume = 18 | issue = 4 | pages = 178–88 | year = 1993 | month = July | pmid = 8104032 | pmc = 1188527 | doi = }}</ref>
 
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]].<ref name="pmid17978097">{{cite journal | author = Gurda GT, Guo L, Lee SH, Molkentin JD, Williams JA | title = Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo | journal = Mol. Biol. Cell | volume = 19 | issue = 1 | pages = 198–206 | year = 2008 | month = January | pmid = 17978097 | pmc = 2174201 | doi = 10.1091/mbc.E07-05-0430 }}</ref>
 
 
Cholecystokinin has been shown to interact with [[orexin]] neurons which control appetite and wakefulness ([[sleep]]).<ref name="pmid16093397">{{cite journal | author = Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = J. Neurosci. | volume = 25 | issue = 32 | pages = 7459–69 | year = 2005 | month = August | pmid = 16093397 | doi = 10.1523/JNEUROSCI.1193-05.2005 }}</ref> Cholecystokinin can have indirect effects on sleep regulation.<ref>{{cite thesis |degree=PhD |first=Levente |last=Kapas |date=2010 |title=Metabolic signals in sleep regulation: the role of cholecystokinin |journal=The Journal of Neuroscience |publisher=University of Szeged | url=http://www.phd.szote.u-szeged.hu/Elmeleti_DI/Disszertaciok/2010/de_Levente_Kapas.pdf }}</ref>
 
   
Cholecystokinin in the body cannot cross the [[blood brain barrier]], but certain parts of the [[hypothalamus]] and brainstem aren't protected by the barrier.
+
==Role in drug tolerance==
  +
Recent evidence has suggested that it also plays a major role in inducing drug [[Drug tolerance|tolerance]] to [[opioids]] like [[morphine]] and heroin, and is partly implicated in experiences of pain hypersensitivity during opioid [[withdrawal]].<ref name="pmid10866896">{{cite journal | author=Kissin I, Bright CA, Bradley EL | title = Acute tolerance to continuously infused alfentanil: the role of cholecystokinin and N-methyl-D-aspartate-nitric oxide systems | journal=Anesth. Analg. | volume = 91 | issue = 1 | pages = 110–6 | year = 2000 | pmid = 10866896 | doi = 10.1097/00000539-200007000-00021| url = http://www.anesthesia-analgesia.org/cgi/content/abstract/91/1/110}}</ref><ref name="pmid17558184">{{cite journal | author=Fukazawa Y, Maeda T, Kiguchi N, Tohya K, Kimura M, Kishioka S | title = Activation of spinal cholecystokinin and neurokinin-1 receptors is associated with the attenuation of intrathecal morphine analgesia following electroacupuncture stimulation in rats | journal=J. Pharmacol. Sci. | volume = 104 | issue = 2 | pages = 159–66 | year = 2007 | pmid = 17558184 | doi = 10.1254/jphs.FP0070475 }}</ref>
   
 
==See also==
 
==See also==
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[[Category:Neuropeptides]]
 
[[Category:Neuropeptides]]
 
[[Category:Neurotransmitters]]
 
[[Category:Neurotransmitters]]
+
[[Categroy:Satiety]]
 
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[[de:Cholecystokinin]]
 
[[de:Cholecystokinin]]

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Cholecystokinin
Symbol(s): CCK
Locus: 3 pter-p21
EC number [1]
EntrezGene 885
OMIM 118440
RefSeq NM_000729
UniProt P06307

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 by I-cells in the mucosal epithelium of the small intestine and secreted in the duodenum, 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.

StructureEdit

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, and CCK8. CCK58 assumes a helix-turn-helix configuration.[1] 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.

FunctionsEdit

CCK mediates digestion in the small intestine by inhibiting gastric emptying and gastric acid secretion. It stimulates the acinar cells of the pancreas to release digestive enzymes and stimulates the secretion of 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. Trypsin, a protease released by pancreatic acinar cells hydrolyzes CCK-releasing peptide and monitor peptide effectively turning off the additional signals to secrete CCK.

Cholecystokinin in the body cannot cross the blood brain barrier, but certain parts of the hypothalamus and brainstem aren't protected by the barrier.

InteractionsEdit

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.[2][3][4]

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.[5]

Role in appetite and satietyEdit

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 chyme entering the duodenum is the greatest stimulator of CCK release.

As a neuropeptide, 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]

Cholecystokinin has been shown to interact with orexin neurons which control appetite and wakefulness (sleep).[8] Cholecystokinin can have indirect effects on sleep regulation.[9]

The effects of CCK vary between individuals. For example, in rats, CCK administration significantly reduces hunger in young males, but is slightly less effective in older subjects, and even slightly less effective in females. The hunger-suppressive effects of CCK also are reduced in obese rats.[10]

Role in anxietyEdit

CCK also has stimulatory effects on the vagus nerve, effects that can be inhibited by capsaicin.[11] The stimulatory effects of CCK oppose those of ghrelin, which has been shown to inhibit the vagus nerve.[citation needed] 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.[12]

Role in drug toleranceEdit

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.[13][14]

See alsoEdit

ReferencesEdit

  1. Reeve JR 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  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.
  7. Shillabeer G, Davison JS (1987). Proglumide, a cholecystokinin antagonist, increases gastric emptying in rats. Am. J. Physiol. 252 (2 Pt 2): R353–60.
  8. 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.
  9. Template:Cite thesis
  10. 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.
  11. 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.
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Target-derived NGF, BDNF, NT-3

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