Am J Physiol Regul Integr Comp Physiol 292: R666 –R678, 2007.
First published October 19, 2006; doi:10.1152/ajpregu.00131.2006.
Invited Review
How does cholecystokinin stimulate exocrine pancreatic secretion?
From birds, rodents, to humans
Bi Jue Wang and Zong Jie Cui
Institute of Cell Biology, Beijing Normal University, Beijing, China
Wang BJ, Cui ZJ. How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292:
R666–R678, 2007. First published October 19, 2006; doi:10.1152/ajpregu.00131.2006.—
The field of cholecystokinin (CCK) stimulation of exocrine pancreatic secretion has
experienced major changes in the recent past. This review attempts to summarize
the present status of the field. CCK production in the intestinal I cells, the molecular
forms of CCK produced and subsequently circulated in the blood, the presence or
absence of CCK receptors on the isolated pancreatic acinar cells and the associated
signaling for acinar cell secretion, and the actual circuits and sites of action for
CCK regulation of exocrine pancreatic secretion in vivo are reviewed in different
animal species with an emphasis on birds, rodents, and humans. Clear differences
in the relative importance of neural and direct modes of CCK action on pancreatic
acinar cells were identified. Rodents seem to be endowed with both modes of
action, whereas in humans the neural mode may predominate. In birds, such as
duck, the direct mode needs further assistance from pituitary adenylate cyclaseactivating peptide/VIP receptors. However, much further work needs to be directed
to the neural mode to map out all sites of CCK action and details of the full circuits,
and we foresee a major revival for this field of research in the near future.
pancreatic acinar cells; vagal afferent nerves; plasma cholecystokinin concentration; species specificity
cholecystokinin (CCK) as a gut
hormone is an important endogenous secretagogue in exocrine
pancreatic secretion. CCK also stimulates gallbladder contraction and enhances growth of the exocrine pancreas (63, 115,
138). CCK is produced and released by the intestinal mucosal
I cells (78). This source of CCK may travel through the
circulation to target tissues that include the exocrine pancreas
and gallbladder (65, 78). CCK peptides are also found in large
quantities in neurons, but neuronal CCK contributes negligibly
to CCK concentration in the circulation (118). This general
picture has been changed drastically by the recent findings that
CCK can also stimulate exocrine pancreatic secretion by the
excitation of sensory nerves and vagovagal and enteropancreatic reflexes, and this may be the only pathway in humans (65,
105). In addition, major differences have been found in the
traditional humoral pathway, depending on the animal species
(35, 149). Therefore, the purpose of this review is to present
the current status of CCK regulation of exocrine pancreatic
secretion with a particular emphasis on species specificity as
shown in birds, rodents, and humans.
IT IS GENERALLY ACCEPTED THAT
GUT CCK-SECRETING CELL
CCK is produced by I cells of the intestinal mucosa, which
in rodents are concentrated in the duodenum and proximal
jejunum (31, 78). I cells are flask shaped, with their microvilliabundant apical surface oriented toward the intestine lumen
(109); their secretory granules, which are ⬃250 nm in size and
Address for reprint requests and other correspondence: Z. J. Cui, Institute of
Cell Biology, Beijing Normal Univ., Beijing 100875, China (e-mail:
zjcui@bnu.edu.cn).
R666
contain packaged CCK, are concentrated around the basolateral surfaces of the cell (13). Because CCK-secreting cells are
diffusely scattered in intestinal mucosa, I cell studies are rather
limited to immortalized cell lines (44). The neuroendocrine cell
line STC-1 was derived from the murine gut and established as
a model system for rodent I cell CCK secretion (120). In
STC-1 cells, SNARE proteins syntaxin-1, synaptosome-associated protein of 25 kDa (SNAP-25), and vesicle-associated
membrane polypeptide 2 (VAMP-2) have been found to be
involved in Ca2⫹-induced CCK secretion (100), and the GTPbound form of rab3A has been found to be a negative clamp for
exocytosis (39).
The most potent stimulants of CCK secretion are digestive
products of fats and proteins, with carbohydrates being less
potent. Of triglyceride hydrolysis products, fatty acids with
longer acyl chains (ⱖ12 carbon atoms) are potent secretagogues for CCK secretion; of protein breakdown products,
tryptophan and phenylanaline are the most potent (79). Soybean agglutinin stimulates CCK release by opening L-type
Ca2⫹ channels in cultured rabbit jejunal cells (62). Fatty acids
elicit a marked increase in intracellular Ca2⫹ concentration
([Ca2⫹]i) and CCK secretion in STC-1 cells; both responses are
blocked by nicardipine (88). In STC-1 and GLUTag cells, fatty
acid induces both [Ca2⫹]i increases and CCK secretion (129).
Sodium oleate has been found to stimulate CCK release in
enriched rat mucosal cells and in STC-1 cells (18).
It was found early on that diversion of bile-pancreatic juice
and infusion of trypsin inhibitors into the intestine of rats led to
enormous increases in pancreatic secretion and CCK release
(45); this formed the basis of negative feedback regulation of
CCK release. The hypothesis postulated that trypsin-sensitive
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SPECIES DIFFERENCES IN EXOCRINE PANCREAS SECRETION
intestinal-releasing factors were present in the small intestine
lumen, and, when pancreatic proteases were absent, endogenously produced releasing factors are intact and would interact with the CCK cell to stimulate CCK release (79). This idea
led to the discovery of luminal CCK-releasing factor (LCRF),
isolated from rat intestinal washings (133), and diazepambinding inhibitor (DBI), isolated from porcine intestine (47).
Both LCRF and DBI are involved in the negative feedback
regulation of CCK secretion because they are intact and functional in the absence of the pancreatic proteases. However,
such mode of CCK feedback regulation may be restricted to
rats because there is no spontaneous release of LCRF in
humans. In humans, the release of LCRF requires the stimulation of luminal amino acids and fatty acids (78).
A peptide isolated from rat pancreatic juice when infused
into rat intestine also stimulated CCK secretion, and this led to
the discovery of the monitor peptide (77, 78, 82). Monitor
peptide, also known as pancreatic secretory trypsin inhibitor
I-61, is produced by pancreatic acinar cells. Monitor peptidebinding sites were found in rodent small intestine mucosa (89).
The monitor peptide monitors the status in the intestinal lumen,
and its increased presence after pancreatic secretion stimulates
CCK release from I cells to trigger more pancreatic secretion
and therefore is involved in a form of positive feedback loop
(77).
The synthetic fragments LCRF(1– 41) and LCRF(1–35)
have similar potency and efficacy for CCK release in conscious
rats (134). Tarasova et al. (137) reported that endogenous
LCRF was present throughout the gut, including in the pancreas, stomach, duodenum, jejunum, ileum, and colon, with the
highest concentration in small intestine, supporting the notion
that LCRF is secreted into intestinal lumen to stimulate CCK
release from mucosal CCK cells. In dispersed human intestinal
mucosal cells and in STC-1 cells, LCRF markedly stimulated
CCK release (141). Porcine intestinal DBI could also stimulate
CCK release when administered intraduodenally in rat (47).
The biologically active DBI fragment DBI(33–50) induces
Ca2⫹ oscillations and CCK secretion in STC-1 cells (151).
In addition to luminal factors, neuropeptide bombesin (101,
131, 136), ␤-adrenergic receptor agonist (127), GABA (44,
54), and orexins (69) could all stimulate I cell CCK secretion.
Both radioligand binding studies and Northern blot analyses
suggested the presence of bombesin-like receptors in CCK
cells (131). Bombesin-stimulated CCK secretion from STC-1
cells was PKC dependent and involved the MAPK pathway
(101) and calmodulin (136). Liddle and colleagues (127) demonstrated the presence of ␤-adrenergic receptors in STC-1
cells, the stimulation of which led to cAMP production and
CCK release (127). Addition of GABA depolarizes STC-1
cells, activating voltage-gated Ca2⫹ channels and subsequent
CCK release (44). Further work found that, in addition to
GABAA receptors (44), functional GABAC receptors were also
present on STC-1 cells (54), and both played important roles in
CCK secretion. Neuropeptide orexin stimulates CCK release in
STC-1 cells, via orexin1 and orexin2 receptors (69).
The distribution of CCK-immunoreactive cells is similar in
birds and mammals (111). In ostrich, CCK is mainly produced
in duodenum, whereas, in chicken, CCK production is concentrated at the transit from jejunum to ileum (61). Chicken CCK
cell secretory granules are ⬃230 nm in diameter (111). In
chicken, both dietary proteins and amino acids are potent
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stimulators of CCK release (37, 150). In addition, two DBIs
have been purified from chicken intestine (19).
PLASMA CCK CONCENTRATION
Hormones classically exert their effect through the circulation
(115). Therefore, measurement of plasma CCK is an important
parameter in CCK physiology. Plasma CCK concentration can be
measured by bioassay and radioimmunoassay (114) with the use
of antibodies. Plasma CCK concentrations are usually in the
picomolar range in each of the animal species examined (see
Table 1). In humans, premeal plasma CCK concentration measured by bioassays or by radioimmunoassays in different studies
varied from 1.1 ⫾ 0.1 to 2.8 ⫾ 0.5 pM; after a meal, plasma CCK
concentration varied from 4.6 ⫾ 0.6 to 8.2 ⫾ 1.3 pM (see Table
1). An exception is a report that human basal CCK level was
8.3 ⫾ 2.5 pM and after a meal was 24.4 ⫾ 6.5 pM (14). The
variation of plasma CCK concentration is partly because of
different techniques and different antibodies used and the ingested
food used to elevate CCK concentration. Before meals, rat plasma
CCK concentrations were found to be in the range of 0.5 ⫾ 0.2 to
2.5 ⫾ 0.3 pM; after feeding, concentrations increased to 4.4 ⫾ 0.8
to ⬃13.4 ⫾ 3.8 pM (29, 30, 81, 84, 128). Basal CCK plasma
concentration in chicken was found to be 5–10 pM; after feeding,
this increased to 15– 40 pM (37, 86).
Table 1. Plasma CCK concentration in different
animal species
Plasma CCK concentration, pM
Before meal
After meal
Reference
Human
2.0⫾0.2
2.0⫾0.2
1.0⫾0.2
8.3⫾2.5
2.8⫾0.5
1.5⫾0.5
1.7⫾0.7
1.1⫾0.1
1.13⫾0.10
7.4⫾0.7
4.6⫾0.–7.3⫾1.0
6.0⫾1.6
24.4⫾6.5
6.5⫾0.7
6.3⫾1.7*
29.8⫾2.9†
8.2⫾1.3
4.92⫾0.34
1.9⫾0.3
2.5
0.5⫾0.2
0.85⫾0.1
2.5⫾0.3
13.4⫾3.8
9.7⫾1.6
7.9⫾1.9
8.2⫾1.1
8.9⫾0.6
16
1.8⫾0.9
5.3⫾0.6
45
4.6⫾1
9.4⫾1.6
10.6⫾1.4
10–30
27.6⫾4.8
80–100
0.5⫾0.3
12.3⫾1.5
15
63
80
14
50
53
53
55
114
Rat
84
29
81
128
30
Dog
33
85
135
Cat
7
6
Pig
17
Chicken
5–10
15–40
37–86
Values are means ⫾ SE. *Medium-chain triglyceride meal; †long-chain
triglyceride meal.
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Fig. 1. Rat proCCK sequence written in single amino acid
format. CCK peptides are numbered backward from the
COOH terminus of CCK octapeptide (CCK-8). The NH2
terminus of the major molecular forms of amidated CCK
peptides is indicated. Three tyrosine residues are sulfated in
the proCCK sequence. Amino acid residues not contained
in the active fragments are numbered ⫺1 to ⫺12. [Modified
from Beinfeld (11).]
DIFFERENT MOLECULAR FORMS OF PLASMA CCK
CCK is a heterogeneous hormone and present in different
molecular forms in mammals: CCK-83, CCK-58, CCK-39,
CCK-33, CCK-22, and CCK-8 (Fig. 1). The different forms are
all carboxyamidated and O-sulfated and are all ligands for the
CCK1 receptor (11, 93, 114, 115). The endoproteolysis of
proCCK occurs mainly at monoarginyl sites, but the presence
of CCK-22 shows that the Lys-61 site is also cleaved (11, 115).
Processing of proCCK is cell specific (11, 115). The plasma
CCK originates almost entirely from I cells in small intestinal
mucosa (78), which contain a mixture of medium-sized CCK
molecules (CCK-58, CCK-33, CCK-22, and CCK-8) that are
released into the blood circulation (11, 115). CCK is also a
widespread neurotransmitter in the nervous system (114), and
neurons mainly release CCK-8 (117). Thus brain and gut
contain drastically different molecular forms of CCK. This is
because proCCK is processed by different isoforms of the
prohormone convertase. Prohormone convertase 1 is present in
the intestines, whereas prohormone convertase 2 processes
proCCK in the brain (116). Different animal species also have
their plasma CCK in diverse forms (Table 2). CCK-33 was
found to be the predominant form in human plasma, CCK-22
being the second most abundant, with CCK-58 less abundant
(118). Moderate amounts of CCK-8 in human plasma have also
been reported (114). CCK-58 is the major circulating form of
Table 2. Plasma CCK forms in different animal species
Plasma CCK Molecular Forms
Reference
Rat
CCK-58*
112
Human
CCK-58, CCK-33,* CCK-22, CCK-8
114, 118
Canine
CCK-58*
32, 135
Cat
CCK-58, CCK-33, CCK-8
7
Pig
CCK-58, CCK-33, CCK-22,* CCK-8
17
Rabbit
CCK-33, CCK-22,* CCK-8*
113
Chicken, intestine
CCK-70 CCK-8* CCK-7*
61
Ostrich, intestine
CCK-70 CCK-8* CCK-7*
61
*Indicates the most abundant form of CCK in blood.
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CCK in canine blood (32, 135). The most abundant forms of
CCK in cat plasma were found to be CCK-8, CCK-33, and
CCK-58 (7). In pig plasma, the bioactive species comprised
CCK-58, CCK-33, CCK-22, and CCK-8, with CCK-22 being
predominant (17). Substantial amounts of CCK-22- and CCK8-like peptides were reported in rabbit plasma, with a small
amount of CCK-33-like peptide (113). The plasma forms of
CCK in ostrich and chicken are not certain, but analysis of
intestinal extracts indicated that some CCK-70 was present,
and the dominant forms were CCK-8 and CCK-7 (61). Human
preproCCK shares 55% identity with chicken amino acid
sequence, further suggesting that CCK is highly conserved
among different vertebrate species (60). It may be worthwhile
to note here that strict blood collection procedures may be
needed to prevent possible degradation of CCK during sample
processing. With this new method, Reeve et al. (112) found that
CCK-58 was the only major endocrine form of CCK in the rat.
CCK RECEPTOR IN DIFFERENT ANIMAL SPECIES
CCK binds to CCK1 receptors (CCK1R) on vagal fibers (75)
or pancreatic acinar cells (93, 103, 142, 152) to evoke pancreatic enzyme secretion and to CCK receptors in the gastrointestinal tract to regulate gastrointestinal motility (46, 70, 87,
99). Receptors for CCK and gastrin are members of the
G-protein-coupled receptor superfamily. Two receptor subtypes for CCK and gastrin have been classified (93, 103, 142).
CCK1R, found in gall bladder, exocrine pancreas, and limited
areas of the central nervous system, is highly selective for sulfated
CCK analogs, whereas the CCK2 receptor (CCK2R), present in
widespread areas in the brain and stomach, has high affinity for
both sulfated and nonsulfated CCK and gastrin analogs (142).
In rodent pancreatic acinar cells, CCK1Rs are coupled to
heterotrimeric G proteins of the Gq family, especially Gq and
G11, which activate PLC␤-mediated phosphatidylinositol 4,5bisphosphate breakdown to increase inositol trisphosphate and
diacylglycerol formation and eventually to stimulate pancreatic
zymogen granule exocytosis (57, 148).
CCK1Rs are highly conserved among different animal species. The amino acid sequences of CCK1Rs in rat, mouse,
rabbit, guinea pig, dog, human, and cynomolgus monkey are
shown in Fig. 2. Rat and mouse CCK1Rs were first characterized in the 1990s, the protein sequences being 95% identical
and 98% similar (40, 144). Such sequence differences may
have important functional significance. Differences in two
amino acid residues in rat and mouse CCK1Rs (Leu-43 and
Ileu-50 in rat and Val-43 and Phe-50 in mouse), for example,
led to completely opposite effects in MAP/ERK kinase kinasemediated Jun activation (52). The guinea pig CCK1R was
found to be 89% homologous to the rat CCK1R sequence (26).
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Human CCK1R has ⬎90% homology to the rat and guinea pig
CCK1R (25). CCK1R of cynomolgus monkey is 98% identical
to the human CCK1R (49). Rabbit CCK1R is 92% homologous
(87% identity) to the rat CCK1R sequence (8, 119). Canine
gallbladder CCK1R is 89% identical to the human and 85%
identical to the rat CCK1R (97).
Different animal species share ⬃90% identity in their
CCK1R amino acid sequence (102). It is noteworthy that there
was a seven-amino acid insertion (GGGGGGS) in the predicted third intracellular loop of the mouse receptor that has not
been seen in CCK receptors from any other species (40) (see
Figs. 2 and 3). The major differences in the sequences are in
predicted intracellular domains, with the third intracellular
loop being predominant and with the COOH-terminal tail also
harboring several differences (40, 49).
Like other members of the G-protein-coupled receptor superfamily, CCK1R has a heptahelical transmembrane (TM)
structure (4, 24, 91, 143) (Fig. 3). Mierke and colleagues (43)
built a model of the human CCK1R. The TM motifs each form
an ␣-helix that embeds into the lipid bilayer (42, 107). There is
a disulfide bond between C18 and C29 in the NH2 terminus
[CCK1R(1– 47)] (107). The first and second extracellular loops
are connected by a disulfide bond (C114 –C196), which plays
an important structural role. The extracellular loops and the
NH2 terminus are vital for both recognition and binding of
CCK (91). The COOH-terminal portion of the third cytoplasmic loop of CCK1R contains a stretch of charged residues that
are thought to form an amphipathic ␣-helical extension of the
sixth transmembrane domain in a critical orientation for G
protein activation (143). Theoretical models of CCK1R have
also been built by others (3, 28).
CCK receptors are present in chicken brain, pancreas, cecum, hypothalamus, and gallbladder, all with a dissociation
constant (Kd) of 1 nM (121). In chicken, two CCK receptor
subtypes exist: a central subtype in brain and hypothalamus
that resembles the mammalian CCK2R in agonist binding and
a peripheral subtype in pancreas, gallbladder, and cecum that
resembles the mammalian CCK1R in agonist binding (102,
121, 140). These similarities notwithstanding, however, rodent
CCK1 antagonist L-364,718 behaves as a chicken CCK2R
antagonist, whereas rodent CCK2 antagonist L-365,260 has
very low affinity for both receptor subtypes in chicken (121).
At the amino acid level, chicken brain CCK receptor (CCKCk) shared ⬃50% homology with mammalian and Xenopus
laevis CCK receptors (102) (see Fig. 2). CCK-Ck resembled
rodent CCK2Rs regarding agonist binding (CCK-8, CCK-4,
gastrin-17). However, CCK-Ck showed higher affinity for the
rodent CCK1R antagonist devazepide than for the rodent
CCK2R antagonist L-365,260 (102, 121, 140).
Human and canine CCK2/gastrin receptors share 90% amino
acid sequence identity and have similar agonist affinities (10, 66,
71). However, human and canine receptor binding affinities for
antagonists L-365,260 and L-364,718 differ by 20-fold. Beinborn
et al. (10) found that a single amino acid in the sixth transmembrane domain of the CCK2/gastrin receptor corresponding to
Val-319 in the human homologue was critical in determining
binding affinity for antagonists L-365,260 and L-364,718. Substitution of Val-319 by leucine decreases affinity for L-365,260
20-fold and increases affinity for L-364,718; an isoleucine in the
same position of human receptor selectively increases affinity for
L-364,718 (10). Kopin et al. (67) identified eight amino acid
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residues in membrane domains adjacent to the cell surface; these
residues project into a putative ligand-binding pocket of the
human CCK2R, and this pocket is very important for ligandreceptor interaction. These data suggest that ligand-binding amino
acid residues, particularly antagonist-binding residues in avian
CCK receptors, may be different than those in mammals. Theoretical model building for the avian CCK receptor may help to
understand this difference.
Early work indicated that a common ancestor CCK receptor
diverged into CCK1R and CCK2R at or before the level of the
divergence of birds and mammals from reptiles (104, 140). The
evolution of CCK probably followed the evolution of CCK
receptors. Johnsen (60) reviewed the sequence variations of
CCK molecules in lower animals. More detailed studies on
CCK receptors in lower animals are obviously needed.
CCK STIMULATION OF EXOCRINE PANCREATIC
SECRETION: DIRECT AND INDIRECT PATHWAYS
Physiologists have used different models to investigate exocrine pancreatic secretion, including the in situ pancreas perfusion model and isolated pancreatic acini. The latter model
makes it possible to study pancreatic acinar cell responses
without influence from neural or humoral factors, and single
cell responses can be easily investigated. Comparison of data
from these two general models revealed significant variations
in the in-born mechanisms in different animal species.
Rodents. CCK-stimulated amylase release in isolated rodent
pancreatic acinar cells is typically “bell-shaped.” At lower CCK
concentrations, amylase release increased progressively with increasing concentrations, whereas, at higher CCK concentrations,
amylase release gradually diminished with increasing CCK concentrations. This results in a maximal stimulating CCK concentration of ⬃100 pM (57, 122, 123). This bell shape may be due to
simultaneous occupation in different proportions of high-affinity
(Kd ⫽ 26 pM), low-capacity and low-affinity (Kd ⫽ 2.2 nM),
high-capacity CCK1R states (123).
Further examination of the dose-response curve revealed
that rodent CCK1Rs are exceptionally sensitive to CCK, with
a threshold concentration at 1 pM (23, 57, 115, 149). Picomolar
CCK concentrations induced significant amylase secretion in
all isolated rodent (rat, mouse, and guinea pig) pancreatic acini,
and maximal stimulating CCK concentration was 100 pM
(149). CCK concentration of 10 pM typically induces regular
Ca2⫹ oscillations in individual rat pancreatic acinar cells in
intact acini (2). This also applies to mouse and rabbit pancreatic cells (5, 146). Atropine does not alter secretory responses
to CCK in isolated rodent pancreatic acini (2, 56, 147), indicating that CCK’s effect on rat pancreatic enzyme secretion in
isolated pancreatic acini is not dependent on cholinergic stimulation. Hence, in rodents, physiological concentrations of
CCK could stimulate pancreatic enzyme secretion by direct
stimulation of CCK1Rs on pancreatic acinar cells (51, 124).
CCK, however, could also influence exocrine pancreatic
secretion in vivo by a neural pathway in rodents. Bilateral
vagotomy, pretreatment with atropine or hexamethonium, or
perivagal treatment with capsaicin in anesthetized rats completely abolished pancreatic protein secretion in response to
low doses of CCK, suggesting that CCK at physiological levels
stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway originating from the gastroduode292 • FEBRUARY 2007 •
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Fig. 3. Structure of human CCK1 receptor (CCK1R), CCK-8, and CCK-8-CCK1R interaction. Middle: serpentine representation of the CCK1R. The
NH2-terminal CCK1R(1– 47), third extracellular loop CCK1R(329 –357), and residues (W39, Q40, A334, Y338) involved in interaction with CCK-8 are denoted
(91). Top left: complex of CCK1R(1– 47) with CCK-8. Receptor fragment is shown as blue and CCK-8 as red ribbons. W39, Q40 of CCK1R(1– 47), Tyr-27,
and Met-28 of CCK-8 are displayed as ball-and-stick representation (107). Top right: structure of CCK1R(329 –357). Transmembrane domain 7 (TM7) and TM6
are depicted on the left and right, respectively. Residues of receptor fragment are color coded according to hydrophobicity (blue ⫽ polar, red ⫽ hydrophobic)
(42). Bottom left: structure of CCK-8. Helix-like loop in center of CCK-8 is highlighted by ribbon diagram. Protons involved in intermolecular interaction with
NH2 terminus of CCK1R are denoted as spheres (91). Bottom right: interactions of CCK-8 (gray ribbon) with NH2 terminus and third extracellular loop (EC3)
of CCK1R (black ribbon). The side chains of the amino acids of CCK-8 and CCK1R stabilizing the CCK-8-CCK1R complex are illustrated as ball-and-sticks
and sticks, respectively. The residues of CCK-8 are denoted by three-letter code and those of CCK1R by one-letter code (42).
nal mucosa (74). In both rats and guinea pigs, atropine decreased CCK-evoked pancreatic secretory response in vivo
(110). In vivo infusion of CCK-JMV-180 (a CCK analog), the
high-affinity agonist of CCK1R, causes dose-dependent increases in pancreatic protein secretion in rats blockable by
CCK1R antagonist L-364,718, and acute vagotomy in anesthetized rats and perivagal application of capsaicin in conscious
rats will abolish pancreatic secretory responses to CCK-JMV180, demonstrating that CCK acts through high-affinity
CCK1Rs on nerves to mediate pancreatic protein secretion (73,
105).
CCK receptors have been detected in rat vagus nerves with
the use of in vitro receptor autoradiography, and these receptors are transported toward peripheral nerve endings from the
nodose ganglia (153). CCK1Rs and axonal transport are found
in vagal trunks and all abdominal vagal branches (95). Both
CCK1R and CCK2R have been found to be present in the
cervical vagus and the nucleus of the solitary tract (20).
Furthermore, the existence of functional CCK1Rs in the nodose ganglion has been confirmed (12, 145). Both CCK1R and
CCK2R have been found to be synthesized in nodose ganglion
cells, and these receptors can be transported to the periphery
along afferent fibers in both rats and humans (96).
CCK may also act on low-affinity CCK1Rs to trigger Ca2⫹
influx into vagal afferent neurons, which in turn may result in
acute activation of vagal afferent neurons (130). Electrophysiological evidence showed that both high- and low-affinity
CCK1Rs exist on rat vagal afferent fibers, and the vagal
CCK-receptor field includes the regions innervated by the
gastric, celiac, and hepatic vagal branches (76). Recent work
Fig. 2. Alignment of CCK receptor sequences in different species. Amino acid sequences of CCK1 receptor from mouse (CCK-M1), rat (CCK-R1), cynomolgus
monkey (CCK-Mk1), guinea pig (CCK-Gp1), rabbit (CCK-Rb1), dog (canine) (CCK-Cn1), and human (CCK-H1); of CCK2 receptors from human (CCK-H2);
and of CCK receptors from chicken brain (CCK-Ck) and Xenopus laevis (CCK-Xp) are shown. Completely identical residues in all receptor homologues are
indicated in white letters on black background, identical residues in a few species are indicated in black letters on gray background, and distinct residues are
indicated in black letters on white background. Compiled from Refs. 40, 49, 97, and 102.
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indicates that CCK1Rs exist in both high- and low-affinity
states in rat nodose ganglia cells. Activation of high-affinity
CCK1Rs in isolated rat nodose ganglia cells elicits regular
Ca2⫹ oscillations, whereas stimulation of low-affinity CCK1Rs
evokes a Ca2⫹ transient followed by a small and sustained
Ca2⫹ plateau. Such Ca2⫹ signaling involves both Gq and
L-type Ca2⫹ channels (68). CCK acts through high-affinity
CCK1Rs on rat vagal afferent fibers to mediate pancreatic
secretion (73). The above observations provide evidence for a
role for CCK receptors in vagal afferent fibers in pancreatic
digestive enzyme secretion.
CCK receptors are also present on rabbit vagus nerve, and
vagal CCK receptors include both CCK1 and CCK2/gastrin
subtypes (83). In rabbit vagal afferent (nodose) ganglion, high
concentrations of CCK- and neuropeptide Y-binding sites have
been found in 10.6% and 9.2% of the nodose ganglion neurons,
respectively; both CCK (CCK1/2) and neuropeptide Y (Y1/2)
receptor binding sites are expressed by discrete populations of
neurons in the nodose ganglia (41). These data suggest that
CCK released from peripheral tissues (mainly from I cells in
the small intestinal mucosa) may interact with CCK receptors
in vagal afferent fibers to modulate a neural circuit.
In addition, it has been found that CCK (10 nM to 10 ␮M)
stimulates [3H]acetylcholine release from rat pancreatic lobules, which was blocked by TTX, by Ca2⫹-free medium, and
by CCK antagonist L-364,718, suggesting that CCK may act
by stimulation of neural acetylcholine release (132). This
provides an additional site for CCK action through the
neural pathway, but apparently with much lower affinity,
because at least nanomolar CCK concentrations were
needed to stimulate acetylcholine release from the rat pancreatic lobules (132).
Together, these findings suggest that in both rodents and
other animals (rabbit) CCK can act both directly on acinar cells
and through neural pathways to stimulate exocrine pancreatic
secretion (Fig. 4A).
Humans. Quantitative RT-PCR indicated that, in human
pancreas, CCK1R mRNA was ⬃30 times lower than CCK2R
mRNA, which was ⬃10 times further lower than M3 muscarinic acetylcholine receptor mRNA (58). In situ hybridization
completely failed to detect either CCK1R or CCK2R mRNA in
adult human pancreas (58, 59). In isolated human pancreatic
acini, CCK or secretin stimulation did not produce any functional responses, and no significant specific binding for CCK
Fig. 4. CCK stimulates physiological exocrine pancreatic secretion through different
pathways: species dependence. CCK is released from intestinal mucosal I cells, which
in turn exert its role via different pathways.
A: in rodents such as rat, CCK released from
I cells is transported to pancreas via circulation, directly stimulating the CCK1 receptors
on pancreatic acinar cells. CCK can also
activate sensory nerve fibers to activate the
long vagovagal and short enteropancreatic
reflexes. B: in humans, released CCK activates CCK receptors in the intestinal sensory
nerve fibers to excite both the long vagovagal and short enteropancreatic reflexes. Efferent vagal nerve terminals eventually release neurotransmitters such as ACh to stimulate pancreatic acinar cells secretion. The
lack of CCK1Rs on human pancreatic acinar
cells dictates that circulating CCK does not
stimulate digestive enzyme secretion. C: in
ducks, circulating CCKs in the presence of
neurotransmitter vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) stimulate pancreatic acinar cell secretion. Dashed lines indicate that more work needs to be done before
confirmation of the reflexes. DVC, dorsal
vagal complex; NG, nodose ganglia; VIP,
vasoactive intestinal polypeptide. Drawn
with the use of an initial template (64, 65).
AJP-Regul Integr Comp Physiol • VOL
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SPECIES DIFFERENCES IN EXOCRINE PANCREAS SECRETION
receptors was found (58, 59, 94). This is in contrast to the high
density of CCK1Rs revealed by microautoradiography in the
mucosa and in smooth muscles in the human duodenum (94).
However, after adenoviral-mediated transfection of either
CCK1R or CCK2R gene to human pancreatic acinar cells,
these cells became responsive to CCK stimulation (58). These
data indicate that human pancreatic acinar cells do not respond
to CCK stimulation due to insufficient levels of CCK1R gene
expression. With advanced quantitative RT-PCR technology,
CCK1R transcription in human pancreas has now become
detectable (38), although the cell type expressing it was not
determined.
In vivo human studies found that the highly specific CCK1R
antagonist MK-329 (also known as L-364,718 and devazepide)
only slightly affected pancreatic enzyme secretion and gastric
emptying but significantly inhibited bile secretion, indicating
that CCK is not an essential mediator of postprandial pancreatic enzyme secretion in humans (16). Others found that CCK
in vivo stimulated pancreatic secretion by interacting with
neural cholinergic system. Atropine in human subjects completely suppressed low-dose CCK-induced digestive enzyme
secretion, indicating that CCK-mediated exocrine pancreatic
secretion required a cholinergic tone in vivo (108). Atropine
blocked significantly meal-stimulated pancreatic digestive
enzyme secretion, and the response to graded doses of
exogenous CCK was significantly inhibited by both atropine
and loxiglumide, a CCK1R antagonist, suggesting that pancreatic enzyme secretion is predominantly dependent on a
cholinergic tone and that CCK modulates the enzymesecretory response in human (1). Atropine (5 ␮g 䡠 kg⫺1 䡠 h⫺1)
reduced the CCK-stimulated increase in pancreatic enzyme
secretion and essentially blocked postprandial enzyme secretion (9). In another study, trypsin output stimulated by
physiological doses of CCK was inhibited by atropine by
84.0%, whereas lipase output was inhibited by 78.6% in
humans (132). Thus the human exocrine pancreas is crucially dependent on a cholinergic background, with CCK
only modulating this secretory response (9).
The above data suggest that CCK can act on vagal afferent
fibers, which explains how physiological plasma CCK levels
act via vagal cholinergic pathways to stimulate pancreatic
secretion. Although knowledge of vagal CCK1Rs has come
from rodents, other work suggests that this information is also
applicable to humans (105). The fact that CCK1Rs exist in
human duodenum seems to support such a notion (possibly
mediating both vagal afferent input and duodenal-pancreas
reflex) (34). Therefore, physiological levels of CCK appear to
act entirely via vagal cholinergic pathways to mediate pancreatic secretion in humans (Fig. 4B).
Birds. The case for avian CCK stimulation of exocrine
pancreatic secretion is different from that for both rats and
humans, although the plasma CCK levels seem to be similar in
all animal species. Proteins and fatty acids are the major
luminal dietary stimuli for CCK release in rat (29, 30, 72, 81,
84). Duodenal infusion of casein, for example, resulted in
elevation of plasma CCK from fasting levels of 0.5 ⫾ 0.1 to
3.8 ⫾ 0.4 pM (72). This picomolar postprandial plasma CCK
concentration is sufficient to stimulate enzyme secretion and
trigger Ca2⫹ oscillation in rat pancreatic acini (2, 21–23, 149).
Soya proteins and amino acid mixtures mimicking soya
protein composition could increase gut CCK release in chicks
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(150). In chickens, plasma CCK increases from a basal level
(control diet) of 9.6 ⫾ 0.6 to 13.4 ⫾ 0.6 and to 18.1 ⫾ 0.8 pM
90 min after ingestion of a diet supplemented with 100 and
1,000 mg soybean trypsin inhibitor, respectively (37). Plasma
CCK concentration is also significantly enhanced in chicks fed
medium-chain triglycerides but not in chicks fed long-chain
triglycerides (86). However, in chickens, such picomolar CCK
Fig. 5. Simultaneous activation of VIP/PACAP and CCK receptor systems
results in physiological stimulation of exocrine pancreatic secretion. A. leftward expansion by VIP/PACAP of CCK dose-response curve for amylase
secretion from freshly isolated Peking duck pancreatic acini. Acini were
incubated with CCK alone (circles), CCK plus PACAP 1 nM (squares), or
CCK plus VIP 10 nM (triangles) for 30 min. Amylase secreted into the
extracellular medium was then measured and expressed as a percentage of total
amylase present in acini before stimulation. PACAP (1 nM) and VIP (10 nM)
alone had little effect on amylase secretion. *Lowest CCK concentration at
which statistically significant stimulation of amylase secretion was observed.
Note the 3 orders of magnitude difference in the absence and presence of
PACAP/VIP. Redrawn from data published in Ref. 149. B: low, physiological
concentrations of CCK alone do not stimulate amylase secretion in freshly
isolated duck pancreatic acini; only when CCK concentration reaches supraphysiological levels will it have a stimulatory effect on amylase secretion, with
a maximal stimulatory concentration of 10 nM (solid blue line). Similarly, not
until CCK concentration reaches 100 pM will it induce regular Ca2⫹ oscillations. In the presence of physiological concentrations of VIP/PACAP, low
physiological concentrations of CCK start to induce significant amylase
secretion, higher CCK concentrations induce more amylase secretion, and
supraphysiolgical CCK concentrations result in a reduction in amylase secretion (solid black line). Also, in the presence of VIP/PACAP, low physiological
concentrations of CCK induce regular Ca2⫹ oscillations. The CCK doseresponse curve in the presence of VIP/PACAP could possibly be broken down
into 2 components: at high CCK concentrations, VIP and PACAP serve the
purpose of priming zymogen granules for exocytosis (dashed green line); at
low CCK concentrations, VIP and PACAP not only prime zymogen granules
but also serve to sensitize Ca2⫹ signal generation (dashed yellow line).
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SPECIES DIFFERENCES IN EXOCRINE PANCREAS SECRETION
concentrations do not stimulate pancreatic acini secretion;
CCK concentrations 100 times higher are required to elicit
secretory response from isolated chicken pancreatic acini. This
has led to the belief that endogenous CCK does not have any
important role in digestive enzyme secretion from exocrine
pancreas in birds (35, 36, 98, 125).
In the isolated duck pancreatic acini, picomolar concentrations of CCK do not stimulate either an increase in [Ca2⫹]i or
digestive enzyme secretion. CCK at 1 nM was required for
stimulation of amylase secretion, with a maximal effect being
achieved at 10 nM (149). Vasoactive intestinal peptide (VIP)/
pituitary adenylate cyclase-activating peptide (PACAP) receptor (VPAC) agonists such as PACAP38 and PACAP27 and
VIP alone had little effect on amylase secretion in duck
pancreatic acini but could make picomolar concentrations of
CCK effective. Furthermore, PACAP27 and VIP shifted the
maximal stimulating CCK concentrations from 10 to 1 nM
(149). Subthreshold CCK (10 pM) in the presence of VPAC
agonists induced Ca2⫹ spikes. CCK (10 nM)-induced secretion
was inhibited by CCK1R antagonist FK-480 (1 ␮M). Gastrin
did not stimulate amylase secretion and did not induce [Ca2⫹]i
increase (149). These data suggest that duck pancreatic acini
possess both CCK1 and VPAC receptors and that simultaneous
activation of both is required for each to play a physiological
role (149) (Fig. 5A). As such, VIP/PACAP sensitization of
CCK stimulation could probably be broken down into two
components. At higher CCK concentrations, VIP/PACAP may
primarily serve the purpose of priming zymogen granules for
exocytosis; at lower CCK concentrations, VIP/PACAP may
also sensitize Ca2⫹ signal generation (Fig. 5B).
The presence of VIP/PACAP innervation in avian exocrine
pancreas provides a direct line of evidence that VIP or VIP-like
receptors are likely to have a physiological role in exocrine
pancreatic secretion. In situ studies show that chicken VIP
increased the flow of pancreatic juice in turkey (27). Vaillant et
al. (139) identified VIP in the gut and pancreas of turkey.
Mensah-Brown and Pallot (90) found that Houbara Bustard
(Chlamydotis undulata) exocrine pancreas was innervated by
VIP, galanin, neuropeptide Y, and some other neurotransmitters. Mirabella et al. (92) found that, in duck, both PACAP38
and PACAP27 are present in neurons and fibers of the enteric
nervous system, and PACAP is colocalized with VIP. Peeters
et al. (106) also suggested that PACAP receptor exists in
chicken pancreas. The well-established innervation of VIP/
PACAP and related receptors in avian pancreas lend support to
a role for VIP/PACAP receptors in avian exocrine pancreatic
secretion (149).
Presently, there is scant information about vagal reflexes
and their potential role in exocrine pancreatic secretion in
birds. However, there is evidence to indicate that chicken
exocrine pancreatic secretion is controlled by the vagus
nerve (48). In addition, turkey pancreatic secretion may be
controlled by a cholinergic pathway (126). Therefore, neural
or vagal reflexes may also exist in avian species. Figure 4C
depicts the presently known situation for exocrine pancreatic secretion in birds.
CONCLUSIONS AND PERSPECTIVES
The hormone CCK is the most important mediator of postprandial pancreatic secretion, particularly concerning digestive
AJP-Regul Integr Comp Physiol • VOL
enzyme output. Pancreatic secretion can be influenced by CCK
either directly via actions on pancreatic acinar cells or indirectly via actions on afferent vagus nerves. The mechanisms of
action are species specific. In rodents, CCK acts both directly
through the blood and neurally to mediate pancreatic secretion.
In humans, CCK appears to act entirely via vagal cholinergic
pathways to mediate pancreatic secretion. In birds, VIP/
PACAP and CCK are mutually dependent to directly stimulate
exocrine pancreatic secretion at physiological concentrations.
This latter conclusion implies mutual dependence of the endocrine and nervous systems.
In birds, whether VIP/PACAP and CCK are also needed
together to excite the sensory nerves, triggering vagovagal and
enteropancreatic reflexes to stimulate pancreatic enzyme secretion, remains unclear. This will require future studies.
Avian CCK receptors have not received much attention
before, largely because of the uncertainty about its physiological role in exocrine pancreatic secretion. Now that its role is
established and significant differences in CCK receptors of bird
and mammals are quite obvious both structurally and functionally, more attention should be directed to that respect in the
future.
ACKNOWLEDGMENTS
We thank the anonymous reviewers for suggestions for improving our
manuscript. We are gratefully to Prof. Dale Mierke of Brown University for
kindly providing the original high-resolution files for Fig. 3.
GRANTS
This work was supported by Natural Science Foundation of China Grants
39825112, 30070286, 30472048, and 30540420524, by Ministry of Education
Grant 104186, and by Natural Science Foundation Beijing Grant 6062014.
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