Cholecystokinin and the hormone concept

in Endocrine Connections
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  • 1 Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Correspondence should be addressed to J F Rehfeld: jens.f.rehfeld@regionh.dk

The birth certificate for endocrinology was Bayliss’ and Starling’s demonstration in 1902 that regulation of bodily functions is not only neuronal but also due to blood-borne messengers. Starling named these messengers hormones. Since then transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones are not only produced and released to blood from endocrine cells but also released from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Today’s multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells – irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone, growth factor, neurotransmitter, adipokine, cytokine, myokine, or fertility factor.

Abstract

The birth certificate for endocrinology was Bayliss’ and Starling’s demonstration in 1902 that regulation of bodily functions is not only neuronal but also due to blood-borne messengers. Starling named these messengers hormones. Since then transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones are not only produced and released to blood from endocrine cells but also released from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Today’s multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells – irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone, growth factor, neurotransmitter, adipokine, cytokine, myokine, or fertility factor.

Introduction

The word hormone originates from the Greek word ’hormoa’. It was proposed by the British linguist WB Hardy and introduced by Ernest Starling in his Croonian Lectures published in ‘The Lancet’ in 1905 (1) – 3 years after his and William Bayliss’ breakthrough discovery of the first hormone in history, secretin (2). ‘Hormone’ was rapidly accepted as a general designation for blood-borne chemical messengers of which secretin was the first and gastrin the second example (2, 3). Accordingly, hormones and blood-borne regulation became core-concepts in endocrinology as complementary to neuronal regulation, which until then had been considered the only way for regulation and coordination of bodily functions (4, 5).

In the wake of the secretin discovery, endocrinology blossomed with uncoverings of a multitude of additional hormones, endocrine glands and ensuing paradigmatic shifts in the understanding of regulatory physiology. Chemically, the structure of hormones turned out to vary from proteins and peptides, to steroids, thyronins and monoamines. And cellularly, most new hormones appeared to originate from glands such as the pituitary, thyroid, parathyroids, pancreatic islets, adrenals, ovaries and testes. A major exception from the glandular origin, however, was the gastrointestinal hormones, because endocrine cells in the gut are distributed in a regional manner among non-endocrine cells in the gastrointestinal mucosa and not collected in the glands. Hence, we have the puzzling paradox that many endocrinologists do not consider the gut to be a classic endocrine organ, although the gastrointestinal tract by all parameters is the largest and in evolutionary as well as historical terms the oldest endocrine organ in the body (for reviews, see 6, 7, 8, 9).

For hormones in general, however, the progress in cellular and molecular biology during the last decades has in a fundamental manner deepened the insight into a new biology (10). This insight has changed both basic and clinical endocrinology. The following story about cholecystokinin (CCK) illustrates how studies of a single peptide hormone from the gut (CCK-33) has gradually contributed to expand endocrinology into a considerably wider concept than just being about blood-borne messenger molecules.

The cholecystokinin (CCK) story

Six chronological descriptions of CCK as a blood-borne hormone

The prehistory

Almost a century before CCK was discovered in 1928 as a gallbladder-emptying hormone (11), European physiologists took a broad interest in bile secretion and the role of bile in digestion (for reviews, see 12, 13). For instance, Claude Bernard (who introduced the concept of ‘sécrétion interne’) reported in 1856 that installation of hydrochloric acid into the duodenum increased the secretion of bile (14). In 1903, another French physiologist, Wertheimer, reported that duodenal stimulation of bile secretion persisted after cutting vagal and sympathetic neurons to the duodenum (15). And in the same year, Fleig described how blood from an isolated loop of the small intestine, into which acid was injected, increased bile-flow when transfused into another dog (16). Thus, already 1 year after Bayliss’ and Starling’s discovery of secretin, French physiologists had evidence to suggest that the duodenum might release a blood-borne chemical messenger or hormone that stimulated bile secretion. But they were not sure whether the bile-stimulating effect was still to some extent caused by secretin. During the following years, Okada studied bile secretion in Starling’s laboratory in London. And in 1914, he reported that acid in the duodenum not only stimulated the secretion of hepatic bile but it also emptied gallbladder bile into the small intestine (17).

In retrospect, it may be surprising that so many bile secretion studies over almost a century did not ignite the idea that the upper small intestine harbored a specific bile-releasing hormone, different from secretin. Therefore, further experiments were necessary in order to rule out a possible bile-secretagogue activity of secretin. Such studies were eventually performed by Andrew Ivy and colleagues in Chicago in the late 1920s (11, 18, 19, 20).

The functional identification

Ivy et al. examined first whether different preparations of secretin of various purity affected the gallbladder in dogs (20). They concluded – pretty inconclusively – from this study that an observed gallbladder contracting activity was due to ‘secretin or some substance closely associated with it’ (13, 20). After further cross-circulation studies in dogs, they saw that hydrochloric acid in the duodenum of a dog caused gallbladder contraction in another. And when they kept that observation together with differences in solubility of secretin preparations and preparations containing the gallbladder contracting activity, they concluded that the small intestine produced a new hormonal activity which they decided to name cholecystokinin (11, 18, 19, 20). Thus, a third and separate gut hormone-like activity was entering the scene. And from being concerned mainly with secretin and a little with gastrin, gastrointestinal endocrinology broadened. Today, secretin, gastrin, and CCK are – for good reasons – accepted as the classical troika of gut hormones. Nevertheless, compared to secretin, the interest in CCK was limited in the following decades. In 1946, Ivy therefore tried to evoke clinical interest for CCK by suggesting that CCK injections might be of use for the diagnosis and therapy of biliary dyskinesia (21). But the response from clinicians remained meager.

In the meantime, another hormonal activity from the duodenal mucosa had been found by Harper and Raper in 1943 (22). Its existence was rapidly confirmed in Ivy’s laboratory (23). The active substance was named pancreozymin, because it stimulated the secretion of pancreatic enzymes. Pancreozymin was for more than 20 years considered a separate gut hormone (22, 23, 24). It was noted, however, that pancreozymin preparations also stimulated gallbladder contraction (25). This side effect was, however, considered to be due to contamination of the partly purified pancreozymin preparations with CCK. The situation illustrated the need for pure hormone preparations that hopefully also would allow identification of the structure of the hormones.

Already from 1912, attempts had been made in several laboratories to purify and isolate secretin from intestinal extracts (26, 27, 28, 29). The goal was – as just mentioned – to have a pure and stable secretin preparation for physiological and clinical tests of exocrine pancreatic functions (30). Similarly, attempts to purify CCK was also initiated early (19, 31). In retrospect, however, these purification attempts were premature and too optimistic because the necessary biochemical technology was not yet available (for review, see 32). Peptide purification required at least electrophoretic, ion-exchange chromatographic and counter current distribution techniques, which became available in the 1950s.

The structural identifications

The identification of the CCK structure was again associated with secretin. After pilot extractions and early purification steps in the late 1940s and early 1950s (30, 31), Jorpes and Mutt in Stockholm decided to establish a large-scale platform of almost industrial size for extractions of porcine small intestines in order to have sufficient material for purification of secretin, CCK and pancreozymin (33, 34). That was a wise decision, because the intestinal tissue concentrations of both secretin and CCK have turned out to be low (35, 36). Mutt and Jorpes managed to collect the proximal 1 m small intestine from 20,000 hogs (20 km of intestine!). After boiling, acetic acid extractions, absorption to alginic acid, fractionations with ethanol and methanol, ion-exchange and later size chromatographies, and finally counter current distributions, they had approximately 10 mg essentially pure peptides for sequence analysis (37, 38, 39).

This more than 20 years’ tour de force is probably the most important single effort in furthering gastrointestinal endocrinology. And the results were worth the effort: After identification of the secretin structure, CCK was identified as a tyrosyl-sulfated and carboxyamidated peptide of 33 amino acids, now called CCK-33 (Fig. 1). But the bioassay monitoring of gallbladder contractions and pancreatic bicarbonate and enzyme secretion of the different purification steps also revealed that CCK and pancreozymin was one and the same peptide hormone (40). After some discussion, consensus was obtained about maintaining the name cholecystokinin and its acronym, CCK, rather than the ungainly double name cholecystokinin-pancreozymin, or CCK-PZ (41, 42). Moreover, the structure also showed an unexpected close homology between the bioactive C-terminal sequences of CCK and that of the in 1964 sequenced gastric hormone, gastrin (43, 44) (Fig. 2).

Figure 1
Figure 1

The amino sequence of porcine cholecystokinin-33 (CCK-33), the originally identified CCK-peptide (Mutt & Jorpes (39)). The bioactive CCK-8 sequence (26, 27, 28, 29, 30, 31, 32, 33) is underlined. Only the amino acids in the encircled positions no. 7, 9, 10, and 15 differ from those in the human sequence (Met, Ile, Val, and Asn, respectively).

Citation: Endocrine Connections 10, 3; 10.1530/EC-21-0025

Figure 2
Figure 2

The bioactive sequences of peptide systems belonging to the cholecystokinin (CCK) family. CCK and the antral hormone, gastrin (43, 44), are the only mammalian members of the family. Caerulein and phyllocaerulein are identified from frog skin extracts (45, 46). Cionin is a neuropeptide isolated from the central ganglion of the protochord, ciona intestinalis (47). Note the unique disulfated sequence, which might suggest that cionin may resemble a common ancestor of CCK and gastrin (48). The core of the bioactive sequences, the common C-terminal tetrapeptide amide, is boxed. The lower panel shows the bioactive sequences of the insect neuropeptides, the sulfakinins, which are homologous to vertebrate and protochordian members of the CCK family (49, 50). Also their C-terminal tetrapeptide amide sequence is boxed.

Citation: Endocrine Connections 10, 3; 10.1530/EC-21-0025

The homology story, however, turned out to be even greater. In addition to the mammalian gastrins, the CCK-structure showed an even higher degree of homology with the simultaneously isolated frog skin peptides, caerulein and phyllocaerulein (45, 46). And particularly interesting in evolutionary terms was the disulfated cionin-peptide from the central ganglion of the protochordate, Ciona Intestinalis, which revealed a hybrid structure (47) similar to that of the presumed common ancestor of CCK and gastrin (48). Finally, also insects express a group of neuropeptides, the sulfokinins, with significant homologies to the CCK structure (49, 50) (see also Fig. 2). Thus, CCK represents a large family of potent bioactive peptides in the animal kingdom that in phylogenetic terms is 500–600 million years old (51, 52, 53).

Knowledge of the CCK-33 structure was a decisive milestone. Viktor Mutt generously supplied purified CCK-33 from Stockholm to interested research laboratories for functional studies, antibody production and chromatographic calibrations. And with the almost coincident chemical synthesis of the bioactive C-terminal octapeptide sequence (CCK-8), material became available for further CCK-research (54). Subsequent chromatographic studies on intestinal extracts showed, however, that CCK-33 was only one among several bioactive CCK-peptides (36, 55, 56, 57, 58). These other CCKs have been purified and their structures determined to be CCK-58, CCK-22, CCK-8 and CCK-5. The longer forms are released in both tyrosyl-sulfated and non-sulfated forms (59), whereas CCK-5 only exists as non-sulfated in lack of a tyrosyl residue for O-sulfation (58, 60). Thus, CCK is in molecular terms a highly heterogenous peptide system. Understanding of this molecular heterogeneity requires, however, insight into the CCK-gene expression cascade with emphasis on the posttranslational maturation of proCCK-expressing cells.

The CCK biogenesis

The CCK gene was cloned and sequenced from a rat cell line in 1985 by Deschenes et al. (61). Only two of its three exons are coding. They are transcribed to one mRNA of 750 bases of which 345 are translated to a preproCCK protein of 115 amino acids (Fig. 3). The first part of the preproprotein is the signal peptide that is cleaved off by a signalase, leaving intact proCCK. Then follows a spacer-peptide in whose sequence there are several variations from species to species (51). The spacer sequence is followed by the CCK-58 sequence with only few species variations (51). The intestinal CCK-58 sequence undergoes extensive endoproteolysis by primarily prohormone convertase 1/3 at monobasic and a single dibasic cleavage site (62). As a result, the endocrine I-cells in the intestinal mucosa contain in their secretory granules a mixture of CCK-58, -33, -22, -8 and -5 of which CCK-33 appears to be the predominant form in the human intestine and circulation (63). As mentioned previously, however, 20–30% of the bioactive CCK-peptides in the small intestine are not tyrosyl-sulfated (59). The non-sulfated, but still carboxyamidated, CCK-peptides are not agonists for the CCK1-receptor and are consequently without effect on hepatic bile secretion and emptying of the gallbladder. But they are still bioactive as agonists for the CCK2 receptor. They function – in other words – as intestinal gastrins (64).

Figure 3
Figure 3

The posttranslational maturation of preprocholecystokinin in the endocrine I-cells of the small intestine. Mono-and dibasic cleavage sites (arginyl (R) and lysyl (K) residues) are indicated on the schematic figure of preprocholecystokinin (upper part of the figure). In the remaining part of the figure, the asterisks (*) indicate tyrosyl O-sulfation sites on the procholecystokinin processing intermediates and bioactive endproducts. Decisive processing enzymes (sulfortransferases, prohormone convertases, carboxypeptidase E, and the amidation enzyme (pepdityl-glycyl-α-amidating monooxygenase complex (PAM)) are also mentioned at the cellular level of the posttranslational processing pathway, where they act. In the intestinal endocrine I-cells, prohormone convertase 1/3 (PC 1/3) is predominant, whereas prohormone convertase 2 (PC 2) predominates in cerebral CCK neurons (see also 62). CCK-83 has been identified in tissue extracts but not in plasma (63).

Citation: Endocrine Connections 10, 3; 10.1530/EC-21-0025

As indicated by Fig. 3, the cellular posttranslational maturation of proCCK involves multiple often incomplete processing steps catalyzed by enzymes that have been reviewed in detail elsewhere (62, 65, 66, 67). After release of the CCK peptides from enteroendocrine I-cells to blood the plasma pattern changes, because the longer molecular forms (CCK-58, -33 and -22) are cleared at a slower rate from circulation than the short CCKs (CCK-8 and -5).

The hormonal functions and receptors

The CCK-synthesizing I-cells in the gut mucosa have an apical membrane in direct contact with the intestinal lumen where it can taste the luminal content. The basal cell region is close to capillaries, to which the CCK-containing secretory granules are released upon stimulation (68, 69). The most important stimulus is food, in particular protein- and fat-rich food (70, 71). Of the major constituents, protein, L-amino acids and digested fat cause the largest release of CCK-peptides (70, 72). The chain length of the fatty acids determines the magnitude of the CCK response to lipids with long-chain fatty acids being more stimulatory than medium and short chain (73, 74, 75, 76). The response to carbohydrates is lower but still significant (77, 78).

The I-cells in the intestinal mucosa have the highest density in the duodenum and the proximal jejunum (59, 68, 69, 79). But there are still fair amounts of I-cells and CCK in the remaining small intestine and even a few in the colon (59, 79, 80). It is a mistake to consider the duodenum as the main source of intestinal CCK. Careful quantitation shows that the jejunum contains considerably more CCK, and even the ileal mucosa also expresses more bioactive CCK peptides than the duodenum (59). The explanation is simple: The duodenum constitutes only a short part of the small intestine. Besides, some immunohistochemical countings of I-cells in the duodenum have been false high due to use of antibodies that cross-react with duodenal gastrin cells (G-cells) that can be quite abundant (59, 69).

Bioactive CCK peptides in blood circulate in the low picomolar range (63, 70, 71, 72). They potently stimulate their target cells via one of the two CCK receptors (81, 82) expressed on the target cell membrane. The CCK1 and CCK2 receptors are both of the GPRC type and show extensive homology (81, 82, 83). The CCK1 receptor, earlier named the CCK-A receptor, is also called the alimentary receptor. It mediates hepatic bile secretion, gallbladder contraction (Fig. 4), relaxation of the sphincter Oddi, pancreatic enzyme secretion and growth, inhibition of gastric acid secretion via somatostatin cells and inhibition of gastric emptying (84), satiety via afferent vagal fibers (85), and gut motility. Only tyrosyl-sulfated CCK peptides are agonists for the CCK1 receptor, which do not bind non-sulfated CCK peptides, nor any gastrins (81).

Figure 4
Figure 4

The concentrations of bioactive CCK in plasma vs gallbladder emptying during a mixed meal in normal human subjects. Data from (141) with permission.

Citation: Endocrine Connections 10, 3; 10.1530/EC-21-0025

The CCK2 receptor is primarily expressed in the brain – and therefore earlier named the brain or CCK-B receptor. The CCK2 receptor was, however, originally cloned and structurally identified as the gastrin receptor (82). Accordingly, it is also expressed in the stomach with particularly high density on enterochromaffin-like (ECL) cells and occasionally on parietal cells. The CCK2 receptor therefore mediates gastrin’ergic acid secretion via histamine release from the ECL cells (86). Notably, the CCK2 receptor is also expressed on human and porcine pancreatic islet cells (87), where it contributes to the gut hormonal incretin effect on insulin and glucagon secretion (88). The CCK2 receptor is less specific than the CCK1 receptor, as it binds all carboxyamidated CCK and gastrin peptides irrespective of the degree of tyrosyl-sulfation (82, 83).

The differentiated receptor distribution in the gastrointestinal tract illustrates the central hormonal role that blood-borne intestinal CCK peptides play in digestion and metabolism.

The plasma measurements

In accordance with the origin of endocrinology, a defining character of hormones has been their traveling via blood to their targets. Consequently, it is in endocrinology necessary to be able to measure the concentrations of hormones in plasma. Both the understanding of basal regulatory and pathophysiological functions of the hormone as well as its impact as biomarker in clinical diagnosis and therapy-monitoring require accurate plasma measurements. And that has been a major challenge for CCK.

Accurate and sophisticated bioassays for plasma CCK were described in the 1980s (70, 89, 90). But the complexity and labor intensiveness precluded, however, wider use in other laboratories. Therefore, the only feasible approach has been development of RIAs with the necessary sensitivity and specificity. It took decades to develop such assays (71, 91, 92, 93). The challenges were first to raise antibodies of very high affinity, because bioactive CCK in plasma from normal subjects circulate in femtomolar to low picomolar concentrations (70, 71, 89, 92). Secondly, the antibodies must in molar terms bind all the different bioactive peptides in circulation (CCK-58, -33, -22, and -8) equally well – in analogy with the CCK1 receptor binding; and finally, the antibodies should not bind any of the homologous gastrin peptides. This last criterion has been the largest challenge, because the gastrin concentrations in plasma are about ten-fold higher than those of CCK (70, 71). And in a clinical context, hypergastrinemic patients are not uncommon (94). An additional problem with low-quality and unreliable commercial kits for plasma CCK measurements was recently reviewed (95). In view of the challenges for measurement of the true concentrations of CCK in plasma, users of commercial kits have to evaluate the reliability of each kit carefully.

In summary, since almost all CCK in blood originates from the enteroendocrine I-cells in the gut, specific measurement of CCK in plasma has confirmed that intestinal CCK fulfills all criteria for being a classic blood-borne hormone (see also Fig. 4). But it is not a simple hormone: The molecular heterogeneity and the low concentrations in circulation have to be considered. Moreover, the close structural homology with gastrin as well as their sharing of the CCK2 receptor also requires attention in the understanding of CCK as a hormone. And the concept becomes even more challenged with the recognition of expression of CCK also in extraintestinal endocrine cells and non-endocrine cells (vide infra).

Six descriptions of the discoveries of CCK in extraintestinal cells

CCK in central and peripheral neurons

It came unexpectedly when Vanderhaeghen et al. in late 1975 reported that the vertebrate brain contained a ‘new peptide reacting with gastrin antibodies’ (96). Soon after, three gastrin immunoassay laboratories (from Liverpool, New York, and Aarhus) began to characterize the gastrin-like peptide in extracts of brain tissue (36, 97, 98, 99). In rapid succession, but with the Liverpool-laboratory first, they revealed that the predominant molecular form of the gastrin-like neuropeptide was not a gastrin peptide but sulfated CCK-8 (36, 97, 99, 100). Further studies showed that also longer (CCK-58 and CCK-33) as well as a shorter forms (CCK-5) are expressed in cerebral neurons, although in concentrations lower than those of CCK-8 (36, 60, 80). In accordance with the widespread occurrence of especially the CCK2 receptor in cerebral tissues, neuronal CCK peptides turned out to be potent neurotransmitters in all brain regions except the cerebellum (101, 102). For the sake of completeness, it should be noted that true gastrin peptides also are expressed in central and peripheral neurons (36, 103, 104) but considerably more sporadic and in low amounts as compared to the CCK peptides (36, 80).

In fact, the brain in higher mammals expresses more CCK than the gut (Table 1). Moreover, cerebral CCK neurons are more abundant than neurons of any other neuropeptide, giving CCK a unique status as brain peptide (80, 105, 106). While most peptidergic neurons are present in subcortical regions, CCK is expressed in the highest concentrations in neocortical neurons (36, 80, 107). The perikarya of the cortical CCK nerves are distributed in layers II-VI, with the highest frequency in layers II and III (80, 108). CCK in mesencephalic dopamine neurons projecting to the limbic area of the forebrain (105) has aroused some clinical interest because these neurons are supposed to be involved in schizophrenia.

Table 1

The expression of cholecystokinin in normal adult mammalian tissue.

TissueTissue concentrationa (pmol/g)
Intestinal tract
 Duodenal mucosa200
 Jejunal mucosa150
 Ileal mucosa20
 Colonic mucosa5
Central nervous system
 Cerebral cortex400
 Hippocampus350
 Hypothalamus200
 Cerebellum2
 Spinal cord40
Peripheral nervous system
 Vagal nerve25
 Sciatic nerve15
 Nerveplexes in colonic wall5
Extraintestinal endocrine glands
 Adenohypophysis25
 Neurohypophysis20
 Thyroid gland2
 Adrenal medulla1
Genital tract
 Testicles5
 Spermatozoas1
Cardiovascular system
 Atrial myocytes10
 Ventricular myocytes2
Mononuclear immune cellsb++

aOrders of magnitude based on measurement of tissue extracts from different mammalian species. bExpression determined only by immunocytochemistry.

Outside the brain, the colon contains numerous CCK neurons, whereas jejunum and ileum are more sporadically innervated (80). Colonic CCK fibers penetrate the circular muscle layer to form a plexus in the submucosa (80). In accordance with these locations, CCK peptides excite colonic smooth muscles and release acetylcholine from neurons in both plexus myentericus and submucosa (109). Ganglionic cell somas and endocrine cells in pancreatic islets are also surrounded by CCK nerves (110, 111). Finally, afferent vagal nerve fibers also contain CCK (112, 113).

The physiologic and pathophysiologic roles of the high concentrations of CCK in the brain are far from settled. But there are indications that cerebral CCK neurons are involved in central satiety regulation and in memory. And clinically, cerebral CCK seems involved in anxiety and – as mentioned – perhaps in schizophrenia (105).

CCK in extraintestinal endocrine cells

The CCK gene is expressed also in several well-known endocrine cell types outside the gut. Hence pituitary corticotrophs and melanotrophs express significant amounts of proCCK fragments but the posttranslational processing results in only trace amounts of conventional α-amidated CCK peptides (114, 115). Also, thyroid C-cells produce CCK,but mainly as non-sulfated but amidated CCK-8 (116). Since C-cells also are well equipped with CCK2-receptors (117), the thyroid unsulfated CCK-8 is probably an autocrine stimulator of growth of the normal and not least malignant C-cells. Adrenal medullary cells produce small amounts of CCK, although amidated and with a low degree of sulfation (118). The significance of adrenal CCK is so far unknown. Finally, and as mentioned previously, CCK nerve terminals are present also in pancreatic islets, where short molecular forms of CCK can contribute to the regulation of the secretion of islet-cell hormones (111).

CCK in male germ cells

It was a major surprise to see that spermatogenic cells – although transiently – express the CCK gene in most mammals (119, 120). Less than 25% of the amidated CCK is sulfated. Interestingly, the CCK peptides in mature spermatozoa are concentrated in the acrosomal granule, which opens the possibility that CCK may play a role in fertilization due to the acrosomal reaction (120). The acrosomal expression is species-specific, as human spermatozoa in addition to CCK also express its homologue, gastrin (121). The reason for the dual expression is unknown.

CCK in immune cells

Cholecystokinin immunoreactivity has consistently been found to be expressed in human and rat mononuclear cells in blood (122, 123). Moreover, CCK-8 (sulfated as well as non-sulfated) has been reported to exert a wide spectrum of stimulation and inhibition on lymphocytes, macrophages, and cytokine release, with ensuing anti-inflammatory effects (124, 125, 126, 127). The field is complex due to the many peptide players; but the clinical impact of CCK in inflammatory diseases and endotoxin shock may be significant.

CCK in cardiac myocytes

Fetal mice express high levels of CCK mRNA in cardiac myocytes (128). Accordingly, adult cardiomyocytes in mice, rats, and pigs contain substantial amounts of the proCCK protein (129). The processing, however, of cardiac proCCK is unique, as the end product of the posttranslational maturation is a long triple-sulfated and N-terminally truncated fragment 25–94 with only trace amounts of the conventionally amidated and sulfated CCK peptides (129). The tissue concentration of the long proCCK fragment is higher in atrial than ventricular myocytes. The proCCK25-94 fragment is released to plasma and may find use as a marker of the risk of mortality in heart failure patients (129). The fate of the corresponding N-terminal 1–24 fragment of proCCK has remained obscure in spite of several attempts to find it.

CCK in tumor cells

The cholecystokinin gene is expressed at highly variable amounts in different neuroendocrine tumors, especially corticotrophic pituitary tumors (130), medullary thyroid carcinomas (116), phaeochromocytomas (118), and pancreatic islet cell tumors of which some may cause a specific clinical CCKoma syndrome (131, 132, 133, 134). The CCK gene is also expressed in Ewing’s sarcomas, where proCCK is apparently is poorly processed. However, specific proCCK measurements may be used to monitor the treatment of sarcomas (135). Cerebral gliomas, astrocytomas, and acoustic neuromas also express CCK peptides (136, 137, 138). The present knowledge about tumor expression of CCK has been summarized in a recent review that also discusses measurements of CCK and proCCK in plasma as tumor markers (139).

Concluding comments

Since the structural identification of CCK half a century ago as a single peptide with a sequence of 33 amino acid residues (CCK-33), the CCK story has been full of major, unexpected revelations: First, it was shown that the bioactive C-terminus of CCK was similar to that of the gastrins and those of amphibian skin peptides as well as protochordean and insect neuropeptides. Moreover, CCK and gastrin peptides all turned out to be agonists for one of the two CCK receptors, the CCK2 receptor. In the late 1970s and in the 80s, it was also demonstrated that bioactive CCK occurs in multiple molecular forms – from CCK-58 to CCK-5 with and without tyrosyl O-sulfations – as a consequence of complex, cell-specific posttranslational maturation processes. At variable intervals, it was subsequently shown that CCK peptides are expressed all over the body: abundantly in central and peripheral neurons as potent neurotransmitters, in intestinal and extraintestinal endocrine cells as classical hormones, in germ cells as putative fertility factors, in cardiac myocytes for unknown reasons, and in immune cells of significance for inflammatory diseases. Finally, the proCCK maturation appears to be cell specific also in tumors expressing the CCK gene. The tumors therefore release a multifaceted pattern of CCK peptides that may cause a specific CCKoma syndrome. In summary, CCK should today be seen as a rather ubiquitous system of intercellular messenger peptides.

A point is, however, that CCK is only one example of a hormonal peptide system with a molecular and cellular complexity as described previously. In fact, all gastrointestinal peptide hormones (ghrelin, gastrin, secretin, the gut glucagons, neurotensin, the tachykinins, somatostatin, etc.) are also complex systems widely expressed in multiple bioactive forms both within and outside the gastrointestinal tract. And similar features are seen for extraintestinal peptide hormones such as the calcitonins, parathyroid hormones, and neuropeptides originally discovered in extracts of central and peripheral nervous tissue. In other words, most peptide hormones have a wide range of activities, of which only some are due to peptide messengers traveling via blood (for reviews, see 140).

This situation challenges the classical hormone concept. Etymologically, the Greek origin of the word ‘hormone’ (hormoa) means ‘I arouse to activity’, which is exactly what bioactive peptides do irrespective of the routes to their targets. Consequently, there are now biological as well as etymological reasons for expansion of the hormone concept to cover all bioactive messenger molecules whose target cells express specific receptors.

Ernest Starling was in good faith when he introduced the word ‘hormone’ as a designation for blood-borne messenger molecules 116 years ago (1). Secretin and blood-borne regulation as an alternative supplement to neural regulation was indeed a decisive paradigmatic shift in physiology (1, 2). Starling could not know that the same peptides acted both as neurotransmitters and blood-borne messengers – not to speak of further roles as growth factors, fertility factors, cytokines, myokines, and adipokines.

Declaration of interest

The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Acknowledgements

The author wishes to thank Connie Bundgaard (MA) for excellent and patient help in the writing of this review. The CCK research in the laboratory of the author was initiated fifty years ago, and has been supported by the Danish Medical Research Council, the Danish Cancer Union, the Novo Nordic Foundation, the Lundbeck Foundation, and the State Biotechnology ‘Center for Cellular Communication’.

References

  • 1

    Starling EH The Croonian Lectures: on the chemical correlation of the functions of the body. Lancet 1905 2 339441; 423425; 501503; 579583.

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  • 2

    Bayliss WM & Starling EH The mechanism of pancreatic secretion. Journal of Physiology 1902 28 325353. (https://doi.org/10.1113/jphysiol.1902.sp000920)

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    • Export Citation
  • 3

    Edkins JS The chemical mechanism of gastric secretion. Journal of Physiology 1906 34 133144. (https://doi.org/10.1113/jphysiol.1906.sp001146)

    • Search Google Scholar
    • Export Citation
  • 4

    Pavlov IP Beiträge zur Physiologie der Absonderung. Zeitblatt für Physiologie 1888 2 137138.

  • 5

    Popielsky LB Über das periferische reflektorische Nervencentrum Des Pankreas. Pflügers Archiv für Physiologie 1901 86 215246.

  • 6

    Makhlouf GMEd). Neural and endocrine biology of the gastrointestinal system In Handbook of Physiology, Vol. 6/II, pp. 1722. Bethesda, Maryland: American Physiological Society, 1989.

    • Search Google Scholar
    • Export Citation
  • 7

    Walsh JH, Dockray GJ, . Gut peptides: biochemistry and physiology. In The Endocrinologist, Vol. 4, pp. 1884. New York: Raven Press, 1994. (https://doi.org/10.1097/00019616-199411000-00012)

    • Search Google Scholar
    • Export Citation
  • 8

    Belfiore A, LeRoith D. In Principles of Endocrinology and Hormone Action, pp 1–796. Springer International Publishing AG, 2018.

    • Export Citation
  • 9

    Rehfeld JF The endocrine gut. In Principles of Endocrinology and Hormone Action. Endocrinology, pp. 517531. Eds Belfiore A, LeRoith D Springer International Publishing AG, 2018. (https://doi.org/10.1007/978-3-319-44675-2_19)

    • Search Google Scholar
    • Export Citation
  • 10

    Rehfeld JF The new biology of gastrointestinal hormones. Physiological Reviews 1998 78 10871108. (https://doi.org/10.1152/physrev.1998.78.4.1087)

    • Search Google Scholar
    • Export Citation
  • 11

    Ivy AC & Oldberg E Hormone mechanism for gallbladder contraction and evacuation. American Journal of Physiology 1928 86 599613. (https://doi.org/10.1152/ajplegacy.1928.86.3.599)

    • Search Google Scholar
    • Export Citation
  • 12

    Babkin BP Die Sekretorische Tätigkeit der Verdauungsdrüsen. In Handbuch Der Normalen und Patologischen Physiologie, Vol. 3/II, pp. 689818. Berlin: Springer Verlag, 1927.

    • Search Google Scholar
    • Export Citation
  • 13

    Jorpes JE & Mutt V The discovery of cholecystokinin. In Secretin, Cholecystokinin, Pancreozymin and Gastrin. Handbook of Experimental Pharmacology, Vol. XXXIV, pp. 1618. Eds Jorpes JE, Mutt V Berlin, Heidelberg, New York: Springer Verlag, 1973.

    • Search Google Scholar
    • Export Citation
  • 14

    Bernard C Mémoire sur le pancreas. Compte Rendue de Academie de Science 1856 (Supplement 1) 379563.

  • 15

    Wertheimer E De l’action des acides et du chloral sur la sécrétion biliaire. Compte Rendue de Societé Biologique 1903 55 286287.

  • 16

    Fleig C Réflex de l’acide sur la secretion biliaire. Compte Rendue de Societe Biologique 1903 55 353355.

  • 17

    Okada S On the secretion of bile. Journal of Physiology 1915 49 457482. (https://doi.org/10.1113/jphysiol.1915.sp001722)

  • 18

    Ivy AC, Oldberg E, Kloster G & Lueth HC A hormone mechanism for gallbladder contraction. American Journal of Physiology 1928 85 381383.

  • 19

    Ivy AC, Kloster G, Lueth HC & Drewyer GE On the preparation of ‘cholecystokinin’. American Journal of Physiology: Legacy Content 1929 91 336344. (https://doi.org/10.1152/ajplegacy.1929.91.1.336)

    • Search Google Scholar
    • Export Citation
  • 20

    Ivy AC & Oldberg E Contraction and evacuation of gallbladders caused by a highly purified ‘secretin’ preparation. Proceedings of the Society for Experimental Biology 1927 25 113115. (https://doi.org/10.3181/00379727-25-3724)

    • Search Google Scholar
    • Export Citation
  • 21

    Ivy AC Motor dysfunction of the biliary tract; an analytical and critical consideration. American Journal of Roentgenology and Radium Therapy 1947 57 111.

    • Search Google Scholar
    • Export Citation
  • 22

    Harper AA & Raper HS Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. Journal of Physiology 1943 102 115125. (https://doi.org/10.1113/jphysiol.1943.sp004021)

    • Search Google Scholar
    • Export Citation
  • 23

    Greengard H, Grossman MI, Woolley JR & Ivy AC A confirmation of the presence of pancreozymin in the duodenal mucosa. Science 1944 99 350351. (https://doi.org/10.1126/science.99.2574.350)

    • Search Google Scholar
    • Export Citation
  • 24

    Duncan PR, Harper AA, Howat HT, Oleesky S & Varley H The effects of pancreozymin on human subjects. Journal of Physiology 1950 111 63p.

  • 25

    Duncan PR, Evans DG, Harper AA, Howat HT, Oleesky S, Scott JE & Varley H The use of the cholecystokinetic agent in preparations of pancreozymin to study gall bladder function in man. Journal of Physiology 1953 121 19P20P.

    • Search Google Scholar
    • Export Citation
  • 26

    Dale HH & Laidlaw PP A method of preparing secretin. Journal of Physiology 1912 44 11P.

  • 27

    Hammarsten E, Wilander O & Ågren G Versuche zur Reinigung von Secretin. Acta Medica Scandinavia 1928 68 239247.

  • 28

    Mellanby JM The isolation of secretin – its chemical and physiological properties. Journal of Physiology 1928 66 118. (https://doi.org/10.1113/jphysiol.1928.sp002503)

    • Search Google Scholar
    • Export Citation
  • 29

    Mortimer B & Ivy AC An attempt to repeat the Mellanby procedure for the isolation and purification of secretin. American Journal of Physiology: Legacy Content 1929 91 220224. (https://doi.org/10.1152/ajplegacy.1929.91.1.220)

    • Search Google Scholar
    • Export Citation
  • 30

    Jorpes JE & Mutt V Purification and isolation of secretin: early attempts. In Secretin, Cholecystokinin, Pancreozymin and Gastrin. Handbook of Experimental Pharmacology, Vol. 34, pp. 69. Eds Jorpes JE, Mutt V Berlin, Heidelberg, New York: Springer Verlag, 1973.

    • Search Google Scholar
    • Export Citation
  • 31

    Ågren G On preparation of cholecystokinin. Scandinavian Archives of Physiology 1939 81 234243.

  • 32

    Rehfeld JF Beginnings: a reflection on the history of gastrointestinal endocrinology. Regulatory Peptides 2012 177 (Supplement) S1S5. (https://doi.org/10.1016/j.regpep.2012.05.087)

    • Search Google Scholar
    • Export Citation
  • 33

    Jorpes JE & Mutt V A new method for the preparation of secretin. Archiv för Kemi 1953 6 273276.

  • 34

    Jorpes E, Mutt V & Sillén LG On the biological activity and amino acid composition of secretin. Acta Chemica Scandinavica 1961 15 17901791. (https://doi.org/10.3891/acta.chem.scand.15-1790)

    • Search Google Scholar
    • Export Citation
  • 35

    Straus E & Yalow RS Immunoreactive secretin in gastrointestinal mucosa of several mammalian species. Gastroenterology 1978 75 401404. (https://doi.org/10.1016/0016-5085(7890840-5)

    • Search Google Scholar
    • Export Citation
  • 36

    Rehfeld JF Immunochemical studies on cholecystokinin. II. Distribution and molecular heterogeneity in the central nervous system and small intestine of man and hog. Journal of Biological Chemistry 1978 253 40224030. (https://doi.org/10.1016/S0021-9258(1734793-2)

    • Search Google Scholar
    • Export Citation
  • 37

    Mutt V, Jorpes JE & Magnusson S Structure of porcine secretin. The amino acid sequence. European Journal of Biochemistry 1970 15 513519. (https://doi.org/10.1111/j.1432-1033.1970.tb01034.x)

    • Search Google Scholar
    • Export Citation
  • 38

    Mutt V & Jorpes JE Structure of porcine cholecystokinin-pancreozymin. I. Cleavage with thrombin and with trypsin. European Journal of Biochemistry 1968 6 156162. (https://doi.org/10.1111/j.1432-1033.1968.tb00433.x)

    • Search Google Scholar
    • Export Citation
  • 39

    Mutt V & Jorpes E Hormonal polypeptides of the upper intestine. Biochemical Journal 1971 125 57P58P. (https://doi.org/10.1042/bj1250057p)

  • 40

    Jorpes E & Mutt V Cholecystokinin and pancreozymin, one single hormone? Acta Physiologica Scandinavica 1966 66 196202. (https://doi.org/10.1111/j.1748-1716.1966.tb03185.x)

    • Search Google Scholar
    • Export Citation
  • 41

    Mutt V & Jorpes JE Secretin and cholecystokinin. In Advances in Experimental Medicine and Biology, pp. 569580. New York: Plenum Press, 1968. (https://doi.org/10.1007/978-1-4614-4612-5_67)

    • Search Google Scholar
    • Export Citation
  • 42

    Grossman MI Proposal: use the term cholecystokinin in place of cholecystokinin-pancreozynin. Gastroenterology 1970 58 128. (https://doi.org/10.1016/S0016-5085(7080107-X)

    • Search Google Scholar
    • Export Citation
  • 43

    Gregory RA & Tracy HJ The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 1964 5 103114. (https://doi.org/10.1136/gut.5.2.103)

    • Search Google Scholar
    • Export Citation
  • 44

    Gregory H, Hardy PM, Jones DS, Kenner GW & Sheppard RC The antral hormone gastrin. Structure of gastrin. Nature 1964 204 931933. (https://doi.org/10.1038/204931a0)

    • Search Google Scholar
    • Export Citation
  • 45

    Anastasi A, Erspamer V & Endean R Isolation and amino acid sequence of caerulein, the active decapeptide of the skin of Hyla caerulea. Archives of Biochemistry and Biophysics 1968 125 5768. (https://doi.org/10.1016/0003-9861(6890638-3)

    • Search Google Scholar
    • Export Citation
  • 46

    Anastasi A, Bertaccini G, Cei JM, De Caro G, Erspamer V & Impicciatore M Structure and pharmacological actions of phyllocaerulein, a caerulein-like nonapeptide: its occurrence in extracts of the skin of Phyllomedusa Sauvagei and related Phyllomedusa species. British Journal of Pharmacology 1969 37 198206. (https://doi.org/10.1111/j.1476-5381.1969.tb09538.x)

    • Search Google Scholar
    • Export Citation
  • 47

    Johnsen AH & Rehfeld JF Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. Journal of Biological Chemistry 1990 265 30543058. (https://doi.org/10.1016/S0021-9258(1939732-7)

    • Search Google Scholar
    • Export Citation
  • 48

    Larsson LI & Rehfeld JF Evidence for a common evolutionary origin of gastrin and cholecystokinin. Nature 1977 269 335338. (https://doi.org/10.1038/269335a0)

    • Search Google Scholar
    • Export Citation
  • 49

    Nachman RJ, Holman GM, Haddon WF & Ling N Leucosulfakinin, a sulfated insect neuropeptide with homology to gastrin and cholecystokinin. Science 1986 234 7173. (https://doi.org/10.1126/science.3749893)

    • Search Google Scholar
    • Export Citation
  • 50

    Nichols R, Schneuwly SA & Dixon JE Identification and characterization of a Drosophila homologue to the vertebrate neuropeptide cholecystokinin. Journal of Biological Chemistry 1988 263 1216712170. (https://doi.org/10.1016/S0021-9258(1837731-7)

    • Search Google Scholar
    • Export Citation
  • 51

    Johnsen AH Phylogeny of the cholecystokinin/gastrin family. Frontiers in Neuroendocrinology 1998 19 7399. (https://doi.org/10.1006/frne.1997.0163)

    • Search Google Scholar
    • Export Citation
  • 52

    Baldwin GS, Patel O & Shulkes A Evolution of gastrointestinal hormones: the cholecystokinin/gastrin family. Current Opinion in Endocrinology, Diabetes, and Obesity 2010 17 7788. (https://doi.org/10.1097/MED.0b013e328334e535)

    • Search Google Scholar
    • Export Citation
  • 53

    Dupré D & Tostivint H Evolution of the gastrin-cholecystokinin gene family revealed by synteny analysis. General and Comparative Endocrinology 2014 195 164173. (https://doi.org/10.1016/j.ygcen.2013.10.019)

    • Search Google Scholar
    • Export Citation
  • 54

    Ondetti MA, Rubin B, Engel SL, Pluscec J & Sheehan JT Cholecystokinin-pancreozymin: recent developments. American Journal of Digestive Diseases 1970 15 149156. (https://doi.org/10.1007/BF02235646)

    • Search Google Scholar
    • Export Citation
  • 55

    Dockray GJ Immunoreactive component resembling cholecystokinin octapeptide in intestine. Nature 1977 270 359361. (https://doi.org/10.1038/270359a0)

    • Search Google Scholar
    • Export Citation
  • 56

    Eng J, Du BH, Pan YC, Chang M, Hulmes JD & Yalow RS Purification and sequencing of a rat intestinal 22 amino acid C-terminal CCK fragment. Peptides 1984 5 12031206. (https://doi.org/10.1016/0196-9781(8490188-8)

    • Search Google Scholar
    • Export Citation
  • 57

    Eysselein VE, Reeve Jr JR, Shively JE, Hawke D & Walsh JH Partial structure of a large canine cholecystokinin (CCK58): amino acid sequence. Peptides 1982 3 687691. (https://doi.org/10.1016/0196-9781(8290171-1)

    • Search Google Scholar
    • Export Citation
  • 58

    Shively J, Reeve Jr JR, Eysselein VE, Ben-Avram C, Vigna SR & Walsh JH CCK-5: sequence analysis of a small cholecystokinin from canine brain and intestine. American Journal of Physiology 1987 252 G272G275. (https://doi.org/10.1152/ajpgi.1987.252.2.G272)

    • Search Google Scholar
    • Export Citation
  • 59

    Agersnap M & Rehfeld JF Nonsulfated cholecystokinins in the small intestine of pigs and rats. Peptides 2015 71 121127. (https://doi.org/10.1016/j.peptides.2015.07.010)

    • Search Google Scholar
    • Export Citation
  • 60

    Rehfeld JF & Hansen HF Characterization of preprocholecystokinin products in the porcine cerebral cortex. Evidence of different processing pathways. Journal of Biological Chemistry 1986 261 58325840. (https://doi.org/10.1016/S0021-9258(1738458-2)

    • Search Google Scholar
    • Export Citation
  • 61

    Deschenes RJ, Haun RS, Funckes CL & Dixon JE A gene encoding rat cholecystokinin. Isolation, nucleotide sequence, and promoter activity. Journal of Biological Chemistry 1985 260 12801286. (https://doi.org/10.1016/S0021-9258(2071240-8)

    • Search Google Scholar
    • Export Citation
  • 62

    Rehfeld JF, Bundgaard JR, Hannibal J, Zhu X, Norrbom C, Steiner DF & Friis-Hansen L The cell-specific pattern of cholecystokinin peptides in endocrine cells versus neurons is governed by the expression of prohormone convertases 1/3, 2, and 5/6. Endocrinology 2008 149 16001608. (https://doi.org/10.1210/en.2007-0278)

    • Search Google Scholar
    • Export Citation
  • 63

    Rehfeld JF, Sun G, Christensen T & Hillingsø JG The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. Journal of Clinical Endocrinology and Metabolism 2001 86 251258. (https://doi.org/10.1210/jcem.86.1.7148)

    • Search Google Scholar
    • Export Citation
  • 64

    Rehfeld JF & Agersnap M Unsulfated cholecystokinin: an overlooked hormone? Regulatory Peptides 2012 173 15. (https://doi.org/10.1016/j.regpep.2011.09.009)

    • Search Google Scholar
    • Export Citation
  • 65

    Rehfeld JF & van Solinge WW The tumor biology of gastrin and cholecystokinin. Advances in Cancer Research 1994 63 295347. (https://doi.org/10.1016/s0065-230x(0860403-0)

    • Search Google Scholar
    • Export Citation
  • 66

    Rehfeld JF The endoproteolytic maturation of progastrin and procholecystokinin. Journal of Molecular Medicine 2006 84 544550. (https://doi.org/10.1007/s00109-006-0055-3)

    • Search Google Scholar
    • Export Citation
  • 67

    Rehfeld JF, Friis-Hansen L, Goetze JP & Hansen TvOH The biology of cholecystokinin and gastrin peptides. Current Topics of Medicinal Chemistry 2007 7 11541165.

    • Search Google Scholar
    • Export Citation
  • 68

    Buffa R, Solcia E & Go VLW Immunohistochemical identification of the cholecystokinin cell in the intestinal mucosa. Gastroenterology 1976 70 528532. (https://doi.org/10.1016/S0016-5085(7680490-8)

    • Search Google Scholar
    • Export Citation
  • 69

    Larsson LI & Rehfeld JF Distribution of gastrin and CCK cells in the rat gastrointestinal tract. Evidence for the occurrence of three distinct cell types storing COOH-terminal gastrin immunoreactivity. Histochemistry 1978 58 2331. (https://doi.org/10.1007/BF00489946)

    • Search Google Scholar
    • Export Citation
  • 70

    Liddle RA, Goldfine ID, Rosen MS, Taplitz RA & Williams JA Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. Journal of Clinical Investigation 1985 75 11441152. (https://doi.org/10.1172/JCI111809)

    • Search Google Scholar
    • Export Citation
  • 71

    Rehfeld JF Accurate measurement of cholecystokinin in plasma. Clinical Chemistry 1998 44 9911001. (https://doi.org/10.1093/clinchem/44.5.991)

    • Search Google Scholar
    • Export Citation
  • 72

    Himeno S, Tarui S, Kanayama S, Kuroshima T, Shinomura Y, Hayashi C, Tateishi K, Imagawa K, Hashimura E & Hamaoka T Plasma cholecystokinin responses after ingestion of liquid meal and intraduodenal infusion of fat, amino acids, or hydrochloric acid in man: analysis with region specific radioimmunoassay. American Journal of Gastroenterology 1983 78 703707.

    • Search Google Scholar
    • Export Citation
  • 73

    McLaughlin J, Lucà MG, Jones MN, D’Amato M, Dockray GJ & Thompson DG Fatty acid chain length determines cholecystokinin secretion and effect on human gastric motility. Gastroenterology 1999 116 4653. (https://doi.org/10.1016/s0016-5085(9970227-1)

    • Search Google Scholar
    • Export Citation
  • 74

    Feltrin KL, Little TJ, Meyer JH, Horowitz M, Smout AJPM, Wishart J, Pilichiewicz AN, Rades T, Chapman IM & Feinle-Bisset C Effects of intraduodenal fatty acids on appetite, antropyloroduodenal motility, and plasma CCK and GLP-1 in humans vary with their chain length. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 2004 287 R524R533. (https://doi.org/10.1152/ajpregu.00039.2004)

    • Search Google Scholar
    • Export Citation
  • 75

    Beglinger C & Degen L Fat in the intestine as a regulator of appetite – role of CCK. Physiology and Behavior 2004 83 617621. (https://doi.org/10.1016/j.physbeh.2004.07.031)

    • Search Google Scholar
    • Export Citation
  • 76

    Martinussen C, Dirksen C, Bojsen-Møller KN, Svane MS, Carlsson ER, Hartmann B, Clausen TR, Veedfald S, Kristiansen VB & Rehfeld JF et al. Intestinal sensing and handling of dietary lipids in gastric bypass-operated patients and matched controls. American Journal of Clinical Nutrition 2020 111 2841. (https://doi.org/10.1093/ajcn/nqz272)

    • Search Google Scholar
    • Export Citation
  • 77

    Wölnerhanssen BK, Cajacob L, Keller N, Doody A, Rehfeld JF, Drewe J, Peterli R, Beglinger C & Meyer-Gerspach AC Gut hormone secretion, gastric emptying, and glycemic responses to erythritol and xylitol in lean and obese subjects. American Journal of Physiology: Endocrinology and Metabolism 2016 310 E1053E1061. (https://doi.org/10.1152/ajpendo.00037.2016)

    • Search Google Scholar
    • Export Citation
  • 78

    Meyer-Gerspach AC, Biesiekierski JR, Deloose E, Clevers E, Rotondo A, Rehfeld JF, Depoortere I, Van Oudenhove L & Tack J Effects of caloric and noncaloric sweeteners on antroduodenal motility, gastrointestinal hormone secretion and appetite-related sensations in healthy subjects. American Journal of Clinical Nutrition 2018 107 707716. (https://doi.org/10.1093/ajcn/nqy004)

    • Search Google Scholar
    • Export Citation
  • 79

    Fakhry J, Joyce Wang J, Martins P, Fothergill LJ, Hunne B, Prieur P, Shulkes A, Rehfeld JF, Callaghan B & Furness JB Distribution and characterisation of CCK containing enteroendocrine cells of the mouse small and large intestine. Cell and Tissue Research 2017 369 245253. (https://doi.org/10.1007/s00441-017-2612-1)

    • Search Google Scholar
    • Export Citation
  • 80

    Larsson LI & Rehfeld JF Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Research 1979 165 201218. (https://doi.org/10.1016/0006-8993(7990554-7)

    • Search Google Scholar
    • Export Citation
  • 81

    Wank SA, Harkins R, Jensen RT, Shapira H, de Weerth A & Slattery T Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. PNAS 1992 89 31253129. (https://doi.org/10.1073/pnas.89.7.3125)

    • Search Google Scholar
    • Export Citation
  • 82

    Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY, Kolakowski Jr LF & Beinborn M Expression cloning and characterization of the canine parietal cell gastrin receptor. PNAS 1992 89 36053609. (https://doi.org/10.1073/pnas.89.8.3605)

    • Search Google Scholar
    • Export Citation
  • 83

    Dufresne M, Seva C & Fourmy D Cholecystokinin and gastrin receptors. Physiological Reviews 2006 86 805847. (https://doi.org/10.1152/physrev.00014.2005)

    • Search Google Scholar
    • Export Citation
  • 84

    Chen D, Zhao CM, Håkanson R, Samuelson LC, Rehfeld JF & Friis-Hansen L Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology 2004 126 476487. (https://doi.org/10.1053/j.gastro.2003.11.012)

    • Search Google Scholar
    • Export Citation
  • 85

    Smith GP, Jerome C, Cushin BJ, Eterno R & Simansky KJ Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 1981 213 10361037. (https://doi.org/10.1126/science.7268408)

    • Search Google Scholar
    • Export Citation
  • 86

    Chen D, Monstein HJ, Nylander AG, Zhao CM, Sundler F & Håkanson R Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation. Gastroenterology 1994 107 1827. (https://doi.org/10.1016/0016-5085(9490056-6)

    • Search Google Scholar
    • Export Citation
  • 87

    Reubi JC, Waser B, Gugger M, Friess H, Kleeff J, Kayed H, Büchler MW & Laissue JA Distribution of CCK1 and CCK2 receptors in normal and diseased human pancreatic tissue. Gastroenterology 2003 125 98106. (https://doi.org/10.1016/s0016-5085(0300697-8)

    • Search Google Scholar
    • Export Citation
  • 88

    Rehfeld JF Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides. Acta Physiologica 2011 201 405411. (https://doi.org/10.1111/j.1748-1716.2010.02235.x)

    • Search Google Scholar
    • Export Citation
  • 89

    Liddle RA, Goldfine ID & Williams JA Bioassay of plasma cholecystokinin in rats: effects of food, trypsin inhibitor, and alcohol. Gastroenterology 1984 87 542549. (https://doi.org/10.1016/0016-5085(8490524-9)

    • Search Google Scholar
    • Export Citation
  • 90

    Otsuki M, Okabayashi Y, Nakamura T, Fujii M, Tani S, Fujisawa T, Koide M & Baba S Bioassay of plasma cholecystokinin in rat and human: inhibition of protein synthesis prevents the decrease in the sensitivity and responsiveness of isolated rat pancreatic acini to CCK-8. Pancreas 1989 4 447451. (https://doi.org/10.1097/00006676-198908000-00009)

    • Search Google Scholar
    • Export Citation
  • 91

    Rehfeld JF Immunochemical studies on cholecystokinin. I. Development of sequence-specific radioimmunoassays for porcine triacontatriapeptide cholecystokinin. Journal of Biological Chemistry 1978 253 40164021. (https://doi.org/10.1016/S0021-9258(1734792-0)

    • Search Google Scholar
    • Export Citation
  • 92

    Rehfeld JF How to measure cholecystokinin in plasma? Gastroenterology 1984 87 434438. (https://doi.org/10.1016/0016-5085(8490726-1)

  • 93

    Rehfeld JF How to measure cholecystokinin in tissue, plasma and cerebrospinal fluid. Regulatory Peptides 1998 78 3139. (https://doi.org/10.1016/s0167-0115(9800133-5)

    • Search Google Scholar
    • Export Citation
  • 94

    Jacobsen O, Bardram L & Rehfeld JF The requirement for gastrin measurements. Scandinavian Journal of Clinical and Laboratory Investigation 1986 46 423426. (https://doi.org/10.3109/00365518609083693)

    • Search Google Scholar
    • Export Citation
  • 95

    Rehfeld JF On measurement of cholecystokinin in plasma with reference to obesity studies. Nutrition Research 2020 76 18. (https://doi.org/10.1016/j.nutres.2020.01.003)

    • Search Google Scholar
    • Export Citation
  • 96

    Vanderhaeghen JJ, Signeau JC & Gepts W New peptide in the vertebrate CNS reacting with antigastrin antibodies. Nature 1975 257 604605. (https://doi.org/10.1038/257604a0)

    • Search Google Scholar
    • Export Citation
  • 97

    Dockray GJ Immunochemical evidence of cholecystokinin-like peptides in brain. Nature 1976 264 568570. (https://doi.org/10.1038/264568a0)

    • Search Google Scholar
    • Export Citation
  • 98

    Rehfeld JF Gastrins and cholecystokinins in brain and gut. Acta Pharmacology and Toxicology 1977 41 2425.

  • 99

    Muller JE, Straus E & Yalow RS Cholecystokinin and its COOH-terminal octapeptide in the pig brain. PNAS 1977 74 30353037. (https://doi.org/10.1073/pnas.74.7.3035)

    • Search Google Scholar
    • Export Citation
  • 100

    Dockray GJ, Gregory RA, Hutchison JB, Harris JI & Runswick MJ Isolation, structure and biological activity of two cholecystokinin octapeptides from sheep brain. Nature 1978 274 711713. (https://doi.org/10.1038/274711a0)

    • Search Google Scholar
    • Export Citation
  • 101

    Dodd J & Kelly JS Cholecystokinin peptides: excitatory effect on hippocampal neurons. Journal of Physiology 1979 195 61P.

  • 102

    Emson PC, Lee CM & Rehfeld JF Cholecystokinin octapeptide: vesicular localization and calcium dependent release from rat brain in vitro. Life Sciences 1980 26 21572163. (https://doi.org/10.1016/0024-3205(8090603-7)

    • Search Google Scholar
    • Export Citation
  • 103

    Rehfeld JF Localisation of gastrins to neuro- and adenohypophysis. Nature 1978 271 771773. (https://doi.org/10.1038/271771a0)

  • 104

    Uvnäs-Wallensten K, Rehfeld JF, Larsson LI & Uvnäs B Heptadecapeptide gastrin in the vagal nerve. PNAS 1977 74 57075710. (https://doi.org/10.1073/pnas.74.12.5707)

    • Search Google Scholar
    • Export Citation
  • 105

    Hökfelt T, Rehfeld JF, Skirboll L, Ivemark B, Glodstein M & Markey K Evidence for co-existence of dopamine and CCK in mesolimbic neurons. Nature 1980 285 476478. (https://doi.org/10.1038/285476a0)

    • Search Google Scholar
    • Export Citation
  • 106

    Crawley JN Comparative distribution of cholecystokinin and other neuropeptides. Why is this peptide different from all other peptides? Annals of the New York Academy of Sciences 1985 448 18. (https://doi.org/10.1111/j.1749-6632.1985.tb29900.x)

    • Search Google Scholar
    • Export Citation
  • 107

    Fallon JH & Seroogy KB The distribution and some connections of cholecystokinin neurons in the rat brain. Annals of the New York Academy of Sciences 1985 448 121132. (https://doi.org/10.1111/j.1749-6632.1985.tb29912.x)

    • Search Google Scholar
    • Export Citation
  • 108

    Hendry SH, Jones EG & Beinfeld MC Cholecystokinin-immunoreactive neurons in rat and monkey cerebral cortex make symmetric synapses and have intimate associations with blood vessels. PNAS 1983 80 24002404. (https://doi.org/10.1073/pnas.80.8.2400)

    • Search Google Scholar
    • Export Citation
  • 109

    Vizi SE, Bertaccini G, Impicciatore M & Knoll J Evidence that acetylcholine released by gastrin and related polypeptides contributes to their effect on gastrointestinal motility. Gastroenterology 1973 64 268277. (https://doi.org/10.1016/S0016-5085(7380038-1)

    • Search Google Scholar
    • Export Citation
  • 110

    Larsson LI & Rehfeld JF Peptidergic and adrenergic innervation of pancreatic ganglia. Scandinavian Journal of Gastroenterology 1979 14 433437.

    • Search Google Scholar
    • Export Citation
  • 111

    Rehfeld JF, Larsson LI, Goltermann NR, Schwartz TW, Holst JJ, Jensen SL & Morley JS Neural regulation of pancreatic hormone secretion by the C-terminal tetrapeptide of CCK. Nature 1980 284 3338. (https://doi.org/10.1038/284033a0)

    • Search Google Scholar
    • Export Citation
  • 112

    Dockray GJ, Gregory RA, Tracy HJ & Zhu WY Transport of cholecystokinin-octapeptide-like immunoreactivity toward the gut in afferent vagal fibres in cat and dog. Journal of Physiology 1981 314 501511. (https://doi.org/10.1113/jphysiol.1981.sp013721)

    • Search Google Scholar
    • Export Citation
  • 113

    Rehfeld JF & Lundberg JM Cholecystokinin in feline vagal and sciatic nerves: concentration, molecular form and transport velocity. Brain Research 1983 275 341347. (https://doi.org/10.1016/0006-8993(8390995-2)

    • Search Google Scholar
    • Export Citation
  • 114

    Rehfeld JF Preprocholecystokinin processing in the normal human anterior pituitary. PNAS 1987 84 30193023. (https://doi.org/10.1073/pnas.84.9.3019)

    • Search Google Scholar
    • Export Citation
  • 115

    Rehfeld JF Accumulation of nonamidated preprogastrin and preprocholecystokinin products in porcine pituitary corticotrophs. Evidence of post-translational control of cell differentiation. Journal of Biological Chemistry 1986 261 58415847. (https://doi.org/10.1016/S0021-9258(1738459-4)

    • Search Google Scholar
    • Export Citation
  • 116

    Rehfeld JF, Johnsen AH, Odum L, Bardram L, Schifter S & Scopsi L Non-sulphated cholecystokinin in human medullary thyroid carcinomas. Journal of Endocrinology 1990 124 501506. (https://doi.org/10.1677/joe.0.1240501)

    • Search Google Scholar
    • Export Citation
  • 117

    Reubi JC & Waser B Unexpected high incidence of cholecystokinin-B/gastrin receptors in human medullary thyroid carcinomas. International Journal of Cancer 1996 67 644647. (https://doi.org/10.1002/(SICI)1097-0215(19960904)67:5<644::AID-IJC9>3.0.CO;2-U)

    • Search Google Scholar
    • Export Citation
  • 118

    Bardram L, Hilsted L & Rehfeld JF Cholecystokinin, gastrin and their precursors in pheochromocytomas. Acta Endocrinologica 1989 120 479484. (https://doi.org/10.1530/acta.0.1200479)

    • Search Google Scholar
    • Export Citation
  • 119

    Persson H, Ericsson A, Schalling M, Rehfeld JF & Hökfelt T Detection of cholecystokinin in spermatogenic cells. Acta Physiologica Scandinavica 1988 134 565566. (https://doi.org/10.1111/j.1748-1716.1998.tb08534.x)

    • Search Google Scholar
    • Export Citation
  • 120

    Persson H, Rehfeld JF, Ericsson A, Schalling M, Pelto-Huikko M & Hökfelt T Transient expression of the cholecystokinin gene in male germ cells and accumulation of the peptide in the acrosomal granule: possible role of cholecystokinin in fertilization. PNAS 1989 86 61666170. (https://doi.org/10.1073/pnas.86.16.6166)

    • Search Google Scholar
    • Export Citation
  • 121

    Schalling M, Persson H, Pelto-Huikko M, Odum L, Ekman P, Gottlieb C, Hökfelt T & Rehfeld JF Expression and localization of gastrin messenger RNA and peptide in spermatogenic cells. Journal of Clinical Investigation 1990 86 660669. (https://doi.org/10.1172/JCI114758)

    • Search Google Scholar
    • Export Citation
  • 122

    Okahata H, Nishi Y, Muraki K, Sumii K, Miyachi Y & Usui T Gastrin/cholecystokinin-like immunoreactivity in human blood cells. Life Sciences 1985 36 369373. (https://doi.org/10.1016/0024-3205(8590123-7)

    • Search Google Scholar
    • Export Citation
  • 123

    Sacerdote P, Breda M, Barcellini W, Meroni PL & Panerai AE Age-related changes of beta-endorphin and cholecystokinin in human and rat mononuclear cells. Peptides 1991 12 13531356. (https://doi.org/10.1016/0196-9781(9190219-f)

    • Search Google Scholar
    • Export Citation
  • 124

    De la Fuente M, Carrasco M, Del Rio M & Hernanz A Modulation of murine lymphocyte functions by sulfated cholecystokinin octapeptide. Neuropeptides 1998 32 225233. (https://doi.org/10.1016/s0143-4179(9890041-5)

    • Search Google Scholar
    • Export Citation
  • 125

    Carrasco M, Del Rio M, Hernanz A & de la Fuente M Inhibition of human neutrophil functions by sulfated and nonsulfated cholecystokinin octapeptides. Peptides 1997 18 415422. (https://doi.org/10.1016/s0196-9781(9600338-5)

    • Search Google Scholar
    • Export Citation
  • 126

    Meng AH, Ling YL, Zhang XP & Zhang JL Anti-inflammatory effect of cholecystokinin and its signal transduction mechanism in endotoxic shock rat. World Journal of Gastroenterology 2002 8 712717. (https://doi.org/10.3748/wjg.v8.i4.712)

    • Search Google Scholar
    • Export Citation
  • 127

    Li S, Ni Z, Cong B, Gao W, Xu S, Wang C, Yao Y, Ma C & Ling Y CCK-8 inhibits LPS-induced IL-1beta production in pulmonary interstitial macrophages by modulating PKA, p38, and NF-kappaB pathway. Shock 2007 27 678686. (https://doi.org/10.1097/shk.0b013e3180ze26dd)

    • Search Google Scholar
    • Export Citation
  • 128

    Lay JM, Gillespie PJ & Samuelson LC Murine prenatal expression of cholecystokinin in neural crest, enteric neurons, and enteroendocrine cells. Developmental Dynamics 1999 216 190200. (https://doi.org/10.1002/(SICI)1097-0177(199910)216:2<190::AID-DVDY9>3.0.CO;2-K)

    • Search Google Scholar
    • Export Citation
  • 129

    Goetze JP, Johnsen AH, Kistorp C, Gustafsson F, Johnbeck CB & Rehfeld JF Cardiomyocyte expression and cell-specific processing of procholecystokinin. Journal of Biological Chemistry 2015 290 68376843. (https://doi.org/10.1074/jbc.M114.622670)

    • Search Google Scholar
    • Export Citation
  • 130

    Rehfeld JF, Lindholm J, Andersen BN, Bardram L, Cantor P, Fenger M & Lüdecke DK Pituitary tumors containing cholecystokinin. New England Journal of Medicine 1987 316 12441247. (https://doi.org/10.1056/NEJM198705143162004)

    • Search Google Scholar
    • Export Citation
  • 131

    Madsen OD, Larsson LI, Rehfeld JF, Schwartz TW, Lernmark A, Labrecque AD & Steiner DF Cloned cell lines from a transplantable islet cell tumor are heterogeneous and express cholecystokinin in addition to islet hormones. Journal of Cell Biology 1986 103 20252034. (https://doi.org/10.1083/jcb.103.5.2025)

    • Search Google Scholar
    • Export Citation
  • 132

    Madsen OD, Karlsen C, Nielsen E, Lund K, Kofod H, Welinder B, Rehfeld JF, Larsson LI, Steiner DF & Holst JJ The dissociation of tumor-induced weight loss from hypoglycemia in a transplantable pluripotent rat islet tumor results in the segregation of stable alpha- and beta-cell tumor phenotypes. Endocrinology 1993 133 20222030. (https://doi.org/10.1210/endo.133.5.8404649)

    • Search Google Scholar
    • Export Citation
  • 133

    Rehfeld JF, Federspiel B & Bardram L A neuroendocrine tumor syndrome from cholecystokinin secretion. New England Journal of Medicine 2013 368 11651166. (https://doi.org/10.1056/NEJMc1215137)

    • Search Google Scholar
    • Export Citation
  • 134

    Rehfeld JF, Federspiel B, Agersnap M, Knigge U & Bardram L The uncovering and characterization of a CCKoma syndrome in enteropancreatic neuroendocrine tumor patients. Scandinavian Journal of Gastroenterology 2016 51 11721178. (https://doi.org/10.1080/00365521.2016.1183706)

    • Search Google Scholar
    • Export Citation
  • 135

    Reubi JC, Koefoed P, Hansen Tv, Stauffer E, Rauch D, Nielsen FC & Rehfeld JF Procholecystokinin as marker of human Ewing sarcomas. Clinical Cancer Research 2004 10 55235530. (https://doi.org/10.1158/1078-0432.CCR-1015-03)

    • Search Google Scholar
    • Export Citation
  • 136

    Oikonomou E, Buchfelder M & Adams EF Cholecystokinin (CCK) and CCK receptor expression by human gliomas: evidence for an autocrine/paracrine stimulatory loop. Neuropeptides 2008 42 255265. (https://doi.org/10.1016/j.npep.2008.02.005)

    • Search Google Scholar
    • Export Citation
  • 137

    Camby I, Salmon I, Danguy A, Pasteels JL, Brotchi J, Martinez J & Kiss R Influence of gastrin on human astrocytic tumor cell proliferation. Journal of the National Cancer Institute 1996 88 594600. (https://doi.org/10.1093/jnci/88.9.594)

    • Search Google Scholar
    • Export Citation
  • 138

    Rehfeld JF, van Solinge WW, Tos M & Thomsen J Gastrin, cholecystokinin and their precursors in acoustic neuromas. Brain Research 1990 530 235238. (https://doi.org/10.1016/0006-8993(9091288-r)

    • Search Google Scholar
    • Export Citation
  • 139

    Rehfeld JF Cholecystokinin expression in tumors: biogenetic and diagnostic implications. Future Oncology 2016 12 21352147. (https://doi.org/10.2217/fon-2015-0053)

    • Search Google Scholar
    • Export Citation
  • 140

    Kastin AJEd.). Handbook of Biologically Active Peptides, 2nd ed., pp. 11942. Amsterdam, New York, Paris: Academic Press/Elsevier, 2013.

    • Search Google Scholar
    • Export Citation
  • 141

    Cantor P, Petronijevic L, Pedersen JF & Worning H The cholecystokinetic effect of O-sulfated gastrin compared to non-sulfated gastrin and cholecystokinin. Gastroenterology 1986 91 11541163. (https://doi.org/10.1016/s0016-5085(8680011-7)

    • Search Google Scholar
    • Export Citation

 

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    The amino sequence of porcine cholecystokinin-33 (CCK-33), the originally identified CCK-peptide (Mutt & Jorpes (39)). The bioactive CCK-8 sequence (26, 27, 28, 29, 30, 31, 32, 33) is underlined. Only the amino acids in the encircled positions no. 7, 9, 10, and 15 differ from those in the human sequence (Met, Ile, Val, and Asn, respectively).

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    The bioactive sequences of peptide systems belonging to the cholecystokinin (CCK) family. CCK and the antral hormone, gastrin (43, 44), are the only mammalian members of the family. Caerulein and phyllocaerulein are identified from frog skin extracts (45, 46). Cionin is a neuropeptide isolated from the central ganglion of the protochord, ciona intestinalis (47). Note the unique disulfated sequence, which might suggest that cionin may resemble a common ancestor of CCK and gastrin (48). The core of the bioactive sequences, the common C-terminal tetrapeptide amide, is boxed. The lower panel shows the bioactive sequences of the insect neuropeptides, the sulfakinins, which are homologous to vertebrate and protochordian members of the CCK family (49, 50). Also their C-terminal tetrapeptide amide sequence is boxed.

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    The posttranslational maturation of preprocholecystokinin in the endocrine I-cells of the small intestine. Mono-and dibasic cleavage sites (arginyl (R) and lysyl (K) residues) are indicated on the schematic figure of preprocholecystokinin (upper part of the figure). In the remaining part of the figure, the asterisks (*) indicate tyrosyl O-sulfation sites on the procholecystokinin processing intermediates and bioactive endproducts. Decisive processing enzymes (sulfortransferases, prohormone convertases, carboxypeptidase E, and the amidation enzyme (pepdityl-glycyl-α-amidating monooxygenase complex (PAM)) are also mentioned at the cellular level of the posttranslational processing pathway, where they act. In the intestinal endocrine I-cells, prohormone convertase 1/3 (PC 1/3) is predominant, whereas prohormone convertase 2 (PC 2) predominates in cerebral CCK neurons (see also 62). CCK-83 has been identified in tissue extracts but not in plasma (63).

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    The concentrations of bioactive CCK in plasma vs gallbladder emptying during a mixed meal in normal human subjects. Data from (141) with permission.

  • 1

    Starling EH The Croonian Lectures: on the chemical correlation of the functions of the body. Lancet 1905 2 339441; 423425; 501503; 579583.

    • Search Google Scholar
    • Export Citation
  • 2

    Bayliss WM & Starling EH The mechanism of pancreatic secretion. Journal of Physiology 1902 28 325353. (https://doi.org/10.1113/jphysiol.1902.sp000920)

    • Search Google Scholar
    • Export Citation
  • 3

    Edkins JS The chemical mechanism of gastric secretion. Journal of Physiology 1906 34 133144. (https://doi.org/10.1113/jphysiol.1906.sp001146)

    • Search Google Scholar
    • Export Citation
  • 4

    Pavlov IP Beiträge zur Physiologie der Absonderung. Zeitblatt für Physiologie 1888 2 137138.

  • 5

    Popielsky LB Über das periferische reflektorische Nervencentrum Des Pankreas. Pflügers Archiv für Physiologie 1901 86 215246.

  • 6

    Makhlouf GMEd). Neural and endocrine biology of the gastrointestinal system In Handbook of Physiology, Vol. 6/II, pp. 1722. Bethesda, Maryland: American Physiological Society, 1989.

    • Search Google Scholar
    • Export Citation
  • 7

    Walsh JH, Dockray GJ, . Gut peptides: biochemistry and physiology. In The Endocrinologist, Vol. 4, pp. 1884. New York: Raven Press, 1994. (https://doi.org/10.1097/00019616-199411000-00012)

    • Search Google Scholar
    • Export Citation
  • 8

    Belfiore A, LeRoith D. In Principles of Endocrinology and Hormone Action, pp 1–796. Springer International Publishing AG, 2018.

    • Export Citation
  • 9

    Rehfeld JF The endocrine gut. In Principles of Endocrinology and Hormone Action. Endocrinology, pp. 517531. Eds Belfiore A, LeRoith D Springer International Publishing AG, 2018. (https://doi.org/10.1007/978-3-319-44675-2_19)

    • Search Google Scholar
    • Export Citation
  • 10

    Rehfeld JF The new biology of gastrointestinal hormones. Physiological Reviews 1998 78 10871108. (https://doi.org/10.1152/physrev.1998.78.4.1087)

    • Search Google Scholar
    • Export Citation
  • 11

    Ivy AC & Oldberg E Hormone mechanism for gallbladder contraction and evacuation. American Journal of Physiology 1928 86 599613. (https://doi.org/10.1152/ajplegacy.1928.86.3.599)

    • Search Google Scholar
    • Export Citation
  • 12

    Babkin BP Die Sekretorische Tätigkeit der Verdauungsdrüsen. In Handbuch Der Normalen und Patologischen Physiologie, Vol. 3/II, pp. 689818. Berlin: Springer Verlag, 1927.

    • Search Google Scholar
    • Export Citation
  • 13

    Jorpes JE & Mutt V The discovery of cholecystokinin. In Secretin, Cholecystokinin, Pancreozymin and Gastrin. Handbook of Experimental Pharmacology, Vol. XXXIV, pp. 1618. Eds Jorpes JE, Mutt V Berlin, Heidelberg, New York: Springer Verlag, 1973.

    • Search Google Scholar
    • Export Citation
  • 14

    Bernard C Mémoire sur le pancreas. Compte Rendue de Academie de Science 1856 (Supplement 1) 379563.

  • 15

    Wertheimer E De l’action des acides et du chloral sur la sécrétion biliaire. Compte Rendue de Societé Biologique 1903 55 286287.

  • 16

    Fleig C Réflex de l’acide sur la secretion biliaire. Compte Rendue de Societe Biologique 1903 55 353355.

  • 17

    Okada S On the secretion of bile. Journal of Physiology 1915 49 457482. (https://doi.org/10.1113/jphysiol.1915.sp001722)

  • 18

    Ivy AC, Oldberg E, Kloster G & Lueth HC A hormone mechanism for gallbladder contraction. American Journal of Physiology 1928 85 381383.

  • 19

    Ivy AC, Kloster G, Lueth HC & Drewyer GE On the preparation of ‘cholecystokinin’. American Journal of Physiology: Legacy Content 1929 91 336344. (https://doi.org/10.1152/ajplegacy.1929.91.1.336)

    • Search Google Scholar
    • Export Citation
  • 20

    Ivy AC & Oldberg E Contraction and evacuation of gallbladders caused by a highly purified ‘secretin’ preparation. Proceedings of the Society for Experimental Biology 1927 25 113115. (https://doi.org/10.3181/00379727-25-3724)

    • Search Google Scholar
    • Export Citation
  • 21

    Ivy AC Motor dysfunction of the biliary tract; an analytical and critical consideration. American Journal of Roentgenology and Radium Therapy 1947 57 111.

    • Search Google Scholar
    • Export Citation
  • 22

    Harper AA & Raper HS Pancreozymin, a stimulant of the secretion of pancreatic enzymes in extracts of the small intestine. Journal of Physiology 1943 102 115125. (https://doi.org/10.1113/jphysiol.1943.sp004021)

    • Search Google Scholar
    • Export Citation
  • 23

    Greengard H, Grossman MI, Woolley JR & Ivy AC A confirmation of the presence of pancreozymin in the duodenal mucosa. Science 1944 99 350351. (https://doi.org/10.1126/science.99.2574.350)

    • Search Google Scholar
    • Export Citation
  • 24

    Duncan PR, Harper AA, Howat HT, Oleesky S & Varley H The effects of pancreozymin on human subjects. Journal of Physiology 1950 111 63p.

  • 25

    Duncan PR, Evans DG, Harper AA, Howat HT, Oleesky S, Scott JE & Varley H The use of the cholecystokinetic agent in preparations of pancreozymin to study gall bladder function in man. Journal of Physiology 1953 121 19P20P.

    • Search Google Scholar
    • Export Citation
  • 26

    Dale HH & Laidlaw PP A method of preparing secretin. Journal of Physiology 1912 44 11P.

  • 27

    Hammarsten E, Wilander O & Ågren G Versuche zur Reinigung von Secretin. Acta Medica Scandinavia 1928 68 239247.

  • 28

    Mellanby JM The isolation of secretin – its chemical and physiological properties. Journal of Physiology 1928 66 118. (https://doi.org/10.1113/jphysiol.1928.sp002503)

    • Search Google Scholar
    • Export Citation
  • 29

    Mortimer B & Ivy AC An attempt to repeat the Mellanby procedure for the isolation and purification of secretin. American Journal of Physiology: Legacy Content 1929 91 220224. (https://doi.org/10.1152/ajplegacy.1929.91.1.220)

    • Search Google Scholar
    • Export Citation
  • 30

    Jorpes JE & Mutt V Purification and isolation of secretin: early attempts. In Secretin, Cholecystokinin, Pancreozymin and Gastrin. Handbook of Experimental Pharmacology, Vol. 34, pp. 69. Eds Jorpes JE, Mutt V Berlin, Heidelberg, New York: Springer Verlag, 1973.

    • Search Google Scholar
    • Export Citation
  • 31

    Ågren G On preparation of cholecystokinin. Scandinavian Archives of Physiology 1939 81 234243.

  • 32

    Rehfeld JF Beginnings: a reflection on the history of gastrointestinal endocrinology. Regulatory Peptides 2012 177 (Supplement) S1S5. (https://doi.org/10.1016/j.regpep.2012.05.087)

    • Search Google Scholar
    • Export Citation
  • 33

    Jorpes JE & Mutt V A new method for the preparation of secretin. Archiv för Kemi 1953 6 273276.

  • 34

    Jorpes E, Mutt V & Sillén LG On the biological activity and amino acid composition of secretin. Acta Chemica Scandinavica 1961 15 17901791. (https://doi.org/10.3891/acta.chem.scand.15-1790)

    • Search Google Scholar
    • Export Citation
  • 35

    Straus E & Yalow RS Immunoreactive secretin in gastrointestinal mucosa of several mammalian species. Gastroenterology 1978 75 401404. (https://doi.org/10.1016/0016-5085(7890840-5)

    • Search Google Scholar
    • Export Citation
  • 36

    Rehfeld JF Immunochemical studies on cholecystokinin. II. Distribution and molecular heterogeneity in the central nervous system and small intestine of man and hog. Journal of Biological Chemistry 1978 253 40224030. (https://doi.org/10.1016/S0021-9258(1734793-2)

    • Search Google Scholar
    • Export Citation
  • 37

    Mutt V, Jorpes JE & Magnusson S Structure of porcine secretin. The amino acid sequence. European Journal of Biochemistry 1970 15 513519. (https://doi.org/10.1111/j.1432-1033.1970.tb01034.x)

    • Search Google Scholar
    • Export Citation
  • 38

    Mutt V & Jorpes JE Structure of porcine cholecystokinin-pancreozymin. I. Cleavage with thrombin and with trypsin. European Journal of Biochemistry 1968 6 156162. (https://doi.org/10.1111/j.1432-1033.1968.tb00433.x)

    • Search Google Scholar
    • Export Citation
  • 39

    Mutt V & Jorpes E Hormonal polypeptides of the upper intestine. Biochemical Journal 1971 125 57P58P. (https://doi.org/10.1042/bj1250057p)

  • 40

    Jorpes E & Mutt V Cholecystokinin and pancreozymin, one single hormone? Acta Physiologica Scandinavica 1966 66 196202. (https://doi.org/10.1111/j.1748-1716.1966.tb03185.x)

    • Search Google Scholar
    • Export Citation
  • 41

    Mutt V & Jorpes JE Secretin and cholecystokinin. In Advances in Experimental Medicine and Biology, pp. 569580. New York: Plenum Press, 1968. (https://doi.org/10.1007/978-1-4614-4612-5_67)

    • Search Google Scholar
    • Export Citation
  • 42

    Grossman MI Proposal: use the term cholecystokinin in place of cholecystokinin-pancreozynin. Gastroenterology 1970 58 128. (https://doi.org/10.1016/S0016-5085(7080107-X)

    • Search Google Scholar
    • Export Citation
  • 43

    Gregory RA & Tracy HJ The constitution and properties of two gastrins extracted from hog antral mucosa. Gut 1964 5 103114. (https://doi.org/10.1136/gut.5.2.103)

    • Search Google Scholar
    • Export Citation
  • 44

    Gregory H, Hardy PM, Jones DS, Kenner GW & Sheppard RC The antral hormone gastrin. Structure of gastrin. Nature 1964 204 931933. (https://doi.org/10.1038/204931a0)

    • Search Google Scholar
    • Export Citation
  • 45

    Anastasi A, Erspamer V & Endean R Isolation and amino acid sequence of caerulein, the active decapeptide of the skin of Hyla caerulea. Archives of Biochemistry and Biophysics 1968 125 5768. (https://doi.org/10.1016/0003-9861(6890638-3)

    • Search Google Scholar
    • Export Citation
  • 46

    Anastasi A, Bertaccini G, Cei JM, De Caro G, Erspamer V & Impicciatore M Structure and pharmacological actions of phyllocaerulein, a caerulein-like nonapeptide: its occurrence in extracts of the skin of Phyllomedusa Sauvagei and related Phyllomedusa species. British Journal of Pharmacology 1969 37 198206. (https://doi.org/10.1111/j.1476-5381.1969.tb09538.x)

    • Search Google Scholar
    • Export Citation
  • 47

    Johnsen AH & Rehfeld JF Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate Ciona intestinalis. Journal of Biological Chemistry 1990 265 30543058. (https://doi.org/10.1016/S0021-9258(1939732-7)

    • Search Google Scholar
    • Export Citation
  • 48

    Larsson LI & Rehfeld JF Evidence for a common evolutionary origin of gastrin and cholecystokinin. Nature 1977 269 335338. (https://doi.org/10.1038/269335a0)

    • Search Google Scholar
    • Export Citation
  • 49

    Nachman RJ, Holman GM, Haddon WF & Ling N Leucosulfakinin, a sulfated insect neuropeptide with homology to gastrin and cholecystokinin. Science 1986 234 7173. (https://doi.org/10.1126/science.3749893)

    • Search Google Scholar
    • Export Citation
  • 50

    Nichols R, Schneuwly SA & Dixon JE Identification and characterization of a Drosophila homologue to the vertebrate neuropeptide cholecystokinin. Journal of Biological Chemistry 1988 263 1216712170. (https://doi.org/10.1016/S0021-9258(1837731-7)

    • Search Google Scholar
    • Export Citation
  • 51

    Johnsen AH Phylogeny of the cholecystokinin/gastrin family. Frontiers in Neuroendocrinology 1998 19 7399. (https://doi.org/10.1006/frne.1997.0163)

    • Search Google Scholar
    • Export Citation
  • 52

    Baldwin GS, Patel O & Shulkes A Evolution of gastrointestinal hormones: the cholecystokinin/gastrin family. Current Opinion in Endocrinology, Diabetes, and Obesity 2010 17 7788. (https://doi.org/10.1097/MED.0b013e328334e535)

    • Search Google Scholar
    • Export Citation
  • 53

    Dupré D & Tostivint H Evolution of the gastrin-cholecystokinin gene family revealed by synteny analysis. General and Comparative Endocrinology 2014 195 164173. (https://doi.org/10.1016/j.ygcen.2013.10.019)

    • Search Google Scholar
    • Export Citation
  • 54

    Ondetti MA, Rubin B, Engel SL, Pluscec J & Sheehan JT Cholecystokinin-pancreozymin: recent developments. American Journal of Digestive Diseases 1970 15 149156. (https://doi.org/10.1007/BF02235646)

    • Search Google Scholar
    • Export Citation
  • 55

    Dockray GJ Immunoreactive component resembling cholecystokinin octapeptide in intestine. Nature 1977 270 359361. (https://doi.org/10.1038/270359a0)

    • Search Google Scholar
    • Export Citation
  • 56

    Eng J, Du BH, Pan YC, Chang M, Hulmes JD & Yalow RS Purification and sequencing of a rat intestinal 22 amino acid C-terminal CCK fragment. Peptides 1984 5 12031206. (https://doi.org/10.1016/0196-9781(8490188-8)

    • Search Google Scholar
    • Export Citation
  • 57

    Eysselein VE, Reeve Jr JR, Shively JE, Hawke D & Walsh JH Partial structure of a large canine cholecystokinin (CCK58): amino acid sequence. Peptides 1982 3 687691. (https://doi.org/10.1016/0196-9781(8290171-1)

    • Search Google Scholar
    • Export Citation
  • 58

    Shively J, Reeve Jr JR, Eysselein VE, Ben-Avram C, Vigna SR & Walsh JH CCK-5: sequence analysis of a small cholecystokinin from canine brain and intestine. American Journal of Physiology 1987 252 G272G275. (https://doi.org/10.1152/ajpgi.1987.252.2.G272)

    • Search Google Scholar
    • Export Citation
  • 59

    Agersnap M & Rehfeld JF Nonsulfated cholecystokinins in the small intestine of pigs and rats. Peptides 2015 71 121127. (https://doi.org/10.1016/j.peptides.2015.07.010)

    • Search Google Scholar
    • Export Citation
  • 60

    Rehfeld JF & Hansen HF Characterization of preprocholecystokinin products in the porcine cerebral cortex. Evidence of different processing pathways. Journal of Biological Chemistry 1986 261 58325840. (https://doi.org/10.1016/S0021-9258(1738458-2)

    • Search Google Scholar
    • Export Citation
  • 61

    Deschenes RJ, Haun RS, Funckes CL & Dixon JE A gene encoding rat cholecystokinin. Isolation, nucleotide sequence, and promoter activity. Journal of Biological Chemistry 1985 260 12801286. (https://doi.org/10.1016/S0021-9258(2071240-8)

    • Search Google Scholar
    • Export Citation
  • 62

    Rehfeld JF, Bundgaard JR, Hannibal J, Zhu X, Norrbom C, Steiner DF & Friis-Hansen L The cell-specific pattern of cholecystokinin peptides in endocrine cells versus neurons is governed by the expression of prohormone convertases 1/3, 2, and 5/6. Endocrinology 2008 149 16001608. (https://doi.org/10.1210/en.2007-0278)

    • Search Google Scholar
    • Export Citation
  • 63

    Rehfeld JF, Sun G, Christensen T & Hillingsø JG The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. Journal of Clinical Endocrinology and Metabolism 2001 86 251258. (https://doi.org/10.1210/jcem.86.1.7148)

    • Search Google Scholar
    • Export Citation
  • 64

    Rehfeld JF & Agersnap M Unsulfated cholecystokinin: an overlooked hormone? Regulatory Peptides 2012 173 15. (https://doi.org/10.1016/j.regpep.2011.09.009)

    • Search Google Scholar
    • Export Citation
  • 65

    Rehfeld JF & van Solinge WW The tumor biology of gastrin and cholecystokinin. Advances in Cancer Research 1994 63 295347. (https://doi.org/10.1016/s0065-230x(0860403-0)

    • Search Google Scholar
    • Export Citation
  • 66

    Rehfeld JF The endoproteolytic maturation of progastrin and procholecystokinin. Journal of Molecular Medicine 2006 84 544550. (https://doi.org/10.1007/s00109-006-0055-3)

    • Search Google Scholar
    • Export Citation
  • 67

    Rehfeld JF, Friis-Hansen L, Goetze JP & Hansen TvOH The biology of cholecystokinin and gastrin peptides. Current Topics of Medicinal Chemistry 2007 7 11541165.

    • Search Google Scholar
    • Export Citation
  • 68

    Buffa R, Solcia E & Go VLW Immunohistochemical identification of the cholecystokinin cell in the intestinal mucosa. Gastroenterology 1976 70 528532. (https://doi.org/10.1016/S0016-5085(7680490-8)

    • Search Google Scholar
    • Export Citation
  • 69

    Larsson LI & Rehfeld JF Distribution of gastrin and CCK cells in the rat gastrointestinal tract. Evidence for the occurrence of three distinct cell types storing COOH-terminal gastrin immunoreactivity. Histochemistry 1978 58 2331. (https://doi.org/10.1007/BF00489946)

    • Search Google Scholar
    • Export Citation
  • 70

    Liddle RA, Goldfine ID, Rosen MS, Taplitz RA & Williams JA Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. Journal of Clinical Investigation 1985 75 11441152. (https://doi.org/10.1172/JCI111809)

    • Search Google Scholar
    • Export Citation
  • 71

    Rehfeld JF Accurate measurement of cholecystokinin in plasma. Clinical Chemistry 1998 44 9911001. (https://doi.org/10.1093/clinchem/44.5.991)

    • Search Google Scholar
    • Export Citation
  • 72

    Himeno S, Tarui S, Kanayama S, Kuroshima T, Shinomura Y, Hayashi C, Tateishi K, Imagawa K, Hashimura E & Hamaoka T Plasma cholecystokinin responses after ingestion of liquid meal and intraduodenal infusion of fat, amino acids, or hydrochloric acid in man: analysis with region specific radioimmunoassay. American Journal of Gastroenterology 1983 78 703707.

    • Search Google Scholar
    • Export Citation
  • 73

    McLaughlin J, Lucà MG, Jones MN, D’Amato M, Dockray GJ & Thompson DG Fatty acid chain length determines cholecystokinin secretion and effect on human gastric motility. Gastroenterology 1999 116 4653. (https://doi.org/10.1016/s0016-5085(9970227-1)

    • Search Google Scholar
    • Export Citation
  • 74

    Feltrin KL, Little