Physiol Rev 86: 805– 847, 2006;
doi:10.1152/physrev.00014.2005.
Cholecystokinin and Gastrin Receptors
MARLÈNE DUFRESNE, CATHERINE SEVA, AND DANIEL FOURMY
Institut National de la Santé et de la Recherche Médicale U. 531, Institut Louis Bugnard,
Centre Hospitalier Universitaire Rangueil, Toulouse, France
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I. Introduction
II. The Cholecystokinin Receptors
A. Nomenclature
B. cDNAs cloning and deduced protein structures
C. Genes
D. Binding properties and ligands
III. Structure-Function Relationship of Cholecystokinin Receptors
A. Localization of ligand binding sites
B. Activation mechanism and regulation
IV. Signaling Transduction Pathways Activated by Cholecystokinin Receptors
A. Phospholipases/calcium mobilization and protein kinase C activation
B. Adenyl cyclase and cAMP production
C. Nitric oxide and cGMP pathway
D. Mitogen-activated kinase cascades
E. Phosphatidylinositol 3-kinase
F. Focal adhesion kinase and associated proteins
G. The JAK/STAT pathway
H. Other signaling molecules
V. Target Genes of Cholecystokinin Receptors
A. Gastrin-dependent gene regulation
B. CCK-dependent gene regulation
VI. Tissue Distribution and Physiological Actions of Cholecystokinin Receptors in the Gastrointestinal
Tract and Other Peripheral Organs
A. Gastric mucosa, exocrine and endocrine pancreas
B. Gastrointestinal smooth muscles
C. Other peripheral organs and tissues
VII. Pathological Actions of Peripheral Cholecystokinin Receptors and Their Relevance to Clinical
Disorders in Humans
A. Digestive and metabolic diseases
B. Cancers
C. Peptide and receptor targeting
VIII. Conclusion/Prospects
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Dufresne, Marlène, Catherine Seva, and Daniel Fourmy. Cholecystokinin and Gastrin Receptors. Physiol Rev
86: 805– 847, 2006; doi:10.1152/physrev.00014.2005.—Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are
G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding
advances in the understanding of their functioning and physiology. In this review, we first describe general
properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and
the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral
cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.
I. INTRODUCTION
Cholecystokinin (CCK), one of the first gastrointestinal hormones discovered, was originally isolated from
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porcine duodenum as a 33-amino acid peptide (CCK-33).
The sequencing of CCK-33 in 1968 revealed that CCK is
structurally related to gastrin, another gut hormone characterized 4 years earlier (Fig. 1) (343, 530). Indeed, the
0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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DUFRESNE, SEVA, AND FOURMY
FIG.
1. Primary structure of cholecystokinin (CCK) and
gastrin.
II. THE CHOLECYSTOKININ RECEPTORS
A. Nomenclature
Two types of CCK receptors (type A, “alimentary,”
and type B, “brain”) have been identified on a pharmacological basis. The CCK-A receptor was first characterized
in pancreatic acini from rodents (95, 120, 224, 415, 432),
whereas the CCK-B receptor was first found in the brain
(217, 427). Based on recommendations of the InternaPhysiol Rev • VOL
tional Union of Pharmacology (IUPHAR) committee regarding receptor nomenclature and drug classification,
the CCK-A receptor has been renamed CCK1 receptor
(CCK1R), and the CCK-B receptor has been renamed
CCK2 receptor (CCK2R). CCK1R binds and responds to
sulfated CCK with a 500- to 1,000-fold higher affinity or
potency than sulfated gastrin or nonsulfated CCK. The
CCK2R binds and responds to gastrin or CCK with almost
the same affinity or potency and discriminates poorly
between sulfated and nonsulfated peptides. In the periphery, the CCK2R can be considered as the “gastrin receptor” (see sect. IID).
B. cDNAs Cloning and Deduced Protein Structures
Historically, a cDNA encoding gastric gastrin receptor was originally cloned by A. S. Kopin and co-workers
(253) through expression of a canine parietal cell cDNA
library in COS-7 cells and isolation of a cDNA clone
encoding a 453-amino acid protein. Binding of 125I-BoltonHunter-CCK-8 to COS-7 cells expressing this protein was
inhibited by CCK- and gastrin-related peptides with potencies in agreement with CCK2R pharmacology. However, the nonpeptide antagonist for the CCK1R
(L-364,718) competed with labeled CCK-8 to the recombinant receptor with higher potency (19 nM) than the nonpeptide antagonist of the CCK2R (L-365,260, 130 nM), but
this atypical pharmacological feature was further shown
to be species specific (38). In addition to binding parameters, intracellular Ca2⫹ mobilization, inositol 1,4,5trisphosphate elevation in response to gastrin, and affinity
labeling of the 76,000 component confirmed that the
cloned receptor was indeed the gastric gastrin receptor.
The human brain CCK2R cDNA was then isolated and
sequenced, providing evidence that the brain and gastric
CCK2R represent a unique molecular entity encoded by a
single gene (219, 273, 380).
Report of the cloning of the pancreatic rat CCK1R
cDNA by S. A. Wank appeared in the same issue of the
Proceeding of the National Academy of Sciences (USA)
as that of the canine CCK2R (559). Indeed, Wank and
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two gene products that are generated in multiple molecular forms that differ in length both share five COOHterminal amino acids (Gly-Trp-Met-Asp-Phe-CO-NH2).
CCK and gastrin are synthesized and secreted by I cells
from the upper intestine and G cells from the gastric
antrum, respectively. In 1975, a gastrin-like immunoreactive peptide was found in rat brain (537). This peptide was
further identified as CCK-8 (133, 399, 416). Since this
discovery, large amounts of CCK have been identified in
various areas of the central nervous system and in peripheral nerve endings (268, 397, 399). In humans, CCK and
gastrin are encoded by two distinct genes located on
chromosomes 3p22-p21.3 and 17q21, respectively. They
are produced through multi-step processing of large peptidic precursors (134, 400, 510, 569). Posttranslational
modifications found on biologically active peptides include sulfation of the tyrosine at position 7 from the
COOH terminus in CCK, position 6 in gastrin, as well as
COOH-terminal amidation. Biologically active gastrins
and CCKs also exist in nonsulfated forms. In fact, half of
the endogenous gastrins are nonsulfated (134, 183, 184,
400). Because of the sequence similarity in their bioactive
region, CCK and gastrin share some biological and pharmacological effects. These peptides, in their mature
forms, exert their biological functions by interacting with
membrane G protein-coupled receptors named CCK receptors located on multiple cellular targets in the central
nervous system and peripheral organs. Nonmaturated
forms of gastrin have also been shown to exert several
effects (see sect. VIIB).
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CCK RECEPTORS
stance, pancreatic native CCK1R, which migrates as a
85,000- to 100,000-Da component in SDS-PAGE, is shifted
to a 38,000- to 42,000-Da protein after endoglycosidase-F
treatment (152, 372). SDS-PAGE analysis suggested that
the degree of glycosylation of affinity labeled CCK2R
differs according to the cell type in which the receptor is
expressed. Indeed, photoaffinity labeling of canine
CCK2R in isolated parietal cells identified a component of
76,000 Da, while photoaffinity labeling of canine CCK2R
in pancreatic membranes identified a component of
47,000 Da (153, 305). The bovine CCK2R, which appeared
as a 42,000- to 47,000-Da protein in pancreatic membranes, was further identified as a 85,000-Da recombinant
protein in COS-7 cells, with both components yielding a
37,000-Da protein by endoglycosidase-F treatment (140,
275). The precise role of the carbohydrate moieties of
these receptors remains largely unknown.
C. Genes
The CCK1R gene is on human chromosome 4p15.1p15.2 and mouse chromosome 5 (216, 430). CCK2R has
been assigned to human chromosome 11p15.4 and to
distal chromosome 7 in mice (216, 430). The transcriptional start site of human CCK1R was identified 206 bp
upstream of the translation start site. In the mouse
CCK2R gene, the transcriptional start site was identified
at 199 bp upstream of the translation start site in a region
devoid of any TATA-like sequences (157, 262). So far, no
precise data have been reported on CCKR gene regulation. However, several studies have documented polymorphism in CCKR gene promoters associated with diseases
such as panic disorder, alcohol dependence, and obesity
(245, 325, 326, 555).
The two receptor genes are each organized into five
exons (Fig. 2). In the CCK2R gene, the presence of an
exon I variant within intron I was described (317). Ac-
FIG. 2. Schematic representation of genes encoding CCK receptors (CCKRs). The asterisk shows the presence of an exon I variant within intron
I. Introns are represented by yellow boxes. Arabic Numbers indicate nucleotide number in introns and exons. Roman numbers indicate
transmembrane domains of the CCKRs encoded by the different exons.
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colleagues purified to homogeneity a sufficient amount of
receptor protein to obtain partial sequences of five fragments. From these peptides, degenerate oligonucleotides
were designed and used as primers to amplify, by polymerase-chain reaction, a cDNA fragment, which was then
utilized as a probe to screen a cDNA library obtained from
rat pancreas. A complete cDNA, with an open reading
frame encoding a protein of 444 amino acids, was thus
cloned. In vitro transcripts of the cloned cDNA were
injected into Xenopus oocytes and shown to display CCKinduced chloride currents that were inhibited by a specific antagonist of the CCK1R (559).
The CCK1R and CCK2R exhibit a relatively low degree of sequence homology (50%) but present seven hydrophobic segments, likely corresponding to transmembrane domains, with extracellular NH2-terminal and intracellular COOH-terminal ends. Such structures are
characteristic of G protein-coupled receptors (GPCRs) in
agreement with high-resolution three-dimensional structure of rhodopsin (366). Other sequence signatures of
members of the family I of GPCRs that are essential for
receptor activation are also present in the CCK1R and
CCK2R, such as an E/DRY motif at the bottom of transmembrane domain III, and a NPXXY motif within transmembrane domain VII. Cloning of cDNAs encoding
CCK1R in guinea pig gallbladder and pancreas, mouse
pancreas, rabbit stomach, and human gallbladder as well
as those encoding CCK2R in the rat pancreatic cancer cell
line AR4 –2J, an enterochromaffin-like carcinoid tumor of
Mastomys natalensis, rat stomach, and bovine pancreas,
demonstrated a high degree of sequence homology well
within the range expected for interspecies variations of
the same receptor type (122, 140, 165, 345, 403, 534, 560).
CCK1R and CCK2R contain three to four potential Nlinked glycosylation sites in their amino termini, which is
consistent with a high and heterogeneous degree of glycosylation, experimentally noticed in both affinity and
photoaffinity labeling experiments (152, 372). For in-
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DUFRESNE, SEVA, AND FOURMY
D. Binding Properties and Ligands
Many studies have been devoted to the pharmacological characterization of naturally expressed, and more
recently, of recombinant CCK receptors. Radiolabeled
analogs of CCK and gastrin as well as tritiated antagonists
have been used in such works. Binding experiments using
labeled agonists as radioligands yielded the binding parameters of the G protein-coupled state of the receptor,
whereas binding studies with labeled antagonists provided binding parameters of the resting and inactive state
of the receptor. This explains, at least in part, why binding
experiments with antagonists identified a greater number
of binding sites compared with experiments using agonists. The binding affinities of CCK and gastrin agonists
for the different affinity states of the CCK receptors are
different. In general, Kd values for binding of CCK to highand low-affinity sites of the CCK1R are in the range of
50 –300 pM and 50 –200 nM, respectively (224, 225, 432).
While high-affinity sites are much less numerous than
low-affinity sites, both components are functionally important, at least in pancreatic acinar cells (see sect. IVA).
On the other hand, Kd values for high- and low-affinity
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binding of CCK to CCK2R are ⬃100 –300 pM and 2–5 nM,
respectively (264). In addition to these two sites, there
exist very-low-affinity sites as well with Kd values of ⬃10
␮M in both the CCK1R and CCK2R (213).
The natural ligand with the highest affinity for CCK1R
is the sulfated octapeptide of CCK (CCK-8) (Fig. 1). Other
natural molecular variants of CCK such as CCK-33, CCK39, and CCK-58 bind to CCK1R with similar affinity to
CCK-8 (396, 490). Gastrin, at physiological concentrations, is likely a poor activator of CCK1R, its affinity being
100- to 500-fold lower than that of sulfated CCK-8. Structure-activity relationship studies with synthetic CCK analogs have indicated that sulfation of the position 2 tyrosine in CCK-8 (Fig. 1) is critical for binding to CCK1R,
since its removal causes a 500-fold drop in affinity. The
two natural ligands with the highest affinities for CCK2R
are sulfated gastrin-17 (often abbreviated G-17II) and sulfated CCK-8 (140, 214). Nonsulfated gastrin-17 (G-17I)
exhibits a 3- to 10-fold lower affinity than sulfated gastrin17. This affinity order and the fact that postprandial blood
levels of gastrins are 5- to 10-fold more elevated than
those of CCK lead one to consider that sulfated gastrin-17
is the preferred ligand and probably the physiological
ligand of most of the peripheral CCK2R. On the other
hand, due to the abundance of sulfated CCK-8 in the
central nervous system, it is likely the ligand which naturally activates brain CCK2R. Compared with sulfated
gastrin-17, the COOH-terminal tetrapeptide common to
gastrin and CCK and nonsulfated CCK-8 interacts with the
CCK2R with only a 10- to 50-fold decreased affinity.
The variety of physiological functions that can be
regulated through the CCK receptors and their potential
use as targets for the treatment of several human diseases
have stimulated searches for specific, potent agonists and
antagonists of these receptors. For most of these molecules, their chemistry and pharmacological properties are
extensively described elsewhere (Table 1) (201, 351). Historically, amino acid derivatives such as benzotript and
proglumide were the first CCK receptor antagonists reported. They were followed by peptidic analogs of CCK
1. List of some popular cholecystokinin
receptor antagonists
TABLE
Name
L-364,718 (devazepide)
CR2017 (dexloxiglumide)
SR-27,897 (linitrip)
L-365,260
L-369,466
YM-022
CR-2945
YF-476
GV150013X
PD-134308 (CI-988)
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CCKR Selectivity
CCK1R ⬎⬎⬎ CCK2R
CCK1R ⬎⬎ CCK2R
CCK1R ⬎⬎⬎ CCK2R
CCK2R ⬎⬎ CCK1R
CCK2R ⬎⬎⬎ CCK1R
CCK2R ⬎⬎⬎ CCK1R
CCK2R ⬎⬎ CCK1R
CCK2R ⬎⬎⬎ CCK1R
CCK2R ⬎⬎⬎ CCK1R
CCK2R ⬎⬎ CCK1R
Reference
Nos.
82
295
190
291
51
436
296
460
536
215
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cording to the authors, in some cells, especially cancer
cells, exon I would be used alternatively to exon I leading
to synthesis of transcripts encoding an NH2-terminally
truncated CCK2R (317). Gene organization in exon/introns may theoretically lead to protein diversity. The existence of two mRNA isoforms for the CCK2R, produced
by alternate splicing of exon 4 in human stomach, was
also reported (491). Although this possibility exists and
affects the sequence of the third intracellular loop by
introducing a five-amino acid cassette, its functional significance remains controversial. In fact, recombinant human receptors encoded by these two isoforms are undistinguishable in terms of pharmacology and signal transduction features (218). Moreover, the ratio between the
expression levels of the two isoforms was found to be
⬃1:99, supporting the view that the splice site in exon 4 of
the human CCK2R gene is dominant (218). However, the
nature of the predominant variant differs according to
species: small variant in human; long variant in mouse,
rat, dog, and calf (140, 219, 227, 253, 273, 380, 384, 559,
560). Additionally, a misspliced cDNA clone that encodes
a receptor with retention of intron IV in the third intracellular loop (CCK2Ri4sv) was identified from colorectal
and pancreatic tumors (130, 199). This misspliced variant
seems to exhibit spontaneous ligand-independent oscillatory increases in intracellular Ca2⫹ and increases cell
growth rate (199). Concerning CCK1R, the presence of a
seven-amino acid glycine-rich cassette in the third intracellular loop of the murine receptor has been reported to
contribute to species-specific aspects of signaling (384).
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CCK RECEPTORS
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ecules are more capable of efficiently blocking CCK1R- or
CCK2R-related physiological effects (201).
III. STRUCTURE-FUNCTION RELATIONSHIP
OF CHOLECYSTOKININ RECEPTORS
A. Localization of Ligand Binding Sites
A large set of converging data related to binding sites
of cholecystokinin receptors is currently available, giving
a good picture of the binding mode of natural and synthetic ligands to their cognate receptors. The data were
provided using essentially four complementary approaches, site-directed mutagenesis, photoaffinity labeling, NMR-NOE transfer, and three-dimensional modeling.
The binding site for CCK on the CCK1R is of particular
interest due to the high selectivity of this receptor for
sulfated versus nonsulfated CCK and for sulfated CCK
versus gastrin. The two key interactions, which account
for the 500- to 1,000-fold selectivity of CCK1R for sulfated
versus nonsulfated CCK, involve a Met and an Arg in the
second extracellular loop (169, 170). Proximity of the
sulfated moiety of CCK with Arg was recently confirmed
by photoaffinity labeling (17). The NH2-terminal moiety of
CCK is tightly linked to extracellular residues of CCK1R,
including residues in the second extracellular loop at the
top of transmembrane (TM) helix I and within the third
extracellular loop (16, 237). The COOH-terminal tetrapeptide of CCK appears to be embedded between TM helices
III, V, VI, and VII through a network of both ionic and
hydrophobic interactions (16, 145, 168). This binding
mode of the COOH terminus of CCK into CCK1R is in
agreement with an NMR study of the interactions between
CCK and a fragment of CCK1R comprising the top portion
of helix VI and the third extracellular loop as well as a
fragment including amino acids at the top of transmembrane segment I (173, 373). With the use of photoaffinity
labeling, two hits in the CCK1R were identified. The first
was a Trp at the top of TM I using a photoprobe with the
reactive moiety within the COOH-terminal Phe of CCK
and the second was an His within the third extracellular
loop using a probe with a benzophenone in the place of
the Gly of CCK (Fig. 3) (193, 228). Accordingly, a model of
binding of CCK to the CCK1R was proposed in which the
COOH terminus of CCK and the tyrosine sulfate were in
interaction with Trp39 and Arg197, respectively, and the
NH2-terminal moiety was in contact with the third extracellular loop of the receptor (132). This second model of
CCK positioning into the CCK1R binding site is divergent
from that obtained on the basis of site-directed mutagenesis results (16, 237).
The first precise information available on the CCK2R
binding site was the identification of five amino acids of
the second extracellular loop of CCK2R that were essen-
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and gastrin and, more recently, by nonpeptide ligands
with distinct chemical structures.
Among the peptidic analogs, JMV 179 and JMV 180
display nanomolar affinity for CCK1R (159, 286). JMV 179
is a CCK1R antagonist that corresponds to the COOHterminal heptapeptide of CCK where the COOH-terminal
amidated phenylalanyl residue has been replaced by a
phenylethyl ester moiety, and the L-Trp by a D-Trp. Interestingly, unlike in CCK, tyrosine sulfation in JMV 179 is of
minor importance for its binding to CCK1R (17, 470).
Exchange of D-Trp for a L-Trp in JMV 179 yielded an
atypical ligand of the CCK1R JMV 180. Indeed, JMV 180
can act as a full agonist, a dual agonist/antagonist, or a
partial agonist depending on the species, tissue, or biological event under investigation (159, 571, 589). With
respect to CCK1R-mediated stimulation of inositol phosphate production, JMV 180 is a partial agonist. At any
concentrations, this CCK analog causes [Ca2⫹]i oscillation
in pancreatic acini similar to that observed with CCK at
picomolar concentrations (see sect. IVA).
Although the COOH-terminal tetrapeptide of CCK
presents a low affinity for the CCK1R, chemical manipulation of this peptidic fragment successfully generated
selective high-affinity agonists of this receptor which surprised scientists in the field who believed that sulfated
tyrosine was required for optimal binding and activity of
CCK at CCK1R. Substitution of Met by an o-tolylaminoacarbonyl-Lys residue and of Phe by (N-Me)Phe in CCK-4
were key modifications that gave these peptides a CCK1R
personality (288). Interestingly, high-affinity agonists of
CCK2R were obtained by replacement of Met by (NMet)
Nle (351). Such work, which yielded a large variety of
CCK-4 analogs, also indicated that minor structural differences in CCK-4-based peptides dictate affinity and selectivity for CCK1R and CCK2R.
In the benzodiazepine derivative family, L364,718 and
L365,260 appeared as the first potent nonpeptide antagonists of CCK1 and CCK2R, respectively (82, 291). They
were followed by a large series of potent compounds
(201). Interestingly, from a drug design point of view,
CCK1R antagonist L364,718 (MK-329) was generated from
asperlicin, a fermentation product isolated from the fungus Aspergillus alliaceus, which presents micromolar affinity for CCK1R (83).
Several of the nonpeptide agonists and antagonists
have reached phase I and II clinical trials. Indications for
these compounds can be deduced from the pathophysiological role of CCK1R and CCK2R in humans (see sect.
VII). In this context, one major question that recently arose
with some of the nonpeptide antagonists was whether
these were pure antagonists rather than partial agonists.
Indeed, some so-called antagonists turned out to present
some agonist activity in the stomach and pancreas and on
cells transfected with the cDNAs encoding CCK1R or
CCK2R (48, 257, 447). Presumably, newly generated mol-
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DUFRESNE, SEVA, AND FOURMY
tial for high-affinity interaction with gastrin (473). In subsequent mutagenesis studies, the authors showed that
within this five-amino acid sequence, an His is crucial for
CCK recognition and interacts with the penultimate aspartic acid of CCK (471, 472). Furthermore, several amino
acids and key regions that interact with the amidated
COOH-terminal phenylalanine of CCK were identified in
transmembrane helices IV and VI (161, 264). Photoaffinity
labeling experiments using a CCK ligand with a photosensible moiety attached to the NH2 terminus identified
amino acids at the top of helix I, which agrees with results
from site-directed mutagenesis and molecular modeling
experiments that the sulfate on CCK-8 slightly interacts
with an Arg in this region of CCK2R (13, 161). On the basis
of these studies, it appears that binding sites of CCK on
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CCK1R and CCK2R involve residues that are located in
homologous regions. However, detailed analysis also
shows slightly distinct positioning of CCK within the two
receptors. The molecular basis for such divergent positioning is still not clearly understood.
An exciting issue that emerged in the course of binding site studies with CCK receptors was whether synthetic
molecules that are structurally divergent with the natural
ligands of the receptors share the same binding site or
have distinct binding pockets. This issue has been addressed by several authors using site-directed mutagenesis. Regarding CCK1R, it was shown that certain residues
of CCK1R were critical for binding and response to CCK
but were without any importance for binding and activity
of several nonpeptide antagonists. The best illustration
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FIG. 3. Serpentine representation of CCK1R with
amino acids involved in the binding site of CCK (top)
and a side view of the 3-dimensional model of liganded
CCK1R (bottom). Amino acid side chains of CCK1R
binding site are depicted in green, while the ligand
CCK is colored in orange.
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B. Activation Mechanism and Regulation
Residues located inside the ligand binding site in
GPCRs play a key role in the GPCR activation process.
Conserved motifs such as the E/DRY (TM III) and NPXXY
(TM VII) motifs found in members of family I of GPCRs
are critical as mutation in either of these two respective
regions in CCK2R yielded a constitutively active or inactive receptor (160, 162). The constitutively active CCK2R
mutant bearing a mutation in E/DRY motif (Asp mutated
to Ala) was associated with dramatic alterations in cell
morphology in which it was expressed and enhanced cell
proliferation and invasion. On the other hand, while
CCK2R bearing a mutation in the NPXXY motif (Asn
mutated to Ala) was unable to activate phospholipase C,
it still physically coupled to G␣q protein, thereby demonstrating that the Asn of this motif is essential for G protein
activation (160). Other residues, which are conserved in
GPCRs, were also shown to be important for activation of
phospholipase C and adenylyl cyclase by CCK2R and
CCK1R. Transmembrane residues of the CCK2R such as
Asp of TM II, triple basic motif (KKR) at the COOH
terminus of the third intracellular loop, and a Phe residue
of TM VI were shown to play a key role in the coupling of
CCK2R to phospholipase C (222, 383, 554). Interestingly,
mutation of two of these amino acids or motifs, namely,
the Phe of TM VI and the KKR motif of the third intracellular loops, were also demonstrated to be without importance for CCK2R-induced stimulation of arachidonic acid
release, supporting distinct mechanisms of CCK2R coupling to phospholipase C and phospholipase A2 (383). The
chemical nature of residue 121 within TM III of the
CCK1R seems to be very important for activation of the
receptor. In fact, biological experiments with mutants as
well as dynamic simulations of modeled liganded CCK1R
support the conclusion that introduction of hydrophobic
residues near position 121 determines positioning of the
aromatic ring of the Phe of CCK within the binding pocket
(145). This was further documented in a study with JMV
180, a partial agonist of the CCK1R, which partly shares
its binding site with that of CCK (15). In this study, it was
shown that helices III and VI of the CCK1R are functionally linked through the CCK1R agonist binding site and
that positioning of the COOH-terminal ends of peptidic
agonists towards Phe330 of helix VI is responsible for
extent of phospholipase C activation through G␣q coupling (15). The molecular basis for CCK1R coupling to
adenylyl cyclase was investigated based on the data showing that CCK1R, but not CCK2R, stimulates cAMP formation. Chimeric receptors constructed and expressed in
HEK cells provided evidence that a small peptidic sequence of the first intracellular loop of CCK1R is essential
for cAMP signaling (577). The importance of the first
intracellular loop for CCK1R coupling to adenylyl cyclase
was further supported by substitution of a single residue
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was achieved through mutation of the Arg in the second
extracellular loop of CCK1R, which caused dramatic decreases in affinity and potency of CCK but did not change
affinity and antagonistic potency of L364,718 and
SR27,897. In contrast, mutation of Asn333 at the top of
transmembrane helix 6 affected affinity and potency of
both CCK, L364,718, and SR27,897 (168, 170).
A large set of data exists concerning the binding sites
for nonpeptide ligands of CCK2R that were essentially
obtained in the course of studies related to the analysis of
the impact of intra- and interspecies polymorphisms of
this receptor on affinity and partial agonism of a series of
CCK2R antagonists. The first striking interspecies difference to be studied was that between dog and human
CCK2R. Indeed, the CCK1R antagonist L364,718 binds to
the canine CCK2R with an affinity similar to that with
which the CCK2R antagonist L365,260 binds to the human
CCK2R, and vice versa. Mutation of nonconserved amino
acids from transmembrane helices led to the identification of a single amino acid in the canine sequence
(Leu355, TM VI) that is responsible for this reversal of
specificity (38). In general, studies with so-called nonpeptide antagonists of CCK2R revealed that although the
amino acid sequence homology of CCK2R in the different
species is near 90%, the efficacy of the nonpeptide molecules to stimulate phospholipase C varied from 0 to 60% of
the CCK-induced maximal response according to the species and the compound tested (L365,260, L740,093,
YM022, PD135158, PD136,450, PD134,308) (39, 47, 48, 227,
232, 255, 256). Incorporation of nonconservative amino
acids in the human CCK2R sequence enabled identification of amino acids in transmembrane helices that account for these variations (47, 48). These studies contributed to our understanding of the structural basis by which
CCK2R ligands possess agonist activity. Furthermore,
they point out that polymorphisms among receptors from
different species can cause alterations in the apparent
pharmacological profile of a drug.
Another interesting issue, raised by the generation of
nonpeptide ligands for peptide-binding GPCRs, was
whether or not compounds with similar structures but
opposite biological activities share the same binding site
and, so, which intrinsic mechanism(s) govern(s) receptor
function at the binding site level. A nonpeptide agonist of
the CCK1R, SR146,131, was generated starting from the
structure of the antagonist SR27,897 (44). Pharmacological analysis of CCK1R mutants using these compounds,
together with molecular modeling, agreed with the view
that the binding sites of the two nonpeptidic ligands and
of CCK are largely overlapping. Within these binding sites,
a Leu in TM VII interacts with SR146,131 but not SR27897
or L364,718, suggesting that one underlying mechanism of
activation by the nonpeptide ligand resides in this additional site of interaction (145, 182).
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DUFRESNE, SEVA, AND FOURMY
acids within the third intracellular loop for alanine completely abolishes CCK1R phosphorylation, they do not alter
its signaling and internalization (363). A study supports that
an internal region of the COOH-terminal tail of the CCK1R
which is devoid of phosphorylation sites is important for
normal CCK1R trafficking in CHO cells (177). Analysis of the
molecular basis for CCK2R internalization using COOH-terminal truncated receptors indicated that phosphorylation
sites involved in CCK2R endocytosis are mainly located on
the COOH terminus of the receptor (381).
IV. SIGNALING TRANSDUCTION PATHWAYS
ACTIVATED BY CHOLECYSTOKININ
RECEPTORS
In this section, signaling pathways that account for
short- and long-term activation of CCK receptors are described. A summary is depicted in Figure 4.
A. Phospholipases/Calcium Mobilization
and Protein Kinase C Activation
Typically, the superfamily of GPCRs is capable of
inducing a rapid hydrolysis of phosphatidylinositol
bisphosphate by phospholipase C (PLC) family members
to generate inositol trisphosphate (IP3) and diacylglycerol
(DAG), which respectively induce calcium mobilization
and stimulate several protein kinase C (PKC) isoforms.
In different cell types CCK1 or CCK2 receptors
(CCK1R, CCK2R) activate principally PLC-␤ isoforms,
FIG. 4. Schematic description of the signaling
pathways known to be activated by CCK1R and CCK2R.
In addition to signaling pathways classically activated
by G protein-coupled receptors such as the phospholipase C (PLC)-␤/diacylglycerol (DAG)/Ca2⫹/protein kinase C (PKC) cascade or the adenyl cyclase (AC) pathway, CCK receptors also induce several other signaling
pathways known to be activated by tyrosine kinase
receptors: 1) the mitogen-activated protein (MAP) kinase pathways including ERK, JNK, and p38-MAPK; 2)
the phosphatidylinositol 3-kinase (PI3K) pathway; or 3)
the PLC-␥ pathway. Activation of nonreceptor tyrosine
kinases including Src, JAK2, FAK, and PYK2 is also an
early event in CCK receptor signaling. These tyrosine
kinases are involved in particular upstream of the MAP
kinase or PI3K pathways and in intracellular events
related to cell adhesion (see text for details). Finally,
CCK2R are also known to induce epidermal growth
factor (EGF) receptor transactivation. Arrows correspond to positive stimulations.
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(Ser) in the CCK2R by an Asn, which confers a full cAMP
response to CCK and gastrin (575).
CCK receptors, like other GPCRs, were initially thought
to trigger intracellular signals as monomeric membrane proteins. Biochemical and biophysical data have recently challenged this concept and provided evidence that many
GPCRs, if not all, can form homo-oligomeric and heterooligomeric assemblies within the plasma membrane (65,
368). CCK1R may exist as dimers that dissociate under CCK
activation (90). A functional impact of CCK1R⫹CCK2R heterodimerization was suggested on the basis of the observations that coexpression of CCK1R and CCK2R in CHO cells
yields enhanced signaling and cell growth compared with
the expression of a single receptor type (89). This finding
could explain why transgenic mice expressing CCK2R in the
pancreas together with endogenous CCK1R develop preneoplastic lesions and pancreatic cancers. These intriguing data
deserve further investigation to establish the pathophysiological relevance of CCKR heterodimerization.
GPCR-mediated internalization is a biological process that contributes both to the agonist response and to
its desensitization. Both CCK1R and CCK2R have been
shown to undergo internalization in pancreatic acini and
transfected NIH 3T3 or CHO cells (177, 418, 522). Interestingly, in the case of CCK1R, agonist and antagonistinduced desensitization of CCK1R were described (417).
Under CCK stimulation, the CCK1R is rapidly phosphorylated, mostly in the third intracellular loop, both by
protein kinase C and a G protein receptor kinase. There
are at least five distinct phosphorylatable amino acids in
CCK1R. While exchange of two phosphorylatable amino
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CCK RECEPTORS
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cillations is also regulated by the phosphorylation of IP3
receptors in response to physiological doses of CCK
through a mechanism dependent on the protein kinase A
(PKA) pathway (271, 502). In addition, the high-affinity
binding site of CCK1R is coupled to the phospholipase
A2/arachidonic acid cascade that inhibits IP3 and ryanodine receptors (180, 469). Activation of the low-affinity
binding sites by high concentrations of CCK generates a
very different pattern of calcium mobilization, which consists of a rapid global elevation of intracellular calcium
that decreases to a sustained plateau (394). The initial
peak of calcium corresponds to IP3 production and the
subsequent release of calcium from IP3-sensitive intracellular stores, whereas the plateau is dependent on extracellular calcium influx. The mechanisms regulating calcium signals in response to CCK2R activation remain
poorly understood. Both a rapid mobilization of intracellular calcium that decreases to a sustained plateau and
calcium oscillations have been described in numerous
cell types naturally expressing endogenous CCK2R as
well as stably transfected cell lines (6, 462, 463, 517).
In addition to ␤- and ␥-PLC isoforms, two other phospholipases are activated by the CCK receptors: cytosolic
phospholipase A2 (cPLA2), an enzyme that produces arachidonic acid from membrane phospholipids (166, 180,
266, 469, 474, 531), and phospholipase D (PLD), which
induces a sustained diacylglycerol (DAG) production and
activates PKCs (7, 54, 180, 414). Whereas the high-affinity
binding site of CCK1R activates cPLA2, the low-affinity
binding site is coupled to PLD (180, 454).
The PKC family includes three subgroups: conventional PKCs, which are dependent on calcium and DAG
(␣, ␤, ␥); novel PKCs, which show sensitivity to DAG but
are calcium independent (␦, ⑀, ␩, ␪); and atypical isoforms
that are unresponsive to calcium and DAG (␨, ␭, ␫).
Numerous studies have shown the involvement of
PKCs in both CCK1R and CCK2R signaling using broadspectrum PKC inhibitors. In particular, mitogen-activated
protein kinase pathways are activated by CCK1R or
CCK2R through PKC-dependent mechanisms, although
the specific isoforms of PKC involved were not identified
in these studies (107, 111, 116, 528). More recently, the
activation of several PKC isoforms by gastrin and CCK
has been reported. In rodent pancreatic acinar cells, lowaffinity CCK1R occupancy leads to the stimulation of
PKC-␣, -␦, -⑀, and -␨ (33, 280, 377, 435, 519). In different
human gastric tumor cell lines, CCK2R activates PKC-␣,
-␦, -⑀, and -␩ (355, 503).
Like conventional and novel PKCs, protein kinase D
(PKD, also called PKC-␮) and PKD2, which shows a high
homology to PKD, are serine/threonine kinases targets of
both DAG and phorbol esters. However, their structures
and the regulation of their enzymatic activities can be
distinguished from the members of the PKC family. Only
CCK2R, stably transfected in fibroblasts or human gastric
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likely through heterotrimeric G proteins of the Gq family
as demonstrated by immunoblocking experiments with
anti-PLC-␤ or anti-G␣q/␣ antisera (341, 371, 379, 588).
However, two publications suggested that ␤␥-subunits of
G proteins might be also involved in PLC activation by
CCK1R (587, 590).
PLC-␥1 isozyme has also been implicated in IP3 formation through CCK2R (582, 583). Recently, a direct association between CCK2R and PLC-␥1 has been demonstrated implicating the COOH-terminal phospho-Tyr438 of
the receptor and the SH2 domains of the PLC-␥1 (19).
IP3 produced by PLC isozymes leads to the subsequent release of calcium from intracellular stores. In numerous cell types naturally expressing endogenous CCK
receptors or stably transfected with CCK1R or CCK2R,
CCK and gastrin induce calcium mobilization. In particular, calcium signaling in response to CCK has been extensively studied in rat pancreatic acinar cells, which naturally express CCK1R. In this model, the two affinity states
of CCK1R generate different patterns of cytosolic calcium
elevations. Activation of the high-affinity binding sites
with physiological concentrations of CCK generates calcium oscillations resulting from the complex regulation of
different intracellular receptors that control calcium mobilization (374). These oscillations are mediated through
the activation of IP3 receptors, although weak IP3 production has been observed in response to physiological concentrations of CCK (158, 526). This primary release of
calcium from IP3-sensitive stores may be relayed through
calcium mobilization from IP3-insensitive pools by a
mechanism that involves calcium and other types of receptors (551). Among them, two receptors types, the ryanodine receptors and the nicotinic acid adenine dinucleotide phosphate (NAADP) receptors, which are activated
by two different calcium mobilizing messengers, cADPribose (cADPr) and NAADP, have also been implicated in
calcium oscillations evoked by CCK1R (71–75, 525). The
cellular distribution of these receptors, mainly apical for
the IP3 receptor (346), basolateral for the ryanodine receptor (274), and likely over the whole cell for the NAADP
receptor (70) as well as the cooperation that exists between these receptors may explain the spreading of the
calcium wave from the apical region throughout the
whole cell in response to CCK. Recently, CCK1R has been
shown to activate a cytosolic ADP-ribosyl cyclase that
may be responsible for the production of the calcium
mobilizing messenger cADPr (260, 500).
In rat pancreatic acini, calcium oscillations play a
crucial role in enzyme secretion regulated by low doses of
CCK (570).
Several signaling molecules modulate calcium oscillations induced by CCK1R. G␣q, G␣11, G␣14, as well as
the ␤ and ␥ subunits likely released from Gq family members, play an important role in mediating the oscillatory
calcium response (588, 590). The pattern of calcium os-
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DUFRESNE, SEVA, AND FOURMY
cancer cells, induces phosphorylation and activation of
PKD and PKD2 through a PKC-dependent mechanism (93,
503, 504).
B. Adenyl Cyclase and cAMP Production
C. Nitric Oxide and cGMP Pathway
Nitric oxide (NO), a molecule produced from L-arginine by NO synthase (NOS), can initiate cGMP-dependent
or cGMP-independent signaling pathways. Production of
cGMP, through the stimulation of soluble guanylate cyclase by NO, leads principally to the activation of cGMPdependent protein kinases but can also indirectly activate
cAMP-dependent protein kinases by blocking enzymes
involved in the degradation of cAMP (147).
The NO/cGMP pathway has been shown to be activated by CCK1R in different cellular models. In CHO cells
expressing CCK1R, CCK increases NOS activity, NO production, and the intracellular concentration of cGMP. In
this cell model, activation of this signaling pathway by
CCK1R is linked to cell proliferation (101, 102). Stimulation of the NO/cGMP signaling cascade in response to
CCK has also been observed in rodent pancreatic acini
and could be involved in pancreatic secretion in vivo.
Indeed, nonselective NOS inhibitors as well as deletion of
NOS in transgenic mice decrease pancreatic secretion
induced by CCK (2, 125). In addition, the gastroprotective
role of CCK on gastric mucosal is dependent on this
pathway (63, 64, 568).
D. Mitogen-Activated Kinase Cascades
Mitogen-activated protein kinases (MAPKs) are
serine/threonine kinases known to be activated by several
families of receptors including tyrosine kinase receptors,
GPCRs, or cytokines receptors. They include four subPhysiol Rev • VOL
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Although both CCK1R and CCK2R activate the PLC
pathway via a Gq/11 protein, only CCK1R is also coupled to
Gs. In pancreatic acinar cells, CCK induces adenylate
cyclase activity and in CHO cells stably transfected with
CCK1R, high doses of CCK increase intracellular cAMP by
stimulating this enzyme (480, 589). The structural basis
for this activation is described in section IIIB. Although
some studies have reported the effect of pertussis toxin
on signaling pathways activated by CCK receptors (210,
338, 382), coupling to Gi proteins and adenyl cyclase
inhibition remain controversial (378). Numerous publications have shown that CCK1R is not coupled to Gi in
pancreatic acinar cells (303, 543, 576), and only one publication has reported that CCK2R inhibits adenyl cyclase
activity via a mechanism likely to involve Gi (440).
groups: extracellular signal-regulated kinase 1/2 (ERK1/2
also known as p44MAPK and p42MAPK), c-jun NH2-terminal
kinases (JNKs), ERK5, and p38 MAPKs. These kinases are
implicated in numerous cellular functions such as cell
growth, differentiation, survival, and apoptosis.
Several studies using ERK kinases (MEKs) inhibitors
have shown the involvement of the ERK1/2 pathway in
different cellular processes regulated by CCK receptors.
In particular, this signaling cascade controls cell proliferation and migration induced by CCK2R and the transcriptional regulation of gastrin-sensitive genes (208, 353, 496).
In pancreatic acinar cells, the ERK pathway also regulates
protein translation induced by CCK1R, a cellular event
involved in digestive enzyme synthesis (433).
Activation of ERK1 or ERK2 by growth factor receptors with intrinsic tyrosine kinase activity has been well
documented. The best understood mechanism involves
the recruitment of Grb2/Sos or Shc/Grb2/Sos complexes
to tyrosine-phosphorylated receptors. These complexes
subsequently activate the following cascade: Ras/Raf/
ERK-kinases/ERK1/2.
In pancreas-derived AR42J cells, which are known to
express endogenous CCK2R or in stably transfected CHO
cells, gastrin stimulates the Ras-dependent ERK1/2 pathway via tyrosine phosphorylation of Shc, which enables
interaction with the Grb2/Sos complex. This mechanism
is PKC dependent, and Src family kinases, also activated
by CCK2R, have been identified as the tyrosine kinases
mediating gastrin-induced Shc phosphorylation (111, 113,
465). The Ras-dependent MEK/ERK1/2 cascade is also
activated by CCK1R in pancreatic acinar cells (138, 139).
In this cell model, CCK1R stimulates the Shc/Grb2/Sos
complex through a PKC-dependent mechanism. Although
the tyrosine kinase upstream of this cascade has not been
clearly identified, PYK2, a tyrosine kinase related to p125FAK, which is activated by both high- and low-affinity
CCK1R, might be involved (107, 520). In addition, it is
possible that Src family kinases, also known to be stimulated by the CCK1R in pancreatic acini, could play a role
in Shc phosphorylation (533). CCK1R also activates a
downstream effector of the ERKs, the 90-kDa ribosomal
S6 kinase (p90rsk), known to play an important role in
protein synthesis (56). Alternately, ERK1/2 activation by
CCK receptors might be mediated by a Ras-independent
mechanism involving the direct activation of Raf by PKCs
(348, 463).
ERK1/2 activation by CCK2R can occur through a
very different mechanism in gastrointestinal epithelial
cells. This mechanism involves transactivation of the epidermal growth factor (EGF) receptor. In gastric epithelial
cells, gastrin induces the expression and processing of
proHB-EGF leading to the release of HB-EGF, tyrosine
phosphorylation of EGF receptors and the subsequent
activation of downstream signaling pathways (327, 475).
In contrast, gastrin induces EGF receptor transactivation
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CCK RECEPTORS
E. Phosphatidylinositol 3-Kinase
Class I phosphatidylinositol (PI) 3-kinases are a family of lipid kinases that play a central role in numerous
Physiol Rev • VOL
cellular processes including cell proliferation and survival, protein synthesis, motility, and adhesion. These
lipid kinases phosphorylate the D3 position of the inositol
ring on phosphatidylinositols which serve as intracellular
second messengers and recruits pleckstrin homology
(PH) domain-containing proteins, such as AKT, to the
plasma membrane. These kinases are heterodimers composed of the p110 catalytic subunit constitutively associated with the p85 adaptor/regulatory subunit.
Class I PI 3-kinases are subdivided into class IA and
class IB. The PI 3-kinase ␥, belonging to class IB, is mainly
activated by GPCRs. Recently, using pancreatic acini isolated from mice deficient for the catalytic subunit of PI
3-kinase ␥, Gukovsky et al. (188) have shown the role of
this PI 3-kinase isoform in several intracellular events
induced by supramaximal concentrations of CCK including calcium mobilization, calcium influx, and activation of
NF␬B and trypsinogen (188). All these events may play an
important role in acute pancreatitis induced by supraphysiological doses of CCK. However, other PI 3-kinase
isoforms may be activated by CCK1R.
In pancreatic acinar cells, the PI 3-kinases also play
an important role in protein synthesis activated by low
doses of CCK. In this model, Bragado et al. (57, 58)
demonstrated that activation by CCK1R of two components of the translational machinery, p70S6kinase, which
phosphorylates the ribosomal protein S6, and the initiation factor eIF4E, which is involved in cap-dependent
translation, can be blocked by PI 3-kinase inhibitors (57,
58). However, the isoform involved in this process remains to be identified. Mechanisms leading to PI 3-kinase
activation by CCK1R are poorly understood. They might
involve Src family kinases. Indeed, immunoprecipitation
studies in pancreatic acini have shown that CCK induces
an association between Src and PI 3-kinase (240).
Class IA PI 3-kinases are known to be activated by
receptor tyrosine kinases (RTKs) through at least two
different mechanisms. First, the SH2 domains of p85 can
bind directly to specific phosphotyrosine-containing sequences on tyrosine kinase receptors. Conformational
changes in the p85/p110 complex following recruitment
by the receptor and the proximity to lipid substrates lead
to kinase activation. Another mechanism has been described for insulin and insulin-like growth factor (IGF)-I
receptors, in which receptor autophosphorylation following ligand stimulation permits the binding of scaffold
proteins called insulin receptor substrates (IRS). Subsequent phosphorylation of IRS proteins by the receptor
recruits the p85/p110 PI 3-kinase and leads to its activation.
This class of PI 3-kinase has been reported to be
activated in response to gastrin in different cell lines
expressing endogenous CCK2R as well as stable transfectant (43, 113, 149, 258). The molecular mechanism involves Src phosphorylation of the adaptor protein IRS-1
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in intestinal cells via an intracellular signaling pathway
mediated by Src family kinases (191). The transactivation
of a receptor tyrosine kinase has never been reported for
CCK1R.
Phosphorylation of GPCRs by specific GPCR kinases
(GRKs) is a mechanism that contributes to receptor desensitization. It also plays an important role in regulation
of MAPK cascades. Particularly, for the ␤2-adrenergic receptor, serine and threonine phosphorylated residues bind
␤-arrestins, which serve as adapter proteins in the recruitment of signaling molecules. The resulting complex is internalized with the ␤2-adrenergic receptor and leads to activation of MAPKs (315). Although CCK receptors are known to
be phosphorylated by serine/threonine kinases such as
PKCs or GRKs and internalized (164, 177, 363, 381, 393),
MAPK stimulation by a ␤-arrestins-dependent mechanism
has never been described for the CCK receptors.
JNK and p38-MAPK were initially identified as two
signaling cascades mediating cellular stress induced by
exposure to ultraviolet radiation, proinflammatory cytokines, and osmotic shocks. Afterwards, several studies
have shown that they are also activated by receptor tyrosine kinases and GPCRs (192). JNK and p38-MAPK
cascades are both stimulated by CCK receptors. Activation of these pathways by CCK2R can be blocked by PKCs
or Src kinases inhibitors and is involved in the regulation
of cell proliferation and survival by gastrin (115, 116).
In rat pancreatic acini, which naturally express
CCK1R, supraphysiological concentrations of CCK activate JNK. In this model, CCK-induced JNK activation is
mediated through a Ras-dependent mechanism that does
not involve PKCs or calcium mobilization (106). Little is
known about the role of the JNK pathway in CCK1Rmediated effects. However, it has been suggested that
JNK activation by high doses of CCK might be a stress
response, since these doses also induce pancreatitis (443,
549). In addition, the JNK pathway may be also involved
in DNA synthesis stimulated by CCK1R in pancreatic cells
(348).
In contrast, in the same cellular model, the p38MAPK pathway is induced by physiological doses of CCK
and mediates actin cytoskeleton reorganization, likely
through the phosphorylation of the small heat shock protein Hsp27 (442, 550).
In addition to ERK1/2, JNK, and p38-MAPK, the ERK5
pathway is activated by gastrin in the intestinal cell line
RIE-1 transfected with CCK2R. In this cell line, ERK5 may
participate in the activation of the transcription factor
MEF2 and the regulation of COX-2 downstream of CCK2R
(191).
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DUFRESNE, SEVA, AND FOURMY
F. Focal Adhesion Kinase and Associated Proteins
p125-focal adhesion kinase (FAK) is a cytoplasmic
protein tyrosine kinase, localized to focal adhesion sites,
that controls multiple intracellular signaling pathways involved in cell morphology, cell motility, and invasion. This
protein is activated by numerous membrane receptors
including integrins, RTKs, and GPCRs. In many cell types,
p125-FAK phosphorylation leads to the recruitment of Src
kinases and the formation of an activated p125-FAK/Src
complex. This complex associates and phosphorylates
integrin-associated proteins such as paxillin and talin, as
well as adaptor proteins such as Shc and p130Cas (446).
Phosphorylation of p125-FAK, p130Cas, and paxillin have
been reported for both CCK1R and CCK2R in numerous
cell models. These phosphorylations are regulated by the
small GTPase Rho that also plays an important role in
stress fiber formation and modulation of cell morphology
observed in response to activation of CCK receptors (163,
239, 365, 463, 517, 518, 586).
Formation of an activated p125-FAK/Src complex has
also been observed following CCK2R activation, and
phosphorylation of p130Cas by gastrin has been shown to
be Src dependent (112, 115).
PYK2 is also a nonreceptor focal adhesion tyrosine
kinase closely related to p125-FAK. In pancreatic acini,
CCK, through CCK1R, induces the phosphorylation and
the activation of PYK2 by a calcium- and PKC-dependent
mechanism. Once phosphorylated, PYK2 can associate
with Grb2 or a p130Cas-associated protein, CrkII, leading
to the activation of downstream signals (520).
G. The JAK/STAT Pathway
Janus kinases (JAKs) are a family of nonreceptor
tyrosine kinases which includes four members: the ubiquitously expressed JAK1, JAK2, TYK2, and JAK3 which is
found in hematopoietic cells. They are known to phosphorylate and activate the STAT family of transcription
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factors (signal transducers and activators of transcription). Once phosphorylated, STAT proteins dimerize and
translocate to the nucleus where they bind to target
genes. The JAK/STAT signaling pathway that is well
known to be activated by cytokines and growth factor
receptors is involved in a wide variety of cellular processes including immune response, differentiation, cell
survival, proliferation, and oncogenesis. The mechanism
of JAK activation by cytokine receptors has been elucidated. Ligand binding induces dimerization of the receptors and a transphosphorylation of the associated JAK
tyrosine kinases. Activated JAKs in turn phosphorylate
the receptor that recruits the STAT proteins. To date, very
few GPCRs have been shown to be connected to the
JAK/STAT pathway. Recently, CCK2R has been shown to
activate the JAK2/STAT3 pathway in different cell lines in
vitro and in vivo, such as in transgenic mice expressing
the receptor in pancreatic acini (148, 149). The mechanism of JAK2 activation involves G␣q proteins and requires the NPXXY motif, located at the end of the seventh
TM domain of CCK2R This motif, which is critical for
Gq-dependent signaling pathways, is also required for
STAT3 activation by CCK2R. This signaling pathway participates in CCK2R-mediated growth effects. JAK2 could
also be involved in gastrin-induced modulation of cell-cell
adhesion.
H. Other Signaling Molecules
1. Small GTPases
The small G protein superfamily, which includes at
least five subfamilies (Ras, Rho/Rac/Cdc42, Rab, Arf/Sar1,
and Ran), plays a key role upstream of numerous signaling cascades and regulates a large number of cellular
processes.
CCK2R stimulates the small GTPase Ras upstream of
the ERK1/2 and PI 3-kinase/AKT pathways, mediating the
proliferative and antiapoptotic action of gastrin (495).
Ras is also activated by CCK1R, in pancreatic acini.
This activation does not appear to be involved in pancreatic enzyme secretion stimulated by CCK but could lead
to a stimulation of DNA synthesis through a mechanism
independent of the ERK1/2 pathway (139, 348).
Among the Rho family members, Rho, Rac, and
Cdc42 have been reported to be activated by CCK2R. Rho
and Cdc42 appear to regulate the PI 3-kinase pathway and
the proliferative effects mediated by this receptor (495).
In addition to their role in regulating cell proliferation,
Rho and Rac are able to switch on signaling pathways
involved in amylase secretion evoked by CCK1R (41, 354)
and stress fiber formation and morphological changes
induced by both CCK receptors (see sect. IVF).
In numerous cell systems, Rho can be activated
through the ␣-subunits of the heterotrimeric G proteins,
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on tyrosine residues, which serve as binding sites that
recruit and activate p85/p110 PI 3-kinase complex (113,
259). The downstream effector of p85/p110 PI 3-kinase,
AKT (also known as PKB), has also been identified to play
a role in CCK2R signaling and is rapidly activated by
phosphorylation in response to gastrin. The PI 3-kinase/
AKT pathway is involved in the proliferative and antiapoptotic action of CCK2R as well as the regulation of cell
adhesion and migration mediated by this receptor (43,
149, 198, 527). Another role of this pathway in CCK2R
signaling is to control protein synthesis by regulating
components of the translational machinery. In particular,
CCK2R activates p70S6K and the initiation factor eIF4E
(119, 392, 466).
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CCK RECEPTORS
G12 and G13. In intestinal smooth muscle cells, high concentrations of CCK activate G12, G13, and RhoA (342).
More recently, it has been reported in NIH3T3 cells transfected with CCK1R that occupation of the low-affinity
binding site of the receptor leads to Rho activation and
cytoskeletal remodeling mainly through a G13-dependent
mechanism (276). In addition to the Ras and Rho families,
several members of the Rab family have been implicated
in CCK1R signaling. Although the precise mechanisms are
not known, a role for Rab3D, Rab4, Rab11, and Rab27b in
regulating CCK-induced acinar exocytosis has been reported by several groups (87, 88, 212).
Supramaximal concentrations of CCK, known to induce pancreatitis in rats via CCK1R, activate NF␬B, a
transcription factor that regulates inflammatory processes. In most cells, NF␬B is sequestered in the cytoplasm through interactions with the I␬B (inhibitor of
NF␬B) family of inhibitory proteins. The mechanism leading to CCK induction of NF␬B involves the activation of
an I␬B kinase. Phosphorylation of I␬B and its subsequent
ubiquitination and degradation by proteasome activity
dissociates NF␬B from I␬B. Nuclear translocation of
NF␬B leads to transcription of target genes such as the
mob-1 chemokine. Several signaling pathways triggered
by CCK1R are upstream NF␬B activation, including calcium mobilization, the novel PKCs ␦ and ⑀, and PI 3-kinase
␥ (197, 435, 514).
In gastric epithelial cells, CCK2R also activates
NF␬B, leading to expression of proinflammatory genes
such as interleukin (IL)-8 (206).
V. TARGET GENES OF CHOLECYSTOKININ
RECEPTORS
A. Gastrin-Dependent Gene Regulation
Gastrin is known to regulate gastric acid secretion by
acting on enterochromaffin-like (ECL) cells that control
synthesis and secretion of histamine. This process requires expression of three target genes regulated by gastrin and CCK2R in ECL cells: 1) histidine decarboxylase
(HDC), the rate-limiting enzyme for histamine biosynthesis; 2) vesicular monoamine transporter 2 (VMAT2), involved in histamine accumulation into secretory vesicles;
and 3) chromogranin A (CgA), which plays a role in
vesicle stability and propeptide processing (208). In gastric epithelial cells, CgA expression is regulated by gastrin
via the binding of three transcription factors, SP1, CREB
and Egr-1, to a GC-rich element of the promoter. In the
VMAT2 gene promoter, two sequences are involved in
gastrin-mediated effects: a cAMP responsive element
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2. NF␬B/I␬B
(CRE) that binds the transcription factor CREB and an
overlapping AP2/SP1 site regulated by an uncharacterized
nuclear protein. A gastrin-responsive element has also
been identified in the HDC gene promoter that allows the
association of two uncharacterized nuclear factors, gastrin responsive element binding proteins 1 and 2. In gastric epithelial cells, gastrin likely stimulates the expression of these three target genes through the activation of
a Raf/MEK/ERK1/2 cascade in a ras-independent mechanism involving the direct activation of Raf by PKCs (208).
In glucagon-producing pancreatic cells, CCK2R also
regulates glucagon gene expression via activation of the
ERK1/2 pathway and binding of the transcription factor
Egr-1 to the islet-specific G4 element present in the proximal glucagon promoter (277).
In addition to secretion, CCK2R is known to regulate
cell proliferation by stimulating the expression of early
response genes and other growth-related genes. In the
tumor pancreatic cell line AR4 –2J, in ECL cells, and in
fibroblasts, c-Fos expression has been shown to be regulated by CCK2R. In particular, the CA-rich G box of the
serum response element (SRE) has been reported to play
a crucial role in gastrin-induced c-Fos promoter activation. However, maximal activation of the SRE by gastrin
also requires the binding of ternary complex factors
(TCFs) such as Elk1 and SAP1a to an E26 transformation
specific (Ets) motif. This activation is PKC dependent and
mediated by the ERK pathway. In addition, specific activation of the CArG box by CCK2R involves the small G
protein RhoA (496, 499). One publication also mentions
the importance of the CRE promoter element in gastrininduced c-Fos expression that might cooperate with the
two other binding sites (523). In gastrointestinal cells,
CCK2R was also described to induce the expression of the
protooncogenes c-Jun and c-Myc, although the mechanisms involved are unknown (517, 556).
Cyclins, that control the G1/S transition during the
cell cycle, play a crucial role in cell proliferation. Several
studies have shown an increase in the transcription of
cyclin D1, D3, and E in response to gastrin (388, 594). The
mechanism by which gastrin induces cyclin D1 transcription has been studied in a model of gastric tumor cells
expressing CCK2R. The CRE site of the cyclin D1 promoter was shown to predominantly mediate cyclin D1
induction by gastrin via the binding of two transcription
factors CREB and ␤-catenin (388).
Proteins of the Reg family have been recognized as
novel growth factors whose expression is increased under cellular stress, during inflammatory processes and
tumor development. Reg-1 gene expression in response to
gastrin has been reported in ECL cells and may be involved in gastric mucosal cell growth (20, 156). A C-rich
region has been identified in the Reg-1 promoter sequence
that binds transcription factors of the Sp-family, SP1 and
SP3, in response to gastrin and mediates the effects of
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Physiol Rev • VOL
B. CCK-Dependent Gene Regulation
In contrast to gastrin and CCK2R, very little information is available on gene regulation by CCK and CCK1R.
Intravenous infusion of CCK in the rat increases the expression of pancreatic digestive enzymes such as amylase, chymotrypsinogen B, and trypsinogen I (423). In the
same model, CCK also stimulates pancreatic ornithine
decarboxylase (ODC) expression, a key enzyme in polyamine biosynthesis, that is potentially involved in pancreatic growth (422). In pancreatic acini, CCK1R has also
been shown to induce the expression of immediate early
genes including c-fos, c-jun, and c-myc (292). More recently, in the same cell model, CCK1R has been reported
to regulate mob-1 chemokine gene expression by activating NF␬B through a mechanism dependent on PKCs and
intracellular calcium (196, 197).
VI. TISSUE DISTRIBUTION AND
PHYSIOLOGICAL ACTIONS OF
CHOLECYSTOKININ RECEPTORS IN THE
GASTROINTESTINAL TRACT AND OTHER
PERIPHERAL ORGANS
All data concerning the expression of CCK receptors
and their function in normal (nonpathological) tissues
and organs are summarized in Table 2.
A. Gastric Mucosae, Exocrine and
Endocrine Pancreas
1. Stomach
The stomach is one of the main targets of gastrin, and
several of the physiological functions of the hormone
have been well characterized in this organ. Gastrin is
produced in gastric endocrine G cells and has been initially identified as the key stimulus of gastric acid secretion by Edkins (142, 143). In addition to the control of
gastric secretion, recent observations in mice overexpressing gastrin or in which the gastrin gene has been
deleted demonstrate that the hormone has important
roles in the control of proliferation, differentiation, and
maturation of the different cell types of the stomach
(reviewed below). As a matter of fact, CCK2R that is
expressed in the stomach is an important part of the
system that regulates functions of the gastric epithelium.
CCK is also involved and appears to be a negative regulator through binding to CCK1R, also expressed in the
stomach.
Mapping of the receptors in human and dog gastric
tissues has shown that CCK2R is predominantly expressed in the midglandular region of the fundic mucosa,
corresponding to the location of parietal cells. CCK1R is
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CCK2R activation. This transcriptional regulation of Reg-1
involves, in gastric epithelial cells, the activation of PKCs
and the small G protein RhoA (20). In the same cells,
CCK2R also increases the expression of plasminogen activator inhibitor-2 (PAI-2), known to be upregulated in
gastric cancers. The binding of CREB to a CRE and of
c-jun to an AP-1 site have been shown to be responsible
for PAI-2 induction by gastrin. As for c-Fos gene expression, the transcriptional regulation of PAI-2 by
CCK2R is mediated by Rho, PKCs, and the ERK1/2
pathway (539).
In gastric epithelial cells, the growth stimulatory effect of CCK2R could be partially mediated through the
expression of HB-EGF, release of this factor, and stimulation of the EGF receptor. In these cells, the mechanism
by which CCK2R induces HB-EGF gene transcription involves activation of PKCs and the EGF receptor and
requires a GC-rich region of the promoter (475).
In several cellular models such as gastric and colonic
cancer cells, intestinal epithelial cells and fibroblasts
transfected with the CCK2R, gastrin has been shown to
enhance cyclooxygenase-2 (COX-2) gene expression (100,
191, 482). This key enzyme of prostaglandin synthesis is
known to play an important role in inflammation processes and carcinogenesis. In particular, COX-2 has been
involved in hyperproliferation, transformation, invasion,
and angiogenesis. In colon cancer cells, the ERK1/2 and PI
3-kinase pathways are involved in gastrin-induced COX-2
expression (100), whereas in intestinal cells, multiple
MAPK cascades, including ERK1/2, ERK5, JNK, and P38MAPK, contribute to the increase of COX-2 transcription
regulated by gastrin (191). Two cis-activating consensus
sequences, AP-1 and MEF2, have been identified within
the COX-2 promoter, as responsible for CCK2R-mediated
COX-2 expression.
In gastric tumor cells expressing CCK2R, gastrin also
regulates the expression of genes associated with cell
migration and invasion such as MMP9, a matrix metalloproteinase. This induction requires a pathway including
PKCs/Raf/ERK1/2 (574).
However, gastrin has also been reported to stimulate
genes that might counterbalance its proliferative action in
some circumstances. In particular, the trefoil factor TFF1
has been identified as a gastrin responsive gene in gastric
cells. This factor known to participate in the repair of
gastrointestinal mucosa by stimulating cell migration
might be involved in the inhibition of cell proliferation as
well. A GC-rich region of the TFF1 promoter has been
identified as a gastrin-responsive element that binds the
transcription factors SP3 and MAZ (238). As seen with
genes involved in gastric acid secretion, CCK2R stimulates the expression of TFF1 through the Ras-independent
activation of a Raf/MEK/ERK cascade.
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CCK RECEPTORS
TABLE
2.
Physiological function and tissue distribution of cholecystokinin receptors
CCK1R
Tissue/Organ
GI tissues
Stomach
RNA
CCK2R
Protein
Human (IS RT-PCR) Dog, human, rat,
(451)
(RA) (410)
Dog (RA) (299)
Function
RNA
Secretion of
somatostatin (D
cells)
Leptin secretion
(chief cells)
Human (IS RT-PCR) Dog (RA) (299)
(261, 451)
Guinea pig
(IHC) (521)
Human (IHC) (451)
Human (RT-PCR)
(96, 226)
Dog, human, rat
(RA) (410)
Rat (binding) (217)
Enzyme secretion
Mouse (binding)
(572)
Trophicity and
proliferation
Human (RT-PCR)
(96, 226)
Human (Northern
blot) (275, 380)
Bullfrog (binding)
(544)
Guinea pig (binding)
(223)
Dog (binding) (153)
Endocrine
pancreas
Liver
Rat (ISH) (236)
Not determined
Smooth muscles
Gallbladder
Cynomolgus
monkey (RNase
PA) (209)
Stomach
Guinea pig (cDNA
cloning) (123)
Bowel
Not determined
Adipocytes
Absent
Adrenal gland
Human (RT-PCR)
(307)
Rat (RT-PCR) (297)
Calf (binding) (272)
Pig (binding) (375)
Pig, rat, human
(IHC) (337, 458)
Insulin, somatostatin, Human (ISH) (409)
pancreatic
polypeptide
secretion
Not determined
Bovine (binding)
(494)
Rat cholangiocyte
(RT-PCR) (174)
Contraction of
gallbladder
Guinea pig (binding)
(385, 548)
Human (binding)
(529)
Hamster (RA) (14)
Alligator (RA) (359)
Human (RA) (410)
Gastric motility and
emptying
Rat pyloric
sphincter (RA)
(487)
Rat pyloric
sphincter (IHC)
(370)
Human (RA) (402,
Bowel motility
412)
Guinea pig (binding)
(340)
Absent
Rat (RA) (297)
Aldosterone
secretion
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Human (IHC)
(261, 451)
Dog (binding)
(153)
Guinea pig
(binding)
(585)
Calf (binding)
(272)
Pig (binding)
(375)
Human
(binding)
(515)
Human (RA)
(409)
Absent
Guinea pig (cDNA
cloning) (123)
Human (RA)
(410)
Not determined
Guinea pig
(binding)
(340)
Rat (RT-PCR) (21)
Rat (binding)
(21)
Rat (RA) (297)
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Regulation of acid
secretion
Trophicity,
proliferation of
gastric mucosa
Differentiation of
ECL and
parietal cells
Migration of
parietal cells
Unresolved
Glucagon
secretion
Human, rat, pig, Development,
horse, rat, dog
beta cell
(IHC) (337,
neogenesis
426)
Bile secretion
Absent
Human (RT-PCR)
(307)
Rat (RT-PCR) (297)
Function
Leptin gene
regulation
Aldosterone
secretion
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Exocrine
pancreas
Protein
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TABLE
DUFRESNE, SEVA, AND FOURMY
2—Continued
CCK1R
Tissue/Organ
RNA
CCK2R
Protein
Function
Blood cells
Human
mononuclear
cells (RT-PCR)
(453)
Unresolved
Kidney
Human, rat (RTPCR) (329)
Unresolved
Human, rat (RTPCR, ISH) (62,
336)
Rabbit (binding)
(287)
Satiety
Rat (IHC) (369, 501) Pancreatic enzyme
secretion
Rat (binding) (336)
Leptin secretion
Protein
Function
Jurkat cells
Antiproliferative
(binding) (135,
effects, unclear
285)
Guinea pig
Potassium and
(binding) (121,
sodium
547)
absorption
Rat (IHC) (546)
Rabbit (binding)
(287)
Rat (binding)
(336)
GI, gastrointestinal; IHC, immunohistochemistry; ISH, in situ hybridization; RT-PCR, reverse transcription-polymerase chain reaction; IS
RT-PCR, in situ reverse transcription-polymerase chain reaction; RA, receptor autoradiography; RNase PA, ribonuclease protection assay.
mostly found in the basal region of the fundic mucosa
where chief cells are located (299, 410). In several rat
studies, treatment with CCK2R antagonists caused
changes in ECL cell activity, indicating the presence of
the receptor on these cells (131, 195). Binding and functional studies demonstrated that both CCK1R and CCK2R
are present on guinea pig chief cells (91, 389). In addition
to detection on parietal and chief cells in the guinea pig
stomach, CCK2R was also detected on rare unidentified
endocrine cells that were negative for gastrin, histamine,
secretin, somatostatin, enkephalin, and gastrin-releasing
peptide (521). Precise cellular localization of human
stomach CCK2R by in situ RT-PCR and immunohistochemistry demonstrated expression in gastric parietal,
ECL, and putative precursor cells (261, 451). Expression
of CCK1R was visualized in neuroendocrine D cells in
antral mucosa and in nonparietal cells of the oxyntic
mucosa, most likely chief cells, mucous cells, and undifferentiated precursor cells of the stem cell compartment
of the oxyntic gland (451). Presence of CCK1R and
CCK2R in putative precursor cells supports the model
that depending on the cell lineage, expression of one or
either or even both receptors is switched off.
The cellular distribution of CCK2R within the acidproducing mucosa is in agreement with the major role of
gastrin in the regulation of gastric acid secretion. However, the question of whether the parietal cell CCK2R is
linked to acid secretion has been a matter of debate (289,
391, 552). A number of physiological studies have demonstrated the predominant role of histamine released from
ECL cells on acid secretion (30). Pharmacological studies
using histamine-2 blockers support the concept that gasPhysiol Rev • VOL
trin stimulates acid secretion via the release of histamine
from ECL cells (134, 203). The importance of gastrin was
confirmed by studies performed on gastrin or CCK2Rdeficient animals that exhibit similar abnormalities in the
stomach with reduced acid secretion and elevated basal
gastric pH (155, 248, 265, 344). The significance of gastrin
was corroborated by partial restoration of gastric secretion following gastrin infusion in gastrin-deficient mice
(155). Actually, a gastrin-ECL cell-parietal cell axis is
generally proposed for the control of gastric acid secretion. Nevertheless, morphological data showing expression of CCK2R on parietal cells support a contribution of
gastrin to the acid secretory response by direct activation
of parietal cells (450). However, the population of parietal
cells appears to be heterogeneous with regard to CCK2R
presence, thus suggesting that direct stimulation of parietal cells is a less efficient stimulus than the gastrinmediated release of histamine from ECL cells.
In addition to its well-known effect on acid secretion,
gastrin has for many years been recognized for its trophic
effects in the stomach (229). Targeted disruption of the
gene for CCK2R or gastrin in mice demonstrated the
importance of gastrin and the CCK2R in maintaining the
normal function, cellular composition, and organization
of the gastric mucosa. In addition to reduced acid secretion, these mutants exhibit marked atrophy of the gastric
mucosa, a decrease in the number of parietal and ECL
cells, and an increase in the number of mucous neck cells
(84, 248, 265, 344). These studies showed an essential role
of CCK2R and gastrin not only in proliferation but also in
the regulation of ECL and parietal cell differentiation (84,
246). First, parietal cells are present in gastrin-deficient
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Human
mononuclear
cells (RT-PCR)
(453)
Human lymphocyte
(RT-PCR) (105)
Guinea pig
(Northern blot)
(121)
Rat (Northern blot)
(546)
Mouse (RT-PCR)
(270)
Human, rat (RTPCR, ISH) (62,
336)
Mouse (RT-PCR)
(270)
Vagal afferent
fibers
RNA
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CCK RECEPTORS
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FIG. 5. Schematic representation of an acid-secreting gastric gland
showing the different cell types and sites of action of gastrin. Gastrin is
produced by endocrine G cells present in the antropyloric region and
stimulates acid secretion via the release of histamine from ECL cells.
Gastrin stimulates proliferation and differentiation of ECL and parietal
cells as well as migration of parietal cells either directly or via paracrine
cascades downstream of the CCK2R (induction of HB-EGF, TGF-␣, and
Reg1␣). CCK acting at CCK1R on D cells inhibits parietal cell, ECL cell,
and gastrin-producing cell functions via the release of somatostatin from
endocrine D cells. CCK1R expressed on chief cells mediates gastric
leptin secretion.
leptin gene promoter in gastric cells (179). These data
argue for a role of CCK1R in the physiological functions of
gastric leptin. CCK receptor status and a schematic representation of the regulatory pathways activated by gastrin and CCK are depicted in Figure 5.
2. Exocrine pancreas
A major physiological function of CCK is the stimulation of pancreatic enzyme secretion. This effect has
been widely studied in rodents where pancreatic acinar
CCK1R was first characterized in the 1980s (95, 120, 224,
415, 432). Functional, pharmacological, structural, and
biochemical characterization as well as cloning of CCK1R
were performed with rat pancreas. However, several reports suggested variations in the type of CCK receptor
expressed, with the presence and even the predominance
of CCK2R in the exocrine pancreas. Indeed, a few CCK2R,
representing ⬃20% of the total CCK binding sites, were
characterized in the exocrine pancreas of dog, but their
presence has not been linked to any physiological event
(153). A similar situation was found in guinea pig pancreas where 4% of CCK binding sites are CCK2R (585).
Predominance of CCK2R, compared with CCK1R, was
demonstrated in the adult calf exocrine pancreas,
whereas CCK1R is almost exclusively present during the
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mice but appear immature and refractory to secretagogues (155, 248). Infusion of gastrin for 6 days can
partially reverse this effect, thus suggesting that gastrin
stimulates parietal cell differentiation (155). Moreover, a
slowed rate of progression of parietal cells along the
gastric gland axis in gastrin-deficient mice indicates that
gastrin plays a role in parietal cell migration (241). In mice
overexpressing the gastrin gene, hypergastrinemia is associated with increased acid secretion and an increase in
parietal cell number. However, following this initial response, there is decreased parietal cell number with age
and hypochlorhydria (558). Interestingly, this condition is
similar to atrophic gastritis in humans and is found in
association with Helicobacter pylori at a premalignant
stage. Therefore, it seems that while gastrin is required for
gastric epithelial function, gastrin can also lead to disruption of epithelial organization. Second, although some
ECL cells are produced in gastrin or CCK2R-deficient
mice, gastrin is an important regulator of ECL cell number, as it is known to stimulate proliferation of ECL cells
(23). In hypergastrinemia, there is ECL cell hyperplasia
and in extreme cases the development of ECL carcinoid
tumors (53). Gastrin also regulates several genes in ECL
cells that direct histamine synthesis and storage (see sect.
VA) (126 –129). Moreover, CCK2R blockade with antagonists was linked to changes in ECL cells morphology,
indicating that CCK2R activity is needed to maintain the
shape, size, and activity of ECL cells (86). It is noteworthy
that gastrin does not act as a trophic agent in the rat
stomach before weaning (45). In vivo and in vitro data
also suggested that CCK2R, in regenerative rat gastric
oxyntic mucosa, enhances trophic effects during gastric
wound healing (448). Finally, while it is clear that CCK2R
is expressed by parietal and ECL cells, the presence of
this receptor on the gastric proliferating progenitor cell
population remains to be confirmed, and gastrin is actually considered to act indirectly via the release of growth
factors such as HB-EGF and Reg (20, 327, 540). Moreover,
since the proliferation rates are similar in wild-type and
gastrin-deficient mice, other factors must maintain a proliferative balance in the absence of gastrin (248).
CCK acting on CCK1R in D cells inhibits the functions of parietal cells, ECL cells, and gastrin-producing
cells via the release of somatostatin. This inhibitory role
of CCK is now confirmed in mice invalidated for CCK and
gastrin genes and is in line with enhanced acid secretion
observed in CCK1R-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats (85, 233, 318). CCK1R expressed on chief cells was also characterized as a mediator of gastric leptin secretion (22, 488). Indeed, colocalization of CCK1R and leptin was demonstrated in canine
chief cells, and activation of CCK1R was shown to enhance leptin protein amounts as well as to dose-dependently stimulate leptin secretion (532). In agreement with
this study, CCK was recently reported to activate the
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DUFRESNE, SEVA, AND FOURMY
Physiol Rev • VOL
present on pancreatic acini, CCK1R appears to play a
minor role in mediating pancreatic secretion. Indeed, earlier canine studies showed inhibition of pancreatic enzyme secretion in response to low doses of CCK by atropine (252). Li and Owyang (283) demonstrated that atropine and hexamethonium abolished the pancreatic
enzyme response to physiological doses, but not supraphysiological doses of CCK in rats, thus suggesting that
CCK acts on a presynaptic site along the cholinergic
pathway. Similar effects were obtained using perivagal
pretreatment with capsaicin or gastroduodenal application of capsaicin or transection of afferent nerves. This
gives strong evidence for a neuronal action of endogenous CCK, via an afferent vagal pathway originating in the
duodenal mucosa, on pancreatic secretion. High-affinity
CCK1R binding sites on the vagus nerve were demonstrated to mediate CCK-stimulated pancreatic secretion in
the rat (281). At pharmacological doses, CCK can act
directly on acinar cells when CCK1R is present. The neural circuitries involving CCK1R of capsaicin-sensitive vagal afferent neurons, central synapses, and vagal cholinergic efferent fibers (represented in Fig. 6) were recently
confirmed by Yamamoto et al. (580). Although most of the
information on the vagal CCK1R is obtained from research in animals, observations were reported in humans
suggesting that CCK stimulates the pancreas via a pathway dependent on cholinergic innervation (35, 493).
In addition to effects on secretion, CCK exerts trophic and proliferative effects in the pancreas. The essential contribution of CCK1R for pancreatic regeneration
following pancreatectomy or pancreatic duct ligation has
been demonstrated in OLETF rats as well as in a congenic
rat carrying a CCK1R null allele (321, 322, 332, 333). The
importance of CCK for normal pancreatic growth has also
been reported in this rat strain or in control rats after
FIG. 6. Mechanisms of action of physiological doses of CCK, produced by I cells present in the duodenum, to stimulate pancreatic
secretion. ACh, acetylcholine; CNS, central nervous system.
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early postnatal period (275). Indeed, the percentage of
CCK2R was 10% of CCK binding sites at birth and almost
100% in the adult calf pancreas (140). CCK and gastrin
stimulate pancreatic secretion in calves via both CCK1R
and CCK2R but CCK1R, although not predominantly expressed, seems to play a major role (272). CCK2R was
also found to predominate in the pig pancreas where a
proportion of 70% CCK2R and 30% CCK1R was estimated;
however, the functional role of CCK2R in pig pancreatic
secretion remains uncertain (146, 279, 375). These data
raise the question of which functions are under the control of the CCK2R in the exocrine pancreas.
Moreover, the abundance of CCK2R mRNA and that
of CCK2R binding sites was reported in the human pancreas (96, 273, 380, 515), with however no determination
of a precise cellular localization. More recently, predominant level of CCK2R mRNA, compared with that of
CCK1R (⬃30-fold higher), was confirmed in human pancreatic acinar cells (226). However, both CCK1R and
CCK2R mRNA levels were estimated to be very low compared with other receptors such as m3 acetylcholine receptors. This was confirmed with in situ hybridization
experiments that did not observe CCK1R or CCK2R on
human pancreatic acinar cells (226). These very low expression levels are likely to be the reason that CCK receptor expression in human acinar cells has been difficult
to ascertain.
Whether or not pancreatic CCK2R participates in
physiological functions of the human exocrine pancreas
remains unanswered, possibly due to the fact that studies
using RT-PCR from pancreas homogenates or binding
studies performed on membranes may be contaminated
by nonexocrine tissues. However, the presence of CCK2R,
identified by receptor autoradiography in the acini of
chronic pancreatitis, indicates that human acini have the
potential to express CCK2R (409). On the other hand,
recent data suggesting that CCK2R is involved in the
regulation of pancreatic blood flow and vascular conductance might warrant further localization investigations
with regard to human pancreas (185).
As in the rodent pancreas, CCK is the major secretagogue of human exocrine pancreas, and most pharmacological data support that pancreatic CCK-mediated exocrine secretion relies upon activation of CCK1R (78). The
participation of acinar CCK1R in human pancreatic secretion has been investigated, but direct functional responses to CCK or gastrin were never characterized (226,
323). In fact, the vagovagal reflex plays an important role
in the mediation of pancreatic secretion evoked by CCK.
CCK1R is expressed on abdominal branches of the vagus
nerve in several species (see sect. viC). These findings,
together with experimental evidence, suggest that the
major effects of CCK on pancreatic secretion are mediated by receptors on vagus nerve, even in species that
bear CCK1R on pancreatic acinar cells (362). When
823
CCK RECEPTORS
injection of agonists or antagonists (118, 150, 319, 387).
Conversely, CCK- and CCK1R-deficient mice demonstrate
that CCK is not a required growth factor for the murine
pancreas (263, 513), nor is CCK1R required for the growth
of the guinea pig pancreas (202).
3. Endocrine pancreas
Physiol Rev • VOL
4. Liver and intestine
Although the expression of CCK2R mRNA was reported and related to modulation of rat cholangiocyte
function by gastrin, there is until now no other evidence
for the presence of CCK receptors in the liver (174, 270,
546). The role of CCK as a stimulant for small bowel and
colon growth is unclear. The majority of reports suggest
that the normal colon does not appear to express CCK2R,
with the exception of detection by RT-PCR in the mouse
colon (270). To date, there is also insufficient evidence for
the presence of CCK2R in the small intestine.
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For decades, research with several different species
has demonstrated that CCK regulates pancreatic hormone
secretion. CCK binding sites have been found in rat islet
insulin, glucagon, and blood vessel cells (428). While this
study supported the concept of CCK regulation of endocrine pancreas, information about the type of CCK receptor and the nature of the endocrine cell was lacking.
Studies using morphological methods, particularly immunofluorescence and confocal microscopy, are scarce and
have only recently been performed, yet these studies still
result in controversial data. CCK1R transcripts were detected in the center of rat islets, a location that corresponds to the distribution of the insulin cells (236). With
the use of immunohistochemistry, CCK1R was detected in
glucagon cells in pig pancreas (458). Immunofluorescence
and confocal microscopy studies have confirmed the localization of CCK1R in both insulin and glucagon cells in
the rat and in glucagon cells in pig and human endocrine
pancreas (230, 337). Recent immunofluorescence data
combined with in situ hybridization studies support that
CCK1R is expressed in both insulin and glucagon cells in
rat pancreas. Results of studies aimed at defining the
localization of CCK2R are still a matter of debate. Glucagon cells were reported to be the major site of CCK2R
expression in adult and fetal human pancreas (426). Other
data localized CCK2R in the calf, horse, pig, rat, dog, and
human pancreas in somatostatin cells (337). The reason
for such discrepancy is at present still unknown and may
be due to the specificity of the antibodies that were used.
Although their specificity was tested against the peptide
used to raise them, a comparative localization test on
pancreas from knockout and wild-type mice would be the
most appropriate and unequivocal confirmation. Noteworthy, the presence of CCK2R in human islets cells was
also recently confirmed by in situ hybridization and in
vitro receptor autoradiography using CCK1R- and CCK2Rselective analogs (409). However, in the latter study, the
islet cell type expressing CCK2R was not identified, and
CCK1R was found in pancreatic nerves.
A number of studies have indicated that CCK plays a
role in blood glucose regulation through stimulating insulin secretion as demonstrated in vivo in dogs, sheep, pigs,
rats, and mice, as well as in vitro in the rat perfused
pancreas and in rat isolated islets (4, 186, 234, 235, 316,
401, 431, 506, 508, 535, 541, 542). In humans, the ability of
CCK to stimulate insulin secretion is controversial (5, 141,
151, 249, 284, 424). On the other hand, while CCK might
not be a physiological incretin in humans, its pharmacological insulinotropic action might be useful in the treatment of diabetes (3, 34, 349, 457).
The role of CCK1R in mediating insulin release was
either assessed using CCK receptor antagonists or confirmed in the genetically diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats that lack CCK1R (234, 235, 316,
508). In addition to stimulation of insulin release, CCK1R
have been shown to be involved in the release of somatostatin and pancreatic polypeptide release in humans (249, 284).
In line with the previously suggested role of CCK2R in the
modulation of pancreatic endocrine function, expression of
CCK2R on human pancreatic glucagon cells was linked to a
physiological secretion of glucagon from isolated human
islets (4, 401, 426). The role of gastrin in the normal islet
glucagon counterregulatory response to hypoglycemia has
been recently confirmed in gastrin knockout mice (55).
Gastrin and CCK2R might be important for pancreatic development as well. In mammals, the major site of
expression of amidated gastrin is in the fetal pancreas,
supporting a specific role for this receptor during the
development of this organ (29, 426). Moreover, demonstration that gastrin stimulates glucagon gene expression
opens new, interesting prospects concerning its contribution to pancreatic development, as glucagon is the earliest
peptide hormone that is expressed in the developing pancreas (277). The fact that glucagon might play a role in the
early phase of insulin cell differentiation suggests that
gastrin could actively contribute to the paracrine induction of differentiation of pancreatic cells (390). Several
studies examining whether gastrin also acts as a beta-cell
proliferative/differentiative factor in the adult pancreas
demonstrated a role for gastrin in islet neogenesis. Indeed, gastrin is expressed with its receptor during this
regenerative process. Hypergastrinemia leads to expansion of islet mass in rat or human pancreas, and combined
therapy with EGF and gastrin stimulates functional betacell neogenesis of human, rat, and mice pancreas (27, 59,
419 – 421, 505, 557).
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B. Gastrointestinal Smooth Muscles
Not only do CCK receptors have a physiological role
in the stimulation of secretion, growth, and differentiation, but they also participate in the regulation of gastrointestinal motility via mechanical actions. These motor
effects include postprandial inhibition of gastric emptying, gallbladder contraction, and inhibition of colonic
transit, all of which are related to the expression of
CCK1R and CCK2R in smooth muscles.
1. Gallbladder
2. Stomach
CCK1R and CCK2R have been identified by receptor
autoradiography on the human gastric muscle tissue,
which predominantly expresses CCK1R (410). In contrast
to the canine stomach, neurons in human gastric muscles
do not express CCK2R (299, 410). On the other hand,
labeling of CCK receptors in rat and dog gastric muscles
was comparatively weaker than in human tissue, suggesting interspecies differences in gastric emptying mechanisms. Particularly, CCK receptor expression was restricted to the circular smooth muscle of rat pyloric
sphincter (487). Both CCK receptors transcripts are also
present in guinea pig stomach smooth muscles (123).
Localization of CCK1R in cell membranes of rat pyloric
muscle cells has been confirmed by immunohistochemistry (370). In addition, CCK1R was localized on mouse and
Physiol Rev • VOL
3. Bowel
There is no report to date of morphological studies
aimed at localizing CCK receptors in intestinal smooth
muscle at the cellular level. Two studies evaluated CCK
receptors by in vitro receptor autoradiography in human
nonmalignant tissues adjacent to resected colonic tumors
(402, 412). CCK1R was found at moderate-to-low density
in colonic longitudinal smooth muscle and on nerve cells
of the myenteric plexus. CCK2R binding activity was
more rarely characterized. Results of ligand binding performed on dispersed cells suggested the presence of both
CCK1R and CCK2R in cecal circular smooth muscle cells
of guinea pig (340). Other data supporting the presence of
CCK1R on intestinal smooth muscle mostly arise from
bioassays. With the use of human muscular strips, contraction of the ascending colon was demonstrated to result from exclusive activation of CCK1R (339). These data
suggest that CCK exerts its action on bowel motility, at
least in part, directly on CCK1R from smooth muscle cell
in addition to acting via the myoenteric plexus. As observed in vitro, experiments with the CCK1 receptor antagonist loxiglumide indicate that CCK affects human
colonic motility in vivo. Indeed, this compound accelerates colonic transit in normal volunteers (313, 438, 449,
538). Moreover, demonstration that small intestinal motility is in part mediated by CCK1R-induced signaling was
recently supported by significantly lower transit rates in
CCK1R null mice (553).
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The gallbladder was the first recognized target of
CCK. CCK induces gallbladder contraction via activation
of CCK1R located on smooth muscle cells. Presence of
CCK1R on the muscularis layer of bovine gallbladder,
where binding sites are absent on both the mucosal and
serosal membranes, demonstrated a direct myogenic effect of the hormone for the contraction of the gallbladder
(494). This localization was further confirmed by autoradiographic studies in several species including human (14,
359, 445, 529, 548). The role of CCK1R in gallbladder
contraction was recently confirmed in knockout mice
lacking the CCK1R gene (507). It should be noted that
several studies have clearly demonstrated that CCK also
acts on gallbladder emptying through the cholinergic
pathway, further demonstrated by the finding that the
contractile effect of CCK is inhibited by atropine (189,
584). Physiological plasma levels of CCK were shown to
act via stimulation of presynaptic cholinergic neurons in a
vagally mediated pathway (509). The same study reports
direct activation of CCK receptors on the smooth muscle
at supraphysiological levels of CCK. A dual control of
gallbladder contraction was demonstrated through activation of CCK1R in the vagal pathway and stimulation of
gallbladder smooth muscle contraction (492).
rat pyloric interstitial cells of Cajal that are not smooth
muscle cells but nevertheless influence motility and are
considered pacemaker cells for gastrointestinal slowwave activity (69, 370).
CCK released in the duodenum plays an important role
in the delay of gastric emptying by modulating the contractile state of the stomach and the pylorus. This effect involves
activation of CCK1R, as evidenced by studies with antagonists in rats and humans (131, 154, 437, 459, 591). Reduction
of gastric emptying by a specific CCK1R agonist is also
consistent with a CCK1R-mediated mechanism (80).
In contrast to the expected enhancement resulting
from the lack of CCK1R, OLETF rats have delayed gastric
emptying compared with controls (468). This was linked
to several alterations of smooth muscle and autonomic
transmission (511). However, gastric muscular contraction in the OLETF rat was found to be undeteriorated in
vitro (356). Studies of gastric emptying in CCK1R, CCK2R,
and CCK1,2R knockout mice yielded similarly contradictory results. Gastric emptying was enhanced in mice lacking CCK2R and unchanged in CCK1R⫺/⫺ mice, raising
the question of the mechanism underlying CCK2R regulation of gastric emptying (320).
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CCK RECEPTORS
C. Other Peripheral Organs and Tissues
1. Adipocytes
The demonstration of saturable CCK binding on rat
adipocytes membranes was correlated with the detection
of transcripts for CCK2R, but not for CCK1R, and linked
to the long-term regulation of leptin expression and secretion by gastrin (21). In contrast to rat adipocytes,
RT-PCR and binding experiments demonstrated the lack
of CCK2R as well as CCK1R in murine adipocytes (M.
Dufresne, unpublished observations).
Human and rat adrenal zona glomerulosa cells, but
not inner adrenocortical cells (zona fasciculata-reticularis
cells), express mRNAs for CCK1R and CCK2R (297, 307).
CCK-stimulated aldosterone secretion was related to the
activation of CCK1R and CCK2R in rats but is exclusively
through activation of CCK2R in humans (307). Although
the physiological relevance of these observations requires
further investigations, they suggest new functions for CCK
and/or gastrin in the control of adrenocortical secretion.
3. Blood mononuclear cells
The relationship between CCK and the immune system
has been scarcely studied. In fact, pharmacological demonstration of the existence of CCK2R in human mononuclear
cells was only performed in the human Jurkat lymphoblastic T cell line. Other studies reported the expression
of CCK2R mRNA in blood mononuclear cells (453) or only
in polymorphonuclear cells (221). Moreover, according to
the data in the literature, no conclusion can be drawn
concerning the presence or absence of CCK1R mRNA in
these cell types (105, 453). The antiproliferative effect of
gastrin on human phytohemagglutinin-pretreated peripheral mononuclear cells was reported but whether CCK2R
or the CCK2Ri4sv misspliced variant of CCK2R mediated
the effect was unclear (453). Negative modulation of murine lymphoproliferation and mobility by CCK has also
been described, but the receptor subtype mediating this
effect has not been identified (117). Further elucidation of
the biological functions of CCK receptors in the regulation of immunohematopoietic systems is required.
4. Kidney
Evidence for the presence of CCK2R in the guinea pig
and rat kidney is given by immunohistochemical or binding
data demonstrating the presence of the protein with supporting RT-PCR or Northern-blot RNA analysis. In contrast,
while CCK1R has been detected by RT-PCR in the murine
and human kidney, there are actually no data reporting
expression of the CCK1R protein. CCK2R, expressed in the
rat kidney on tubules and collecting ducts, mediates changes
Physiol Rev • VOL
5. Vagal afferent fibers
A large number of studies, mostly performed in rats,
implicate vagal afferent mechanisms in the control of several CCK actions such as relaxation of proximal stomach
combined with increased antral and pyloric contraction,
increased duodenal motility, gallbladder contraction,
sphincter of Oddi relaxation, and pancreatic enzyme secretion. Expression of both CCK1R and CCK2R has been demonstrated in rabbit vagus nerve, rat vagal afferent fibers,
nodose and dorsal root ganglia, and human nodose ganglion
(62, 287, 336). Indirect evidence strongly suggests CCK1R
localization on vagal nerves in the duodenal mucosa, in the
vicinity of CCK endocrine cells (40), mediates CCK satiety
signals (60, 413). A role for the hepatic vagal branch innervating the proximal duodenum, which contributes to this
effect, was also suggested (103). Several studies indicate
that CCK acts via an afferent vagal pathway originating in
the duodenal mucosa to stimulate pancreatic secretion in
rats as well as in humans (282, 493). Modulation of pancreatic secretion by leptin was also postulated to involve
CCK1R on duodenal afferent vagal fibers (187). Furthermore, activation of these receptors is thought to initiate a
vagovagal reflex inhibition of gastric motor function (175,
176). However, recent attempts to characterize CCK1R immunoreactivity yielded surprising and unexplained negative
results in the duodenal mucosa with positive results in cell
bodies from the nodose ganglia (369, 501).
Data demonstrating CCK receptors on gastric vagal afferents are less convincing. Gastric CCK-responsive vagal afferent
fibers have been identified on in vitro isolated stomach-vagus
nerve preparations (564). A population of CCK1R-immunoreactive fibers, localized in the gastric mucosa, markedly decreased following subdiaphragmatic vagotomy, suggesting a
vagal origin (501). However, expression of these receptors was
not confirmed in other studies (369, 370).
VII. PATHOLOGICAL ACTIONS OF PERIPHERAL
CHOLECYSTOKININ RECEPTORS AND
THEIR RELEVANCE TO CLINICAL
DISORDERS IN HUMANS
A. Digestive and Metabolic Diseases
1. Peptid ulcer
The links between Helicobacter pylori, gastrin, and
gastric ulcers were recognized several years ago (278).
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2. Adrenal gland
in renal potassium and sodium absorption (546). The role of
gastrin as a growth factor has been proposed due to its
ability to induce proliferation of a renal cell line (121, 497).
Surprisingly, impact of CCK2R invalidation on these
effects was not explored in knockout mice. Furthermore,
the physiological relevance of renal CCK2R needs to be
determined in humans.
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DUFRESNE, SEVA, AND FOURMY
2. Irritable bowel syndrome
Because CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating, and
abdominal pain that are often characteristic of functional
gastrointestinal disorders and irritable bowel syndrome
(IBS) that is associated with motor abnormalities in the
small intestine and colon. It has been suggested that
exaggerated and prolonged CCK release in IBS patients
could contribute to intestinal dysmotility (481). Increased
colonic response to CCK in vivo and in vitro has been
observed (92). On the other hand, CCK1R antagonists
have been evaluated clinically to stimulate transit and
treat IBS (438, 538). Loxiglumide caused significant
improvement of symptoms in IBS while, in contrast to
previous studies, dexloxiglumide was very recently reported to delay transit in the ascending colon in patients with constipation-predominant IBS (76, 104, 109).
This indicates that further studies are still required to
characterize the response to CCK1R antagonist therapy
for this pathology.
3. Gallbladder diseases
Gallbladder muscles from patients with cholesterol
stones exhibit contractile defects that are related to altered binding properties of CCK1R, which result from
decreased membrane fluidity (578). In this pathology, abnormalities are reversed when excessive cholesterol is
removed from the plasma membrane. CCK1R gene expression was found to be significantly decreased, and
genetic polymorphism was detected in the receptor promoter region in gallbladders from patients with gallstones
(324). The CCK1R null mouse provides a good model for
the study of cholesterol cholelithiasis. Indeed, absence of
Physiol Rev • VOL
CCK1R impairs gallbladder contraction as well as absorption of cholesterol resulting in enhanced biliary secretion,
bile crystallization, and finally agglomeration of solid
crystals in gallbladders (324, 434, 553).
Although the mechanisms underlying impaired gallbladder emptying have not been completely elucidated,
the existence of a general defect in the contractile apparatus, not a specific abnormality of CCK1R or impaired
nerve-induced contractile responses, has been recently
hypothesized in impaired gallbladder function of patients
with acalculous cholecystitis (11, 312). The muscle cell
defect appears to be specific for this condition and not for
gallbladder disease with cholesterol gallstones.
A CCK provocative test has been developed, in combination with either cholecystography, cholescintigraphy,
or ultrasonography, for assessment of gallbladder motility. This test is based on the concept that induction of
gallbladder dyskinesia, and/or the reproduction of biliary
pain by hormonal stimulation, would help to identify patients more likely to benefit from cholecystectomy. However, many parameters can affect the response of the
gallbladder including the kind of stimulus (intravenous
bolus injection, slow infusion of CCK, or a fatty meal to
release endogenous CCK) (31, 314, 360, 595–597). Moreover, several studies question the value of measuring
gallbladder emptying with the CCK provocative test as a
method to select patients with acalculous gallbladder disease for surgery (267, 395). Further studies are required to
clearly characterize acalculous cholecystitis and the role
of CCK in this pathology.
4. Pancreatitis
Evidence based on animal studies implicates that
CCK acts as an agonist towards low-affinity acinar CCK1R
in the induction and development of acute pancreatitis
(429). Moreover, hyperstimulation of rodent acinar
CCK1R was widely used as an experimental model for the
human disease and thus contributed greatly to the current
knowledge and understanding of the pathophysiology and
cell biology of this disease. Although this model is closely
related to some aspects of the human disease, it is important to note that the absence of functional CCK1R in
human acini excludes a direct action of CCK in the human
pathology. Notwithstanding, one multicenter, controlled
trial evaluated therapeutic efficacy of the CCK1R antagonist loxiglumide in the treatment of acute pancreatitis.
Decrease of pain and serum levels of digestive enzymes in
this study suggested the usefulness of loxiglumide in the
treatment of these patients (467). Of note, CCK2R has
recently been detected in the acini of a few samples of
chronic pancreatitis, yet the biological significance remains to be determined (409).
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Gastric ulcers are primarily caused by H. pylori infection.
H. pylori infects the antrum and is associated with G-cell
hyperfunction (278, 573). The increased gastrin secretion
is a consequence of the action of cytokines on the G cells
(68). Cytokines also inhibit D-cell function, thus contributing indirectly to enhanced G-cell function. Patients with
H. pylori infection restricted to the gastric antrum show
an increased secretion of gastrin that is thought to lead to
increased acid output and tendency to ulceration. However, in patients with infection in both the antrum and
corpus of the stomach, inflammation of the latter can lead
to depressed acid secretion and atrophic gastritis. Atrophy may affect the antrum, leading to a loss of G-cell
number, but where the antrum is spared, there is a further
tendency to enhanced plasma gastrin concentrations due
to lower acid inhibition of G cells (308, 309, 573). The
relationship between H. pylori, increased gastrin synthesis, secretion, and gastric cancer is an important issue
(covered in sect. VIIB).
827
CCK RECEPTORS
5. Obesity
Physiol Rev • VOL
B. Cancers
An increasing body of evidence supports the fact that
CCK and gastrin act via their receptors as growth and
invasiveness factors, thus promoting the development
and progression of cancers. While cell lines are indeed
valuable tools for the elucidation of mechanistic pathways that are switched on during carcinogenesis, the
expression of CCK receptors in cancer cell lines has
mostly given rise to controversial results with regard to
the type and density of CCK receptors. Nevertheless,
several studies aimed at the determination of the levels of
CCK receptors protein expression in human tumors were
recently reported. In addition to clarifying whether or not
CCK receptors might contribute to the tumorigenic process, these data now open new perspectives to the fields
of diagnostic and therapeutic applications such as recep-
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CCK belongs to the growing list of factors modulating
food consumption, and CCK molecules are actually promising targets for antiobesity drugs. Since the initial discovery of its property as a food-intake inhibitor, CCK was
demonstrated to be a short-term, meal-reducing signal in
most mammalian species including humans (243, 485,
486). Besides the demonstration that exogenous CCK significantly decreases meal size, a number of experiments
examined the actions of endogenous CCK with administration of CCK receptor antagonists (24). The inhibitory
action of CCK was shown to depend on the presence of
CCK1R on vagus nerve, which relays to the hypothalamus
via brain stem areas such as the nucleus tractus solitarius
and the area postrema (62, 335, 456). Increased gastric
distension induced by slowing gastric emptying by CCK
constitutes a contributing aspect of the satiety response
(242). This signal is transmitted via CCK-responsive vagal
afferent fibers that express mechanoreceptors and also
respond to CCK (114, 455). Moreover, synergistic interactions with leptin were demonstrated (32). While the satiety actions of peripheral CCK are well characterized, a
role for brain CCK has been more controversial. While
CCK was recently confirmed to centrally act as a neuromodulator to produce satiety, the central mechanisms are
still partly resolved (49, 50). Most works implicate that
CCK1R is involved in the mediation of the control of food
intake. The satiety role of CCK1R was confirmed in
CCK1R-deficient mice, which in contrast to wild-type animals showed no change in food consumption after administration of CCK (254). These mice have normal total
daily food intake and normal body weight, suggesting that
CCK is not essential for these regulatory processes. A
different phenotype was observed in CCK1R-deficient
OLETF rats. OLETF rats exhibit hyperphagia, resulting
from the lack of an intact peripheral satiety system, which
leads to obesity. Comparison of both species with respect
to CCK1R distribution led to the demonstration that mice
are in contrast to rats that have CCK1R in the dorsomedial
hypothalamus, which controls anorexigenic neuropeptide
Y gene expression, thus highlighting important interspecies variation in body weight regulation and raising the
important question of satiety control in humans (334).
Polymorphisms in the promoter region of the human
CCK1R gene were detected in 1.9% of individuals in a
cohort study and were related to increased body fat content (157). The functional significance of this genetic factor is actually unknown, since the reported polymorphism
has no role in the transcriptional regulation of CCK1R
(512). Another mutation detected in obese subjects and
affecting the coding region of CCK1R was demonstrated
to significantly decrease the expression and function of
the receptor, but further studies are needed to validate its
role in human obesity (300). On the other hand, abnormal
plasma CCK levels have been characterized in several
eating disorders. Basal and postprandial CCK was found
to be either increased or decreased in anorectic individuals and reduced in women with polycystic ovary syndrome secretion who tend to binge eat and become overweight (28, 207, 376). Lack of a CCK response to a high-fat
meal was reported to contribute to the hyperphagia-mediated obesity of Prader-Willi subjects (67). Increased
sensitivity to the satiating effect of CCK was observed and
may be related to the decrease in appetite and food intake
that occurs with aging (293). Increased plasma concentrations of CCK were also suggested to contribute to the
inhibition of appetite in acquired immunodeficiency syndrome patients (18). Diverging results of plasma CCK
measurements must be interpreted with caution as they
might be due to inaccurate immunoassays that prevailed
between 1965 and 1995 and thus require further confirmation (367, 398).
To date, the hypothesis that CCK2R may mediate the
modulating action of CCK on food intake cannot be totally
excluded. Indeed, CCK2R is expressed in the vagus nerve
brain stem complex that mediates the satiety effect of
peripheral CCK (62, 336). Moreover, CCK2R is the predominant form found in the brain, particularly in hypothalamic areas, and is therefore an ideally positioned
candidate for the mediation of the action of centrally
released CCK (66, 77, 298, 311, 352). Increased food intake
observed after central or peripheral administration of
CCK2R antagonist gives support to this possibility (136,
137). On the other hand, circulating gastrin can activate
neurons in the nucleus tractus solitarius, the area postrema, and specific brain regions including hypothalamic
areas involved in food intake (110, 579). Finally, the enhanced gastric emptying that is observed following
CCK2R gene invalidation in mice also supports an inhibitory role for feeding behavior (320).
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tor scintigraphy, tumor therapy with radioactive or cytotoxic analogs, and long-term therapy with nontoxic analogs. Importantly, a role for CCK receptors in the early
steps of cancer development, with possible loss of expression at later stages, must also be considered.
1. Gastric cancer
Physiol Rev • VOL
2. Pancreatic adenocarcinoma
A number of data from transgenic animals or chemically induced pancreatic carcinogenesis support the idea
that CCK2R plays a role in tumor development. The azaserine-induced rat pancreatic carcinoma DSL-6 and the
derived cell line AR42J as well as transgenic mice bearing
the elastase I promoter-SV40T-antigen fusion gene show
pancreatic expression of CCK2R (386, 439, 593). Importantly, pancreatic tumors develop with ageing in ElasCCK2 transgenic mice expressing functional human
CCK2R under the control of the elastase I promoter in
pancreatic acinar cells (97, 98, 425). Alteration of cellular
morphology and differentiation was observed before tumor formation, indicating an evolution from an acinar to
a ductal phenotype (42). Recently, increased sensitivity to
an acinar carcinogen was also demonstrated in this transgenic strain (302). Moreover, the upregulation of emergence of pancreatic progenitor cells expressing Pdx1,
now acknowledged as potential sites for initiation of carcinogenesis, was also observed in ElasCCK2 mice (205,
302).
The role of CCK1R and CCK2R in human pancreatic
carcinogenesis is unclear and remains a much debated
question. The upregulation of gastrin and its receptor that
was localized immunohistochemically in human pancreatic adenocarcinoma suggests mechanisms involving autocrine or paracrine stimulation (79). Others have reported the expression of CCK2R, gastrin, and CCK1R, but
not CCK, in tumors, but the cellular localizations remain
imprecise (178). On the other hand, CCK1R was selectively detected in ductal cells from human pancreatic
adenocarcinoma by in situ hybridization (330, 565, 566).
Expression of a splice variant of CCK2R (CCK2Ri4sv),
which has constitutive activity, was also characterized in
human pancreatic cancers (130, 199). Although the mRNAs
of the receptors have been described, most reports have
failed to provide precise localization of the proteins in
tumors. A recent morphological evaluation of normal and
diseased pancreatic tissue samples demonstrated a low
amount of CCK2R in chronic pancreatitis and carcinoma
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Gastric cancer is one of the most frequent malignancies in the world and one of the leading causes of cancer
death worldwide (124). Epidemiological evidence indicates that environmental factors play a major role in
gastric carcinogenesis in association with immunologic,
genetic, and immunogenetic factors that are thought to
contribute to the pathogenesis of gastric carcinoma. In
the multifactorial model of human gastric carcinogenesis,
Helicobacter pylori (Hp) is a major environmental risk
factor that contributes to the development of this cancer
(301). Hp infection is associated with increased plasma
gastrin release from G cells, which in turn stimulates the
growth of Hp (94). The precise mechanisms by which
gastrin promotes gastric carcinogenesis probably involves upregulation of HB-EGF, COX-2, cyclin D1, and
Reg gene expression as well as intracellular, proliferative
signaling pathways. Regulation of these gastrin-sensitive
genes and signals is described in detail in section V of this
review. The possibility that elevated gastrin is only a
consequence and not a causative factor remains an open
question, as demonstrated in the report describing a synergistic action with Hp infection in hypergastrinemic
transgenic mice (558).
Expression of CCK2R in gastric cancer samples indicates that gastrin stimulates tumor growth by autocrine
mechanisms (96, 200, 250, 310, 358, 412, 592). False-positive detection of CCK1R gene expression was also reported to correspond to sample contamination with noncancerous tissue (412).
Gastric carcinoid tumors are distinct from adenocarcinomas and in general exhibit a more favorable outcome.
These tumors arise from proliferating ECL cells, a major
proliferative target for gastrin. The reason for the recent
increase in gastric carcinoid tumor incidence is unclear
(328). One theory is that the use of acid-suppressive therapy has led to an increased incidence of hypergastrinemia, although no overt relationship has yet been identified
in humans. Hypergastrinemia results in ECL cell proliferation, which initiates and maintains neoplastic changes in
these cells (172, 181, 350). The basis of hypergastrinemia
is usually a low-acid state such as atrophic gastritis/pernicious anemia, but it can also be associated with a gastrin-secreting neoplasm. Up to 30% of gastrinoma patients
on a background of multiple endocrine neoplasia-1
(MEN-1) and ⬃5% of patients with atrophic gastritis/pernicious anemia may develop ECL cell carcinoid tumors
(52, 167). Therefore, the effect of gastrin in promoting the
development of these tumors is enhanced by an acquired
inflammatory condition or by an inherited susceptibility.
Mutations of the growth factor Reg have also been reported in some ECL cell carcinoid tumors (204). The
contribution of a CCK2R-mediated role of gastrin in tumor
formation is well demonstrated in the case of the African
rodent Mastomys natalensis. This animal exhibits an increased susceptibility to ECL cell growth and an elevated
rate of gastric carcinoid formation even with normal gastrin circulating levels. This susceptibility was linked to an
interspecies polymorphism within the coding region of
the CCK2R gene, which confers a constitutive activity
upon the receptor (444).
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CCK RECEPTORS
with no positive signals for CCK1R (409). Of importance,
chronic pancreatitis is associated with a high risk of
developing cancer and exhibits genetic and morphological lesions similar to those seen in pancreatic adenocarcinoma (81, 294). Together with the fact that CCK2R is
present in some transitional acinar cells, typical lesions of
chronic pancreatitis, these data suggest that this receptor
plays a role in the initiation steps of carcinogenesis.
3. Barrett’s esophagus and esophageal
adenocarcinoma
4. Other tumors expressing CCK receptors
5. Colon cancer and gastrin precursors
The incidence and density of CCK receptors, detected using in vitro receptor autoradiography in more
than 100 neuroendocrine tumors, has been recently summarized (407). Some of these tumors are promising targets for the use of CCK/gastrin analogs for detection
and/or therapeutic purposes. Indeed, a high expression
level of CCK2R is found in vipomas (tumors which secrete
excessive amounts of vasoactive intestinal polypeptide),
thus confirming previous reports that studied insulinomas
as well as bronchial and ileal carcinoid (516). While
CCK1R was absent in all insulinomas and rare in vipomas
and bronchial carcinoids, they were highly but heterogeneously expressed in ileal carcinoids. Interestingly, their
expression pattern was related to specific areas in these
Hypergastrinemia has been associated with an increased risk of colorectal carcinoma (108, 489, 524). However, most recent data support the view that gastrin and
CCK2R do not play an important role in colon cancer,
whereas precursors of gastrin could contribute to neoplastic progression in the colon by acting through receptors that are distinct from CCK2R and CCK1R. First, CCK
receptors do not seem to be expressed in normal colonic
epithelial cells and are found in a minority of human
colonic tumors (452). In contrast, high concentrations of
gastrin precursors, such as glycine-extended gastrin (Ggly) and progastrin, have been observed in colon tumors and
in the blood of patients with colorectal cancer (244, 347).
These precursors represent 90 –100% of the gastrin peptides
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Recent studies have demonstrated the presence of
CCK2R and gastrin in Barrett’s metaplasia, a premalignant
condition that predisposes one to developing esophageal
adenocarcinoma. Increased expression of the CCK2R
gene was demonstrated in endoscopic biopsy specimens
and linked to stimulation of DNA synthesis (1, 194, 198).
Signal pathways activated by gastrin were identified in
several esophageal cell lines (OE19, OE21, OE33, SEG-1,
BIC, SKGT-4) that expressed CCK2R. Activation of Erk
pathways and PI 3-kinase was linked to proliferation in
response to gastrin (194, 331). High basal levels of activated PKB/Akt were observed in samples from Barrett’s
metaplasia and linked to the activation of CCK2R in
esophageal cell lines (198). Based on these studies, hypergastrinemia resulting from long-term administration of
proton pump inhibitors for the treatment of Barrett’s
esophagus could play a role in the growth of esophageal
adenocarcinoma via activation of CCK2R. Of note, a significant increase in gastrin gene expression was characterized in Barrett’s metaplasia biopsies in addition to the
de novo expression of the constitutively active CCK2R
splice variant (CCK2Ri4sv) (1, 198). This suggests that an
autocrine signal or constitutive activity of CCK2R could
be involved in the pathogenesis of Barrett’s esophagus
before the development of dysplasia and cancer. This
involvement may be in part through CCK2R induction of
COX-2 expression (1, 251).
tumors. The incidence of CCK1R was ⬃50% in gastrinomas that were devoid of CCK2R. High CCK2R density and
incidence has been shown in medullary thyroid carcinomas. The high sensitivity and specificity of the pentagastrin stimulation test, which detects the presence or recurrence of medullary thyroid cancer (MTC), suggested that
CCK2R is present in malignant calcitonin-producing C
cells (567). Their presence with a very high incidence (92%)
in these tumors and their absence in nonmedullary thyroid
carcinomas as well as normal thyroid glands was demonstrated by binding assays, autoradiography, and RT-PCR (12,
408). However, CCK2R expression was detected more recently in nonmalignant, normal thyroid C cells (46).
The presence of CCK2R and gastrin has been shown
in a high percentage of small cell lung cancers, but not in
lung adenocarcinomas, supporting a possible autocrine
growth regulation (304, 306, 406). In contrast to earlier
studies performed in small cell lung cancers, the presence
of CCK1R was not detected in human biopsies (461). To
our knowledge, only one study has investigated neuronal,
renal, and myogenic stem cell tumors for CCK receptor
expression (441). An unexpected high incidence of gastrin
mRNA was found in these tumors. CCK mRNA was
present in Ewing sarcomas and leiomyosarcomas. Only a
minority of the tumors expressed the receptors except for
Wilms’ tumors, where CCK2R was found, and leiomyosarcomas, which expressed both CCK1R and CCK2R. CCK2R
and gastrin were also detected in all stromal ovarian
cancers (406).
Activation of CCK2R also modulates proliferation of
cells of the immune system, and it has been clearly established that gastrin stimulates growth and growth-associated genes in human lymphoblastic Jurkat T cells and
leukemia cells (221, 357). In the latter study, in addition to
expression of CCK2R, the presence of gastrin-like immunoreactivity was demonstrated in the culture media of
several leukemia cell lines, suggesting the existence of an
autocrine loop promoting the growth of nonepithelial cells.
830
DUFRESNE, SEVA, AND FOURMY
C. Peptide and Receptor Targeting
1. Gastrimmune
Gastrimmune or G17DT is an immunoconjugate of
the NH2-terminal sequence of gastrin-17 linked via a
Physiol Rev • VOL
spacer to diphtheria toxin. It raises antibodies that neutralize both the carboxy-amidated and glycine-extended
forms of gastrin17 but shows no cross-reactivity with
other forms of gastrin or CCK. Preliminary testing of a
potential therapeutic benefit was provided by in vivo studies using animal models. Data from this evaluation gave
evidence for adequate targeted inhibition of primary tumor growth and metastasis of a colorectal tumor. In
addition, it showed a significant improvement in survival
using a xenograft model of gastric cancer (561–563).
These positive results further led to recent phase II clinical studies in patients with gastric, colic, or pancreatic
cancer (61, 171, 483). In these studies, G17DT was well
tolerated in the majority of patients, who developed an
antibody response. Phase III studies with G17DT alone or
in combination with chemotherapy are ongoing.
2. CCK receptors
Peptide receptors are targets for in vivo cancer diagnosis and therapy. While the most frequently targeted
peptide receptor is the somatostatin receptor, some tumors expressing CCK2R with a high incidence and density represent adequate targets for CCK receptor labeling
in vivo. Different groups have developed indium-111,
technetium-99m, or iodine-131 radiolabeled CCK and gastrin analogs suitable for in vivo receptor scintigraphy and
therapy (8, 37, 144, 269, 411, 545). An overview of data
obtained in this field is given in References 9, 36, 404, 405.
As reviewed in the above section, medullary thyroid carcinomas, small cell lung cancers, stromal ovarian cancers,
insulinomas, vipomas, and bronchial and ileal carcinoids
are good candidates for CCK2R labeling in vivo.
VIII. CONCLUSION/PROSPECTS
From this overview and the referenced works, it
appears that available data related to CCK receptors
clearly establish their importance and relevance to human
physiology and pathophysiology. Actions of peripheral
CCK/gastrin receptors have largely extended beyond their
initial spheres where they were first identified and isolated, namely, the pancreatic acinar cells and the gastric
parietal cells. In addition to their peripheral functions,
one must keep in mind the extreme importance of CCK
receptor functions in the central nervous system, which
are not described in this paper. As a corollary of the
recently recognized long-term actions of CCK and gastrin,
recent works have documented that CCK receptors are
capable of using signaling molecules common to growth
factor receptors having tyrosine kinase activity. Although
the use of specific nonpeptide ligands of the two CCK/
gastrin receptors as well as the availability of knock-out
mice have greatly contributed to this knowledge, undesired activities of initial and still popular molecules, as
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produced by colon tumors and are found in 80 –90% of
colorectal polyps in humans (484). In addition, numerous
groups have demonstrated that unprocessed forms of gastrin act as growth factors for colon cancer cell lines that do
not express CCK1R or CCK2R (25, 211, 290, 477, 498).
Trophic effects of gastrin precursors on colonic mucosa have also been confirmed in vivo. Gastrin-deficient
mice perfused with G-gly or progastrin showed a marked
increase in proliferation of colonic epithelial cells,
whereas mature amidated gastrin had no effect on the
same model (247, 361). Similarly, G-gly perfusion into rats
results in proliferation of colonic mucosal cells and the
formation of aberrant crypt foci and increases the sensitivity to azoxymethane, a colon procarcinogen (10). In
addition, transgenic mice overexpressing progastrin
(hGAS mice) or G-gly (MTI/G-Gly mice) exhibit hyperplasia of the colonic mucosa and increased epithelial proliferation, and hGAS mice treated with a chemical carcinogen display an increased predisposition to develop preneoplastic lesions or even colonic adenocarcinoma
compared with wild-type, control mice (99, 247, 478, 479).
On the basis of binding studies, several receptors for
gastrin precursors, with different pharmacological profiles, have been characterized. The first one to be described was a receptor with a high affinity for G-gly,
which does not bind gastrin or the antagonists of the CCK
receptors (211, 231, 464, 498). Afterwards, a second receptor, binding with a strong affinity both amidated gastrin and gastrin precursors but not the CCKR antagonists,
was described by Singh and co-workers (220, 476, 477).
Both receptor types were shown to mediate the proliferative effects of gastrin precursors. However, a receptor
with these pharmacological characteristics has not yet
been cloned. Baldwin et al. (26) have purified a gastrin
binding protein (GBP) that is a member of the enoyl-CoA
hydratase/3-hydroxyacyl-CoA dehydrogenase family of
enzymes but displays a low affinity for gastrin precursors.
In addition, whether this GBP mediates the proliferative
effects of gastrin precursors remains to be confirmed
(581).
The constitutive splice variant of CCK2R, retaining
intron 4 in the third intracellular loop, has recently been
identified in certain human colon tumors (199). However,
this CCK2R splice variant binds gastrin precursors with a
very low affinity. In addition, the presence of this variant
in colon cancer remains controversial since it has not
been found by other groups to be present in human
colorectal tumor samples (452).
831
CCK RECEPTORS
well as interspecies differences concerning the structure,
expression, and localization of CCK receptors, may have
contributed to questions regarding the relevance of these
receptors as targets for human diseases. With all these
data in mind, one can consider that there is still much to
discover about the physiological functions, regulation,
and functioning of these two members of the G proteincoupled receptor family.
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