Cholecystokinin - an overview | ScienceDirect Topics (2023)

Cholecystokinin

CCK is a peptide transmitter produced primarily by enteroendocrine cells of the proximal small intestine and is secreted into the blood following ingestion of a meal. Circulating CCK binds to specific CCK-1 receptors on the gallbladder, pancreas, smooth muscle of the stomach, and peripheral nerves to stimulate gallbladder contraction and pancreatic secretion, regulate gastric emptying and bowel motility, and induce satiety.⁶⁴ These effects serve to coordinate the ingestion, digestion, and absorption of dietary nutrients. Ingested fat and protein are the major food components that stimulate CCK release.

CCK was originally identified as a 33–amino acid peptide. However, since its discovery, larger and smaller forms of CCK have been isolated from blood, intestine, and brain. All forms of CCK are produced from a single gene by posttranslational processing of a preprohormone. Forms of CCK ranging in size from CCK-58 to CCK-8 have similar biological activities.⁶⁵

CCK is the major hormonal regulator of gallbladder contraction. It also plays an important role in regulating meal-stimulated pancreatic secretion (seeChapter 56). In many species, this latter effect is mediated directly through receptors on pancreatic acinar cells, but in humans, in whom pancreatic CCK-1 receptors are less abundant, CCK appears to stimulate pancreatic secretion indirectly through enteropancreatic neurons that possess CCK-1 receptors. In some species, CCK has trophic effects on the pancreas, although its potential role in human pancreatic neoplasia is speculative. CCK also has been shown to delay gastric emptying.⁶⁶ This action may be important in coordinating the delivery of food from the stomach to the intestine. CCK has been proposed as a major mediator of satiety and food intake, an effect that is particularly noticeable when food is in the stomach or intestine. CCK inhibits gastric acid secretion by binding to CCK-1 receptors on somatostatin (D) cells in the antrum and oxyntic mucosa. Somatostatin acts locally to inhibit gastrin release from adjacent G cells and directly inhibits acid secretion from parietal cells.⁶⁷

Clinically, CCK has been used together with secretin to stimulate pancreatic secretion for pancreatic function testing. It is also used radiographically or scintigraphically to evaluate gallbladder contractility. There are no known diseases of CCK excess. Low CCK levels have been reported in individuals with celiac disease who have reduced intestinal mucosal surface area and in those with bulimia nervosa.^68,69 Elevated levels of CCK have been reported in some patients with chronic pancreatitis (seeChapter 59), presumably because of reduced pancreatic enzyme secretion and interruption of negative feedback regulation of CCK release.⁷⁰

Analgesia

CCK acting through the CCK 2 receptor has antiopiate activity (see Opioid Peptide section of this book). Opiate analgesia is mainly mediated by neurons in the rostral ventromedial medulla (RVM). CCK exerts its inhibitory effect on morphine analgesia by inhibiting activation of pain inhibiting output neurons of the RVM.¹⁴ Acute administration of CCK into the RVM causes acute tactile and thermal hypersensitivity that is antagonized by the CCK 2 receptor antagonist or lesion of the dorsolateral funiculus. Continuous administration of morphine produces sustained tactile and thermal hypersensitivity that is reversed by the CCK 2 antagonist. Continuous morphine treatment results in a fivefold increase in basal CCK levels in the RVM relative to controls.³⁴ Activation of the endogenous CCK system by repeated morphine treatment may be partially responsible for the observed hypersensitivity. The opiate antagonist effect of CCK appears to be particularly evident in neuropathic pain where increased CCK release as well as changes in expression of CCK receptors has been reported.³¹

Cholecystokinin (CKK)

Produced by the gastrointestinal tract in response to meal ingestion, the diverse actions of CKK include stimulation of pancreatic enzyme secretion, inhibition of gastric motility, activation of intestinal motility, and the acute suppression of feeding. Early experiments administering CCK peripherally supported a role for increased CCK levels in the early termination of a meal.^331,332 The finding that repeated injections of CCK lead to reduced meal size without a change in body weight, due to a compensatory increase in meal frequency, argued against CCK acting as a signal regulating long-term energy stores.^333,334

Two subtypes of the CCK receptor belonging to the G protein–coupled family of receptors have been described: CCKA and CCKB. Studies using CCK receptor–specific antagonists as well as surgical or chemical vagotomy demonstrated that the satiety effects of CCK are specifically mediated via CCKA receptors on afferent vagal nerves.^335–337

Summary

CCK is an important modulator of food intake at the level of individual meals. Nutrient-induced CCK release is a major controller of meal size. In the absence of CCK signaling, satiety is delayed and larger meals are consumed. CCK satiety signaling is mediated by vagal afferent fibers. CCK activates load sensitive vagal afferent fibers innervating the stomach and proximal intestine resulting in altered neural activity at the level of the brainstem nucleus of the solitary tract. CCK not only alters vagal afferent activity but it also modulates the expression of vagal afferent orexigenic and anorexigenic peptides. These actions can modulate the ability of vagal afferents to respond to a variety of other feedback signals.

Cholecystokinin

Cholecystokinin (CCK) has both anti-opioid and pro-nociceptive actions at multiple levels of the nervous system. CCK peptides, through actions at the CCK2 receptor, act as functional antagonists to the analgesic action of opioids in behavioral studies (Crawley 1991). CCK2 agonists have cellular actions opposite those typically produced by opioids: they decrease K⁺ conductance (Cox et al 1995) and increase release of GABA (Miller and Lupica 1994). A corollary of the functional antagonism of opioids by CCK is that selective CCK2 antagonists can potentiate the analgesic action of morphine and endogenous opioids acting at the μ-opioid receptor and reduce some forms of opioid tolerance through action in the PAG (Zarrindast et al 1999,Tortorici et al 2003). These data indicate that endogenous CCK limits the antinociceptive action of opioids. Consistent with animal research, human studies have demonstrated that CCK antagonism enhances morphine (Price et al 1985) and placebo (Benedetti 1996) analgesia. In the RVM, CCK blocks opioid activation of physiologically identified pain-inhibiting neurons (Heinricher et al 2001a).

In addition to its anti-opioid actions, CCK exerts a pro-nociceptive effect through the PAG–RVM system. Thus, CCK receptor blockade in the RVM attenuates nociceptive hypersensitivity in a range of models (Urban et al 1996b,Kovelowski et al 2000,Ambriz-Tututi et al 2011). This pro-nociceptive action of CCK can be explained by the fact that this peptide activates putative pain-facilitating neurons in the RVM, albeit at doses higher than those required to block opioid activation of the pain-inhibiting neurons (Heinricher and Neubert 2004).

Anxiety, to which brain CCK contributes, can enhance pain sensitivity. The anti-analgesic and pro-nociceptive actions of CCK can therefore be seen as a critical link between anxiety and pain (Colloca and Benedetti 2007,Lovick 2008).

Future Possibilities

CCK-58 is a potential tool for determining the mechanisms that cause pancreatitis. CCK-8 and CCK-58 both stimulate pancreatic digestive enzyme secretion, but only CCK-58 stimulates pancreatic fluid. Even large doses of CCK-58 do not cause pancreatitis, whereas CCK-8 does so in rats.²⁸ Therefore, defining the differences in acinar intracellular messengers stimulated by CCK-8 and CCK-58 may yield candidate mechanisms resulting in pancreatitis.

Surprisingly, 40 years after a structure of cholecystokinin was reported, there are several aspects of primary structure that require further study. These include the actual forms of CCK in brain and peripheral neurons, the presence or absence of nonsulfated peptides in tissue and blood, the relative contribution of CCK to activation of the CCK₂ receptor, new methods for studying the enteric paracrine actions, and the integrative physiological response of CCK in the intact animal, which may not be the same as in isolated cell systems.

The role of cholecystokinin in feeding needs to be reevaluated using the major endocrine form of cholecystokinin, CCK-58. Our preliminary data are tentative, but there is an indication that this larger form differs from the actions of the most studied form, CCK-8. Several studies have shown that CCK-8 reduces meal size, but its utility as a weapon in the fight against obesity has been challenged by the observation that after a smaller meal there is a concomitant reduction in the interval until the next meal. However, although the most abundant form of CCK reduces meal size, CCK-58 does not decrease the interval until the next meal and even tends to extend the interval. This suggests that endogenous CCK-58 may be effective as a tool against obesity.

Abstract

In 1928 cholecystokinin (CCK) was first described as a substance derived from the small intestine of dogs and cats and that induced gallbladder contractions. In vertebrates, mature CCK peptide contains the conserved four amino-acid sequence (Trp–Met–Asp–Phe–NH₂) in the C-terminus. A sulfated tyrosine located seven residues from the C-terminus is also conserved in vertebrates. In mammals, CCK is expressed in a wide range of tissues, including the digestive tract (duodenum and small intestine) and the peripheral and central nervous system. Two CCK receptor subtypes, CCK1R and CCK2R, have been identified. Lipids and proteins induce CCK release from I cells in the duodenum and small intestine. CCK stimulates gallbladder contraction and pancreatic enzyme release via CCK1R. In addition, CCK inhibits gastric emptying and food intake through the vagal afferent neurons. In the central nervous system, CCK is implicated in anxiogenesis, satiety, nociception, memory, and learning.

CCK Receptors

Cholecystokinin acts via two G-protein-coupled receptors (GPCR) – the CCK-1 (formerly CCK-A) and CCK-2 (formerly CCK-B/Gastrin) receptor. Effects of CCK on food intake are mediated by CCK-1-receptor activation. Gastrin or unsulfated CCKs have activity at CCK-2 receptors, but not CCK-1 receptors. Hence, unsulfated CCK and gastrin do not significantly reduce food intake. Reductions of food intake following injection of exogenous CCK, or release of endogenous CCK after intestinal nutrient infusions, are attenuated or abolished by CCK-1 receptor antagonists in the human and the rat, while systemic administration of CCK-2-receptor antagonists are ineffectual. Therefore, it appears that reduction of food intake by both exogenous and endogenous CCK is mediated by CCK-1-receptor-dependent mechanisms.

Molecular Forms

Hormonal CCK circulates predominantly in a 58 amino-acid form (CCK-58) (Rehfeld et al., 2007; Stengel et al., 2009). In contrast, neuronal CCK is an eight amino acid peptide, CCK-8. The biologically active region of CCK resides in its carboxyl terminus, which is identical in all forms of CCK: -Gly-Trp-Asp-Met-Phe-NH2. This terminal sequence is identical to that of gastrin, so that gastrin has some weak CCK-like activity, and CCK has some weak gastrin-like activity. CCK is produced from a single gene that encodes a 115 amino acid preprohormone. In humans, the CCK gene is located on chromosome 3, NC_000003.12. CCK expression developmentally regulated in a tissue-specific fashion. In the intestine, the CCK gene is expressed prenatally and is regulated postnatally primarily by the frequent exposure of CCK cells to nutrients.

Cholecystokinin

CCK was discovered as a factor that stimulated gallbladder contraction. It is secreted by open-type cells (I cells), which are most densely located in the small intestine and gradually decrease in number toward the large intestine. As a neurotransmitter, CCK is found in the central and peripheral nervous systems. The CCK gene is expressed only in rare neuroendocrine tumors and sarcomas. Measurement of circulating CCK by radioimmunoassay has been difficult for several reasons, including low blood concentrations (about 1 picomolar basally), the existence of several biologically active molecular forms, and cross-reactivity with gastrin.

CCK¹¹ is the product of a 115-amino-acid precursor and has several molecular forms, of which the octapeptide of CCK (CCK-8), the eight C-terminal amino acids of CCK and the most abundant form of CCK in the CNS, is the most potent small peptide of CCK isolated. CCK-8, CCK-58, CCK-33, and CCK-39 have all been identified in significant amounts in human plasma. The differential processing of CCK in the CNS and gut is mediated by prohormone convertases (PCs). PC1 appears to be the major processing enzyme in the gut, while PC2 is more important in the brain. Peripherally, CCK acts through CCK1 receptors. CCK receptors have been detected in the gut, the pancreas, central and peripheral nervous systems, and lymphocytes. Several experimental CCK receptor antagonists are available.

The predominant stimulus to CCK release is the presence of breakdown products of fat and protein in the upper small intestine, specifically fatty acids of 10 to 18 carbon atoms, and aromatic-aliphatic amino acids. The CCK response is greater for unsaturated versus saturated fats. The mechanism by which CCK is released in response to nutrients appears to involve CCK-releasing factors.¹² Bile salts may have an inhibitory effect on CCK release, since severe obstructive cholestasis or ingestion of cholestyramine increases plasma CCK levels. The bombesin family and adrenergic receptors stimulate CCK release.

The strongest evidence for the hormonal action of CCK is stimulation of gallbladder contraction, abolished by CCK1 receptor antagonists. Other CCK actions, such as pancreatic enzyme secretion, may be purely neural or have both neural and endocrine actions. CCK may have important trophic effects on normal and neoplastic tissues. CCK delays gastric emptying in several species, an effect that may be vagally mediated. Endogenous CCK may also play a role in gastric acid secretion and in the control of lower esophageal sphincter pressure. Other reported gastrointestinal actions of CCK include acceleration of intestinal transport, postprandial reduction in cephalically stimulated antroduodenal activity, and increased colonic transport. Exogenous CCK decreases meal size in animals and humans. No CCK excess clinical syndromes have been described. CCK has been linked to gastrointestinal motility disorders (e.g., constipation, irritable bowel syndrome), pancreatic disorders (pancreatitis, pancreatic tumor growth), and satiety disorders (obesity, anorexia). While CCK has been linked to these conditions, a pivotal role for CCK has not been unequivocally established.