Introduction

Cholecystokinin (CCK) is a peptide hormone linked to the gastrointestinal tract. The receptors are expressed in the central nervous system,[1] specifically in the hippocampus, cerebral cortex, and striatum.[2] Cholecystokinin is present in the nucleus tractus solitarius and area postrema of the lower portion of the brain stem. Cholecystokinin is tissue-specific and developmentally regulated. The expression of cholecystokinin-producing endocrine cells is biphasic, declining just before birth and increasing immediately after birth. Levels of cholecystokinin-producing neurons in the brain are low at birth but steadily increase into adulthood. Low levels of cholecystokinin are evident in the thyroid C cells, adrenal medulla, bronchial mucosa, pituitary corticotrophs, and spermatogenic cells. Cholecystokinin receptors 1 and 2 are part of the class 1 G protein–coupled receptor family. Cholecystokinin receptor 1 is found in the gallbladder smooth muscle, chief and D cells of the gastric mucosa, pancreatic acinar cells, and selected areas of the central and peripheral nervous systems, whereas cholecystokinin receptor 2 and gastrin receptor are found in the stomach, including the parietal, chief, and.[2]

Cellular Level

In peripheral neurons, such as those found in the intestinal mucosa, CCK is expressed by I-cells. Food intake, pituitary adenylate cyclase-activating polypeptide, and glucocorticoids play a role in regulating CCK expression. Estrogen, dopamine, and injury situations activate CCK-mRNA in neuronal cells. The activation of transcription factors in these signaling pathways is unknown. Receptors in the CNS are G protein-coupled; CCK-2 receptor subtype (formerly known as CCK-B) are found mainly in the brain, and CCK-1 receptor subtype (formerly known as CCK-A) found mainly peripherally, for example, in the pancreas. Adenylyl cyclase is activated, inducing a rise in intracellular cyclic adenosine 3', 5'-monophosphate (cAMP) and the activation of protein kinase A. They associate this rise in cAMP with the CCK-receptor-mediated pathway at high concentrations of CCK. cAMP-dependent protein kinase activity is concentration-dependent for CCK. PKA activity peaks rapidly and remains high at high CCK doses.[3] CCK receptors on pancreatic acinar cells have two types of affinity for CCK, which elicit different responses. At low concentrations, it stimulates zymogen secretion, while at high concentrations, CCK inhibits zymogen secretion and intracellular zymogen proteolysis.[3] Binding sites of CCK-1 and CCK-2 receptors have different affinities for various CCK neuropeptide fragments. CCK-A binding has a higher affinity for sulfated, intermediate, neuropeptide CCK-8 than CCK-4; therefore, most of its action is peripheral. CCK-2R has high affinity for all CCK fragments, with greater affinity for CCK-4, suggesting that most CCK action occurs in the brain. Stimulation of CCK-containing neuronal pathways can lead to a panic-like reaction in humans. Panic attacks could arise from CCK activation. CCK antagonists can provide anxiolytic properties via their action on CCK-2 receptors.[4]

Molecular Level

The specific affinity of membrane receptors on target cells determines the action of CCK and gastrin. CCK-1 and 2 are part of the class 1 G-protein-coupled receptor family. It is made up of seven transmembrane domains connected by intracellular and extracellular loops with an extracellular N-terminal and intracellular C-terminal tails. They divide these receptors into subtypes based on their affinity to CCK or gastrin. The CCK-1 receptor has an affinity 500-times higher for CCK than gastrin. The CCK2 receptor has the same affinity for CCK as it does for gastrin. CCK-1 receptor also has a very high affinity for sulfated CCK than non-sulfated CCK, while the CCK-2 receptor cannot differentiate between the 2. One of the extracellular loops of the CCK-2 receptor contains 5 amino acids paramount to gastrin sensitivity. Loss of His207 in the CCK-2 receptor results in loss of CCK binding. His207 is also found in the CCK-1 receptor binding site, and an exchange in this region for another amino acid and the Asp region of CCK leads to a loss or gain of affinity. Therefore, the binding sites of CCK-1 and CCK-2 receptors share some homologous regions, and the Asp of CCK further demarcates the binding site of the CCK-2 receptor.[2]

Function

Roles

In the intestine:

• Mediates digestion by regulating the release of pancreatic exocrine enzymes, which play a role in the digestion of fats, proteins, and carbohydrates
• Causes contraction and relaxation of the gallbladder via the sphincter of Oddi in response to food; CCK regulates the release of bile acid to aid in further fat digestion in the small intestine
• Regulates overall gastrointestinal tract motility [5]
• Regulates gastric emptying to regulate the flow of chyme into the duodenum [6]
• Inhibits gastric acid secretion after a meal by regulating gastrin production via somatostatin [7]
• Enhances leptin release, which inhibits basal gastric acid secretion after a meal. In the intestine, it promotes further protein absorption.[8]
• Stimulation of cell growth
• Energy production
• Gene expression
• Protein synthesis

In the brain:

• Regulates feeding behavior: Leptin acts on the brain to inhibit food intake, resulting in satiety [8]
• Managing anxiety
• Pain perception
• Memory

Mechanism

Fatty acids and proteins stimulate the release of cholecystokinin through direct action on I cells. G protein–coupled receptor 40 is a G protein–coupled receptor expressed on I cells that responds to long-chain fatty acids. Cholecystokinin acting on cholecystokinin receptor 1 stimulates the discharge of vagal efferent neurons and increases intracellular calcium. These neurons are found in both the stomach and small intestine, and cholecystokinin initially activates the afferent fibers in the small intestine through a paracrine mechanism. This activation inhibits the excitatory vagal efferent pathway to the distal stomach. Gastric vagal afferents are stimulated in response to the hormonal effect coupled with the inhibitory vagal efferent pathway to the proximal stomach.[9] Due to the mechanism mentioned above, CCK can inhibit gastric emptying by relaxing the proximal portion of the stomach, which increases tension in the pyloric sphincter. At high levels, CCK can increase the rate of gastric emptying by increasing its excitatory effects on both the small and large intestines, which leads to bowel movement, or by increasing the tension of the pyloric sphincter.[5] Therefore, the reflex control of gastric emptying is regulated by CCK action on vasovagal reflexes and the hormonal activation of a variety of pathways that are coupled to vagal efferent pathways controlling gastric motility.

Testing

Gallbladder dysfunction is defined as an abnormally low gallbladder ejection fraction.[10] Gallbladder disease can manifest as gallbladder dyskinesia, chronic acalculous cholecystitis, biliary dyskinesia, and functional gallbladder disorder, among others. Cholecystokinin scintigraphy assesses gallbladder ejection fraction and is used to evaluate patients presenting with chronic upper abdominal pain and a normal upper abdominal ultrasonography.[11] Technetium-99m–labeled hepatobiliary iminodiacetic acid collects in the gallbladder after it is absorbed by the liver and excreted by the biliary system. CCK is injected to stimulate gallbladder contraction to calculate the ejection fraction.[10]

Clinical Significance

Obesity blunts the effect of CCK, indicating insensitivity of vagal afferent neurons to CCK. This reduced expression of CCK accounts for the reduced effect on satiety and the fact that most obese people always complain about feeling hungry. High-fat diets with diminished CCK-1 receptor expression increase plasma ghrelin levels. This increases food intake by suppressing the expression of the satiety peptide cocaine- and amphetamine-regulated transcript (CART) in vagal afferent neurons. CCK is also involved in metabolic regulation and lipid absorption. They link inactivation of the CCK signaling pathway to reduced weight gain. Inactivation increases energy expenditure and lowers energy extraction.[9]

CCK acts via the vasovagal pathway and is activated peripherally via gastric wall distension. They use intragastric balloons in clinical practice to treat weight loss by mimicking this pathway. Distending the stomach activates the vagus nerve and the nucleus of the tractus solitarius and the paraventricular nucleus, leading to a centrally mediated feeling of satiety.[12] These devices physically reduce food intake by obstructing the outlet, delaying gastric emptying, and reducing the stomach's capacity. Pancreatic peptide secretion is impaired by decreased gastric emptying, reducing gut-wall interactions with nutrients such as fat and protein that elicit a pancreatic peptide response. Pancreatic peptide secretion is biphasic, and food and secretion of CCK control the second phase.[9]

Cholecystokinin plays a minor role in incretin release compared with glucagon-like peptide 1 from islet cells. Decreased islet cell size and β-cell mass correlate with upregulated cholecystokinin expression and increased sensitivity to cholecystokinin-mediated insulin release in obesity. Cholecystokinin can therefore mediate compensatory mechanisms within the islets of Langerhans.[9] Fat- and energy-restricted meals stimulate CCK and PP secretion and, together with delayed gastric emptying secondary to the intragastric balloon, can lead to substantial weight loss and improved glucose homeostasis.[12] The presence of cholecystokinin in various regions of the midbrain suggests a role in behavioral processes such as anxiety. Panic disorder is described as the feeling of unprovoked fear and an overwhelming feeling of anxiety. Patients with panic disorder or panic attacks may present to the emergency department with a sense of impending doom, chest pain, abdominal pain, and sometimes shortness of breath. Cholecystokinin is expressed in the nucleus tractus solitarius and area postrema. Researchers associate these areas with nociception, and patients with panic disorder are usually sensitive to bodily sensations. Noradrenaline and serotonin (5-HT) containing nuclei found in the brainstem interact with these areas as well, implicating them in the pathogenesis of panic disorder.[4]

Cancers of the gastrointestinal tract, including medullary thyroid cancer and small cell lung cancer, all express gastrin and CCK-2 receptors. Gastrin and CCK2R/gastrin receptor play roles in regulating cellular proliferation, loss of cell-cell adhesion, differentiation and morphology, and enhanced motility/invasion of epithelial cells. The activation of the CCK2R/gastrin receptor via the intracellular signaling pathway can lead to carcinogenesis. These receptors, therefore, play a crucial role in initiating the events that lead to preneoplastic lesions and cancer development.[13]

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References

1.

Ma J, Dankulich-Nagrudny L, Lowe G. Cholecystokinin: an excitatory modulator of mitral/tufted cells in the mouse olfactory bulb. PLoS One. 2013;8(5):e64170. [PMC free article: PMC3655022] [PubMed: 23691163]

2.

Beinfeld MC. An introduction to neuronal cholecystokinin. Peptides. 2001 Aug;22(8):1197-200. [PubMed: 11457511]

3.

Marino CR, Leach SD, Schaefer JF, Miller LJ, Gorelick FS. Characterization of cAMP-dependent protein kinase activation by CCK in rat pancreas. FEBS Lett. 1993 Jan 18;316(1):48-52. [PMC free article: PMC2830555] [PubMed: 7678554]

4.

van Megen HJ, den Boer JA, Westenberg HG. On the significance of cholecystokinin receptors in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Dec;18(8):1235-46. [PubMed: 7863014]

5.

Cao SG, Wu H, Cai ZZ. Dose-dependent effect of ghrelin on gastric emptying in rats and the related mechanism of action. Kaohsiung J Med Sci. 2016 Mar;32(3):113-7. [PMC free article: PMC11916455] [PubMed: 27106000]

6.

Grider JR. Role of cholecystokinin in the regulation of gastrointestinal motility. J Nutr. 1994 Aug;124(8 Suppl):1334S-1339S. [PubMed: 8064380]

7.

Burckhardt B, Delco F, Ensinck JW, Meier R, Bauerfeind P, Aufderhaar U, Ketterer S, Gyr K, Beglinger C. Cholecystokinin is a physiological regulator of gastric acid secretion in man. Eur J Clin Invest. 1994 Jun;24(6):370-6. [PubMed: 7957488]

8.

Konturek JW, Konturek SJ, Kwiecień N, Bielański W, Pawlik T, Rembiasz K, Domschke W. Leptin in the control of gastric secretion and gut hormones in humans infected with Helicobacter pylori. Scand J Gastroenterol. 2001 Nov;36(11):1148-54. [PubMed: 11686213]

9.

Dockray GJ. Cholecystokinin. Curr Opin Endocrinol Diabetes Obes. 2012 Feb;19(1):8-12. [PubMed: 22157397]

10.

Richmond BK, DiBaise J, Ziessman H. Utilization of cholecystokinin cholescintigraphy in clinical practice. J Am Coll Surg. 2013 Aug;217(2):317-23. [PubMed: 23731969]

11.

Watson A, Better N, Kalff V, Nottle P, Scelwyn M, Kelly MJ. Cholecystokinin (CCK)-HIDA scintigraphy in patients with suspected gall-bladder dysfunction. Australas Radiol. 1994 Feb;38(1):30-3. [PubMed: 8147796]

12.

Mathus-Vliegen EM, de Groot GH. Fasting and meal-induced CCK and PP secretion following intragastric balloon treatment for obesity. Obes Surg. 2013 May;23(5):622-33. [PubMed: 23224567]

13.

Rai R, Chandra V, Tewari M, Kumar M, Shukla HS. Cholecystokinin and gastrin receptors targeting in gastrointestinal cancer. Surg Oncol. 2012 Dec;21(4):281-92. [PubMed: 22801592]

Disclosure: Oluchukwu Okonkwo declares no relevant financial relationships with ineligible companies.

Disclosure: David Zezoff declares no relevant financial relationships with ineligible companies.

Disclosure: Adebayo Adeyinka declares no relevant financial relationships with ineligible companies.