Horst Ibelgaufts' COPE: Cytokines & Cells Online Pathfinder Encyclopaedia COPE needs your support to remain a free service!

Cholecystokinin

abbr. CCK. This hormone has been discovered by virtue of the ability of intestinal extracts to stimulate gallbladder contraction (Ivy and Oldberg, 1928). The hormone has been identified independently as pancreozymin, a hormone that stimulates secretion of pancreatic enzymes (Harper and Raper, 1943). Mutt and Jorpes (1968) have shown that cholecystokinin and pancreozymin are identical.

Cholecystokinin has been shown to relax the proximal part of the stomach and to constrict the pyloric sphincter, thus delaying the rate of gastrîc emptying (Anuras and Cooke, 1974; Yamagishi and Debas, 1978). Cholecystokinin has been shown to relax the lower esophageal sphincter (Resin and Stem, 1973), and the sphincter of Oddi in humans (Luman and Williams, 1997). In the intestine, Cholecystokinin stimulates motor activity (Dinoso and Meshkinpour, 1973) and decreases intestinal transit time (Parker and Beneventano, 1976). It also increases blood flow to the intestine (Thulin and Sannegard, 1978). Endogenous cholecystokinin has been shown to regulate postprandial gastrin secretion (Beglinger and Hildebrand, 1992) and to function as a satiety signal during a meal (Gibbs et al, 1973).

The cholecystokinin gene is expressed abundantly in the cerebral cortex and the duodenum of many species. In the brain, cholecystokinin is expressed and released by cortical, mesolimbic and hypothalamic neurons in various sites (Schiffmann and Vanderhaeghen, 1991; Raiteri et al, 1993; Kawaguchi and Kondo, 2002). The hormone is mostly, if not always, co-localized with classic transmitters in central nerve terminals (Ghijsen et al, 2001; Hansen and Nielsen, 2001; Larsson and Rehfeld, 1979). Cerebral cholecystokinin has been implicated in a variety of functions, such as feeding behaviour, anxiety, and memory (Beinfeld, 2001). In the small intestine, cholecystokinin is released from endocrine cells known as cholecystokinin cells or I cells under the influence of a releasing hormone, LCRF [luminal CCK-releasing factor; luminal cholecystokinin releasing factor]. Intestinal expression of cholecystokinin mRNA is modified by diet. It declines during fasting or with a low protein diets and increases with high protein diets (Kayama and Liddle, 1991). Pituitary cells, adrenal medullary cells, and enteric nerves have been shown to produce cholecystokinin (Rehfeld and Hansen, 1984; Crawley and Corwin, 1994). The hormone has been localized also to the male reproductive organs, with high levels in the testis, seminiferous tubules and in human sperm (Persson and Ericsson, 1988; Persson et al, 1989). Cholecystokinin has been shown to be produced by pancreatic Beta-cells (Shimizu et al, 1998), A-cells (Schweiger et al, 2005), pituitary tumour cells (Xu et al, 1996), and various types of human leukemia cells.

The human cholecystokinin gene has been cloned by Takahashi et al (1986). Cholecystokinin is generated from the preprocholecystokinin peptide of 115 amino acids (Deschenes and Lorenz, 1984). Enzymatic cleavage yields various types of the hormone. Cholecystokinin-33 (abbr. CCK-33), isolated originally from porcine intestine (Mutt and Jorpes, 1968), is a hormone of 33 amino acids. Two larger forms, designated Cholecystokinin-39 (abbr. CCK-39) and Cholecystokinin-58 (abbr. CCK-58) have been described (Eysselein and Reeve, 1982). Other intermediate forms include Cholecystokinin-25 (abbr.CCK-25), Cholecystokinin-22 (abbr. CCK-22), Cholecystokinin-18 (abbr. CCK-18), Cholecystokinin-10 (abbr. CCK-10), Cholecystokinin-9 (abbr. CCK-9), Cholecystokinin-8 (abbr. CCK-8; also being referred to as cholecystokinin octapeptide or CCK octapeptide; abbr. CCK-OP), Cholecystokinin-7 (abbr. CCK-7), Cholecystokinin-5 (abbr. CCK-5, which is identical with the 5 C-terminal amino acid fragment known as pentagastrin) and Cholecystokinin-4 (abbr. CCK-4) (Cantor P and Rehfeld, 1987; Liddle, 1997; Rehfeld and Nielsen, 1995). In addition, there are sulfated and non-sulfated isoforms. CCK-8S (sulfated CCK-8) is Asp-Tyr(SO3H)-Met-Gly-Trp-Met-Asp-Phe-NH2. The non-sulfated form is being referred to sometimes as CCK-8NS. Not all variants of cholecystokinin are found in all species. Rats, for example, only express CCK-22 and CCK-8 (Liddle et al, 1984). Humans and pigs express variants from CCK-58 to CCK-4 (Liddle et al, 1985). The major forms of CCK are CCK-58, CCK-33, CCK-22, and CCK-8. To determine The relative abundance of the major cholecystokinin forms in human plasma and intestine have been determined by Rehfeld et al (2001). The major forms of CCK are CCK-58, CCK-33, CCK-22, and CCK-8.

The most potent form in humans (Reeve and Eysselein, 1984), sheep (Calam and Dockray, 1982), pigs (Eng and Shiina, 1983), and rats (Muller and Straus, 1977) is cholecystokinin-8. The cholecystokinin-8 octapeptide is relatively conserved and appears to be the minimum sequence required for biological activity (Crawley et al, 1984).

Two types of cholecystokinin receptors have been identified (Boden et al, 1995). These receptors differ in their relative affinity for the natural ligands, their differential distribution, and their molecular structure (Noble et al, 1999).

The CCK-A receptor (gene symbol CCKAR) (Ulrich et al, 1993; type A for "alimentary", first characterized using pancreatic acinar cells (Sankaran et al, 1980) has been referred to also as the CCK-1 receptor). The effects of cholecystokinin on gastrointestinal motility are mediated mainly by CCK-1 receptors in humans (Varga et al, 2004). This receptor mediates gallbladder contraction, pancreatic enzyme secretion, slowing of gastric emptying, relaxation of the sphincter of Oddi, and potentiation of insulin secretion (see also: incretins). It has been implicated also in pancreatic growth and tumorigenesis. Type A receptors have a high affinity only for sulfated forms of cholecystokinin (Silvente-Poirot et al, 1993).

The CCK-B receptor (gene symbol CCKBR) (Pisegna et al, 1992, Lee et al, 1993; type B for "brain", Innis and Snyder, 1980) has been referred to also as the CCK-2 receptor. Smith et al (2002) have described a splice variant of the CCK-B receptor, which they have termed CCK-C receptor (C for cancer). This receptor variant is expressed in human pancreatic cancer and may mediate cancer cell growth. This receptor discriminates poorly between sulfated and non-sulfated cholecystokinin forms (Saito et al, 1980) and also binds the hormone gastrin. This receptor type is found principally in the CNS and select areas of the gastrointestinal tract.

Cholecystokinin receptors have been shown to be expressed by various cell types, including A-cells (Schweiger et al, 2005), acinar cells of the pancreas (Han and Logsdon, 1999; Yang et al, 2000; Satoh et al, 2004; Granados et al, 2004), adrenocortical cells (Malendowicz et al, 1999), beta-cells of the pancreas (Abdel-Wahab et al, 1999; Kuntz et al, 2004), chief cells (Heim et al, 1995; Pradhan et al, 1995; Tsunoda et al, 2003), D cells (Morisset et al, 2000), ECL cells (Tommeras et al, 2002) interstitial cells of Cajal (Patterson et al, 2001), leukemia cells (Iwata et al, 1996), macrophages (pulmonary interstitial) (Li et al, 2002; Cong et al, 2002) mast cells in the mucosa (Juanola et al, 1998), neural crest cells (Lay et al, 1999), neurons (Gabriel et al, 1996; Sugaya et al, 1992; Sebret et al, 1999; Lay et al, 1999; Patterson et al, 2001; Firth et al, 2002; Sayegh and Ritter, 2003; Simasko and Ritter, 2003; Peters et al, 2004; Giacobini et al, 2004; Appleyard et al, 2005; Tsujino et al, 2005; Gallopin et al, 2005), peripheral blood mononuclear cells (nontransformed human) (Schmitz et al (2001), parietal cells (Tommeras et al, 2002), pituitary tumour cells (Xu et al, 1996), smooth muscle cells (Wang and Sims, 1998; Patterson et al, 2001), T-cells (Akiyoshi et al, 1996; Cuq et al, 1997), thymocytes (Malendowicz et al, 1999).

Nagata et al (1996) have generated knock-out mice lacking expression of the type B cholecystokinin receptor. These mice are characterized by a pronounced atrophy of the gastric mucosa, which is due to a decrease in parietal cells and enterochromaffin-like cells.

As a physiological hormone, cholecystokinin has been shown to contribute to food intake suppression (Reidelberger, 1994). A blockade of CCK type A receptor results in reversal of food intake suppression caused by proteins (Trigazis et al, 1999). Various bioactivities of cholecystokinin peptides resemble those of cytokines and growth factors.

Cholecystokinin-8 has been shown to be chemotactic for human monocytes. The peptide also specifically increases the number of peritoneal macrophages when injected into rat peritoneal cavity (Sacerdote et al (1988, 1991). Cunningham et al (1995) have reported that cholecystokinin may upregulate gut immune responses, with monocytes being able to produce cytokines such as TNF-alpha, IL1, IL6, IL8, GM-CSF in response to cholecystokinin. Li et al (2002) have reported that cholecystokinin inhibits the in vitro expression of CD14 in pulmonary interstitial macrophages. Cholecystokinin also prevents expression of TNF-alpha (Cong et al, 2002). Meng et al (2002) have reported that inflammatory changes of lung and spleen induced by bacterial lipopolysaccharides are alleviated by cholecystokinin-8, which reduces NO production in serum, lung and spleen, and neutrophil infiltration.

Medina et al (1999) have reported that sulfated cholecystokinin-8 stimulates the spontaneous proliferation of leukocytes. De la Fuente et al (1998) have reported that the sulfated form of cholecystokinin-8 inhibits the mobility and mitogen-induced proliferation of mouse lymphocytes. Elitsur and Luk (1991) have reported that cholecystokinin promotes the proliferation of colonic lamina propria lymphocytes and thus may play a role in modulating the human mucosal immune system. Ferrara et al (1990) have reported that proliferating human peripheral blood mononuclear cells produce small amounts of cholecystokinin and acts as a comitogen for these cells. Cholecystokinin, by acting through the A receptor subtype, stimulates the proliferative activity of adrenocortical cells and thymocytes in the rat (Malendowicz et al, 1999)

Kuntz et al (2004) have reported that Cholecystokinin-8 is a potential growth factor for pancreatic beta-cells in diabetic rats.

Smith and McKernan (1999) have desribed proliferative effects of sulfated cholecystokinin on rat anterior pituitary GH3 cells, which express CCK type B receptors.

Han and Logsdon (1999) have reported that cholecystokinin induces the expression of the chemokine CXCL10 in pancreatic acinar cells. These cells also express CCL2 (MCP-1) and CCL5 (RANTES) in response to cholecystokinin (Yang et al, 2000

Oikonomou et al (2005) have reported that cultured human meningioma derived cells express the cholecystokinin type B receptor and that cholecystokinin-8 is an autocrine or paracrine growth factor for these cells. Hellmich et al (2000) have reported expression of a constitutively active splice variant of cholecystokinin type B receptor (designated CCK-BRi4sv) in colorectal cancers. Cells expressing this receptor exhibit an increased growth rate in the absence of gastrin (which also binds to this receptor), suggesting that this variant may regulate colorectal cancer cell proliferation though a mechanism that does not depend on gastrin and, possibly, cholecystokinin. Ohlsson et al (1999) have reported that sulfated cholecystokinin-8 promotes the proliferation of various pancreatic cancer cell lines and that this effect can be blockied by blocking the cholecystokinin receptors.

Giacobini et al (2004) have suggested a developmental role for cholecystokinin, having observed that gonadotropin-releasing hormone-1 GnRH-1 neurons in nasal regions express the type A but not the type B cholecystokinin receptor and that cholecystokinin reduces axon outgrowth and migration of these cells.

LAST MODIFIED: September 2006

See REFERENCES for entry Cholecystokinin

COPE Homepage

Top of Page

 

#

A

B

C

D

E

F

G

H

I

J

K

L

M

N

O

P

Q

R

S

T

U

V

W

X

Y

Z

Space for your TEXTLINK ADVERTISEMENTS. Please Inquire

---

---

supports the COPE bioinformatics project with an unrestricted educational grant
Inquiries from other sides welcome

---

Created, developed, and maintained by Prof Dr H Ibelgaufts               About the author of COPE   |    Contact COPE   |    postcard and stampware

---

Access to COPE is free only for academic institutions and non-profit organizations. OTHER USERS: must contact COPE and pay a site licence fee. Non-payment of the site licence fee is a serious breach of COPE's binding Usage Agreement. If you do not wish to be bound by this agreement, do not use COPE

COPE is not in the public domain! The commercial use of COPE contents is not allowed. Download of complete offline-readable copies and the use of automatic extraction methods are prohibited! Usage Agreement, Disclaimer, Copyright Notice   |  All rights reserved by H Ibelgaufts   |  Privacy Statement U L T R A   P O S S E   N E M O   O B L I G A T U R

cope.cgi version 24.7.07, revision Jun 14, 2010. (c) JI. Powered by Perl 5.008008 [b=5]