The existence of cholecystokinin (CCK) as a gut hormone was suggested in 1928 based on hormonal regulation of gallbladder emptying, later also on stimulation of pancreatic enzyme secretion, and modification of gastrointestinal motor activity. In 1968, a CCK peptide was purified from gut extracts and identified as a 33 amino acid peptide (CCK-33). Based on that structure, research has since expanded the insight into CCK biology remarkably: Thus, CCK was the first discovered intestinal satiety signal from gut to brain. Moreover, the CCK gene is now known to be expressed in different peptide forms not only in the gut, but much so in central and peripheral neurons, in addition to extra-intestinal endocrine cells, immune cells, cardiomyocytes, spermatogenic cells, and certain fat cells. Accordingly, CCK peptides function not only as hormones. They are also neurotransmitters, paracrine growth and satiations factors, anti-inflammatory cytokines, incretins, adipokins, myokins, potential fertility factors, and tumor markers. Thus, CCK research has now opened windows for insights into the pathophysiology of not only gallbladder disease, but also metabolic disorders, neuropsychiatric diseases, cardiac diseases, as well as the diagnosis of neuroendocrine and pediatric tumors.

• Cholecystokinin;

• Cytokine

• Gut hormone

• Neurotransmitter

• Satiation factor

Rehfeld JF (2026) Cholecystokinin – More Than Just a Gallbladder Emptier. JSM Gastroenterol Hepatol 13(2): 1141.

In modern endocrinology, gastrointestinal hormones have recently surfaced as a strikingly dynamic area with considerable clinical impact [1]. Particularly well known examples are glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) from which drugs have already been derived and used in the treatment of diabetes and obesity, with additional candidates in the pipelines for therapy of cardiovascular, renal and perhaps cerebral diseases [2-4].

Other gastrointestinal hormones might also be of interest as drug targets. Among these is not least cholecystokinin (CCK), whose role as an intestinal regulator of gallbladder emptying actually may turn out to be secondary compared to some of the extraintestinal activities implicated in the complex biology of CCK [5,6].

Following a summary of the CCK history, this article will briefly overview the new CCK biology including phylogeny, biogenesis, cellular expression with cell-specific peptide patterns, receptors, and subsequently derived functions.

More than a century ago, European physiologists observed that administration of acid into the duodenum stimulated bile flow from the liver and gallbladder contraction [7-10,11]. In 1928, Ivy and Oldberg provided evidence that the gallbladder effect was due to a new gut hormone, which they named CCK [12]. However, not until Mutt and Jorpes established a large plant for purification from vast amounts of porcine jejunal mucosa did structure identification become possible. The structure was published in 1968 [13] as a peptide sequence of 33 amino acid residues, a C-terminal sequence homologous to that of gastrin, and besides it was O-sulfated (Figure 1).

Figure 1: The structure of the 33 amino acid residues of cholecystokinin as published in 1968 (see ref. [12]). Note that the tyrosyl residue in position 27 is O-sulfated and that the phenylalanyl residue in position 33 is carboxyamidated. The C-terminal boxed sequence is the bioactive, receptor-bound epitope of CCK.

Identification of the structure became a decisive milestone. With synthetic fragments of CCK-33, material became available for physiological studies, for production of antibodies as well as for identification of the CCK gene and new molecular forms of CCK peptides. These tools together with other methods paved the way for a number of paradigmatic shifts that have unfolded a multifaceted biology. Consequently, CCK is now to be seen as a ubiquitous peptide messenger system in the body [5,6].

Phylogenesis

CCK is member of a family that includes the antral hormone gastrin [14,15]; the amphibian skin peptides, the caeruleins [16,17]; and in protochordates, the neuropeptide cionin [18]. Insect neuropeptides, the sulfokinins [19,20] are also structurally related (Figure 2). Consequently, evolutionary studies indicate that CCK peptides originated almost 600 million years ago [21-24].

Figure 2: The decisive homologous structure in members of the cholecystokinin peptide family in mammals, amphibians, protochordates (Ciona Intestinalis), and insects (a cockroach (Leucophaea Madera) and a fruitfly (drosophilia melanogaster)). Note that the boxed C-terminal tetrapeptide sequences are all carboxyamidated and that this tetrapeptide amide as such is the core structure necessary for receptor binding. Note also O-sulfation of the more N-terminal tyrosyl residues. The tyrosyl-sulfation is a derivatization that modifies the affinity and hence the specificity of receptor bindings

Biogenesis and Molecular heterogeneity of peptides

There is one CCK gene [25,26] which is transcribed to a single mRNA of 750 bases [25-27]. The mRNA molecule is then translated to a precursor protein (preproCCK) with a sequence of 115 amino acid residues [27]. The N-terminal signal or pre-sequence is probably removed during translation, leaving a proCCK of 95 amino acids, which subsequently undergoes posttranslational modifications by a multitude of processing enzymes acting along cellular secretory or synaptic pathways [28-37]. The modifications comprise cleavages at mono- and dibasic sites, amino acid derivatizations and N- or C-terminal trimmings. As a result of the posttranslational processing, a number of different bioactive CCK peptides are accumulated in the secretory granules or presynaptic vesicles: CCK-83, -58, -33, -22, -8, and -5. The first five occur in both O-sulfated and nonsulfated forms, whereas CCK-5 is unsulfated. The peptide patterns, however, are cell-specific [6-37].

The Tissue and cell expression

In accordance with the role as gut hormone, specific endocrine cells in the intestinal mucosa, I-cells, have been identified in the duodenum and jejunum as the major source of intestinal CCK [38-40]. A majority of CCK in plasma originates from these cells. The I-cells, however, are present also in the ileum, and sporadically in the proximal colon [41-43].

Most CCK is, however, not synthesized in the gut, but in neurons, central as well as peripheral [30-48]. The CCK neurons also express “classic” transmitters, such as GABA in interneurons and glutamate in pyramidal and thalamic neurons [48,49].

Although cerebral neurons and intestinal I-cells are major expression sites, specific expression has in addition been detected in other cells (Table 1). They include pituitary corticotrophs [50,51], thyroid C-cells [52,53], adrenal medullary cells [54], spermatogenic cells [55,56], cardiac myocytes [57], and circulating monocytes [58-60].

Table 1: Tissue concentrations of bioactive cholecystokinin (CCK) peptides in mammals.

aOrders of magnitude based on measurement of tissue extracts from several mammalian species.

bExpression determined by immunocytochemistry of monocytes.

Cell-specificity of CCK peptide expression

There are at least three different cell patterns of CCK. First, in central and peripheral neurons, O-sulfated CCK 8 predominates, but also unsulfated CCK-5 is present in significant amounts. Second, gut endocrine I-cells express a considerably broader pattern that includes larger molecular forms (CCK-58, -33, and -22) as well as short forms (CCK-8 and -5) [61]. The four longest CCK peptides in I-cells all occur also in nonsulfated variants [35]. Finally, specific patterns are found in lower concentrations in pituitary corticotrophs, thyroid C-cells, spermatogenic cells, cardiac myocytes, and circulating monocytes [50-59].

CCK Receptors

The distribution and distinction between “alimentary” (CCKA ) and “brain” (CCKB ) receptors were studied already in the 1970s and 1980s [64,65]. In 1992, however, the structures of the CCKA and the gastrin/CCKB receptors were deduced after cDNA cloning [66,67]. The receptors are now named CCK1 and CCK2 . Later, informative reviews of receptor distribution, physiology, and pharmacology have been published [68,69]. The binding specificity of the CCK1 and CCK2 receptors differs. Thus, all carboxyamidated CCK and gastrin peptides irrespective of sulfation are bound with similar affinities to the gastrin/CCK2 receptor, whereas the CCK1 receptor is more selective and binds only tyrosyl O-sulfated CCK peptides. A novel CCK receptor was recently detected in brain tissue [70]. Further characterization is awaited.

CCK functions

An overview of the functions of CCK requires recognition of the new biology in its entirety: On one hand, there are the different cellular origins and release mechanisms for CCK peptides. On the other hand, there are the targets in terms of CCK receptors and the routes by which the peptides travel to receptors expressed on target cells (endocrine, neurocrine, paracrine, autocrine, spermiocrine ways and synaptic transmissions). The CCK receptors are expressed in a majority of organs and tissues in the body: central and peripheral neurons as well as glial cells; the entire gastrointestinal tract; myocytes of the gallbladder and the sphincter Oddi muscles; exocrine and endocrine pancreatic cells; the cardiovascular system; the urogenital system; and the immune system [68,69]. Consequently, CCK peptides have many labels and may act independently as neurotransmitters, hormones, growth factors, satiation factors, cytokines, myokines, and perhaps adipokines and fertility factors.

On top of this picture, it is of fundamental significance to realize that the target cells for CCK peptides also express receptors for a multitude of other bioactive peptide systems. Therefore, different peptide systems interact and cross talk along intracellular signal-transduction pathways. Well-known examples are the mutual potentiation of CCK peptides with secretin in their stimulation of exocrine pancreatic enzyme and bicarbonate secretion [71,72]; the CCK potentiation of GLP-1 in stimulation of pancreatic beta cell growth [73]; the interaction of CCK with GLP-1 and PYY in signaling to the brain via afferent vagal fibers to regulate food intake [74]; and, for instance, the balance between sulfated and nonsulfated CCK peptides from CCKomas in the inhibition or stimulation of gastric acid secretion [75]. Probably, studies of the interactive physiology between CCK and other bioactive peptide systems as well as the interaction with non-peptidergic extracellular messenger molecules will be an essential part of the future physiology and pharmacology of CCK [76].

CCK and Gallbladder diseases

The association between CCK and gallbladder function is per definition the basis for the century-old biology of CCK as reflected also in the name of the hormone [11]. Today it is an established fact that CCK peptides from I-cells in the proximal small intestine in a concentration related manner control the intestinal phase of gallbladder emptying via CCK1 receptors expressed on gallbladder muscles [77]. The mechanistic details and the relationship to gastrointestinal disorders, pancreatic insufficiency, and gallstone/gallbladder diseases have systematically been studied not least by Masclee and Lamers et al., [77-83].

The results are summarized in Table 2, which shows that the occurrence of gallstones frequently accompanies the examined disorders. Although gallstone-attacks are painful and annoying, surgical gallbladder removal is today fast and uncomplicated, and life without a gallbladder is almost normal. Remember that the successful rodent, the rat, does not have a gallbladder. Thus, perhaps the pancreozymic effect of CCK should be considered more essential for digestion than the gallbladder-emptying effect, as demonstrated also in normal rats.

Table 2: Cholecystokinin secretion and gallbladder motility in some gastrointestinal disorders.a

aSee also ref. (77) for further details

The skillful and patient linguistic as well as secretarial assistance of Connie Bundgaard (MA) is gratefully acknowledged.

Data availability statement

Data sharing is not relevant for the present perspective article.

Funding statement

The writing of this article received no funding. Earlier cholecystokinin studies in the laboratory of the author, however, received support from the Danish Medical Research Council, the Danish Cancer Union, and the Novo Nordic Foundation.

Conflicts of interest

The author declares no conflicts of interests.

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