CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology
Introduction
Cholecystokinin (CCK) is a gut–brain peptide that exerts a variety of physiological actions in the gastrointestinal tract and central nervous system through cell surface CCK receptors. CCK was initially isolated from the porcine duodenum as a 33 amino acid peptide (Mutt and Jorpes, 1968). A number of biologically-active molecular variants were subsequently described (Rehfeld et al., 1982) and the most abundant peptide present in the brain was shown to be CCK8: Asp–Tyr(SO3H)–Met–Gly–Trp–Met–Asp–Phe–NH2. On the basis of their pharmacological properties and specificities for ligand binding, CCK receptors have been divided into two subtypes, namely, the CCK-A and CCK-B receptors both belonging to the class of G protein-coupled receptors characterized by seven transmembrane (TM) domains. CCK-A receptors are located mainly in the periphery but are also found in some regions of the brain (Hill et al., 1987a, Hill et al., 1987b). The major population of central CCK receptors are of CCK-B subtype (Hill et al., 1987a), which is also found in the stomach and vagus nerve. The gastrin receptor was found to be identical to the CCK-B receptor.
Considerable interest is devoted to the pharmacology of CCK-B receptors, since administration of selective agonists produces behavioral changes such as anxiety, perturbation of memory and hyperalgesia, and dysfunctioning of CCK-B related neural pathways could be involved in neuropsychiatric disorders. Accordingly, CCK-B antagonists have been shown to block panic attacks induced in humans by systemic administration of low doses of CCK4 (Bradwejn et al., 1991), Trp–Met–Asp–Phe–NH2, which has a 300-fold higher affinity for the CCK-B receptor than for the peripheral CCK-A receptor (Daugé et al., 1990).
Section snippets
Design of selective agonists for CCK-B receptors
At CCK-A receptors, sulphated CCK8 [Asp–Tyr(SO3H)–Met–Gly–Trp–Met–Asp–Phe–NH2]was the minimal sequence for high affinity binding, whereas at central binding sites, CCK4, gastrin and unsulphated CCK8 can be bound, albeit they have somewhat lower potency compared to sulphated CCK8.
Different strategies have been followed to design potent and selective agonists and antagonists of CCK-B receptors. In spite of its intrinsic flexibility, CCK8 was found by NMR to exist preferentially under folded form
Cloning and characterization of the CCK-B receptor
Although there is general agreement that the CCK-A receptor has a distinct agonist and antagonist binding profile from the gastrin and CCK-B receptors, controversy remains regarding the existence of distinct CCK-B and gastrin receptor subtypes. Gastrin, CCK and CCK-related peptides comprise a hormone family, characterized by the identical carboxyl-terminal pentapeptide amide structure, a domain critical for receptor binding. Agonist binding studies on brain membranes and parietal cells show a
CCK-B receptor gene structure
The gene for the CCK-B receptor has been cloned in humans (Song et al., 1993). This gene exceeded 8 kb in length and contained a 1356-bp open reading frame which was interrupted by four introns of 164–1177 bp. Exon 1 encodes the putative extracellular amino terminus of the receptor. Exons 2 and 3 encode TM regions I–IV, and exon 4 encodes the fifth TM region and an initial portion of the third intracellular loop. Exon 5 encodes the remainder of this intracellular loop, the remaining TM regions VI
CCK-B receptor localization
CCK-A receptors are found principally in the gastrointestinal tract and select areas of the CNS, while CCK-B/gastrin receptors are found principally in the CNS and select areas of the gastrointestinal tract, on pancreatic acinar cells and parietal cells.
Autoradiographic studies using CCK-related peptide-binding sites in the rat brain, such as [125I]CCK8 (Niehoff, 1989; Pélaprat et al., 1987), [3H]BDNL (Pélaprat et al., 1987), [3H]CCK8 (Dijk et al., 1984), [3H]pentagastrin (Gaudreau et al., 1983
Signal-transduction cascade for CCK-B receptors
The signal transduction mechanism of CCK-A receptors has been best characterized in pancreatic acinar cells, where CCK stimulates digestive enzyme release, usually assayed as amylase activity. One physiologically important signaling pathway is the hydrolysis of polyphosphoinositides (PPI) by phospholipase C and the subsequent formation of the second messengers, inositol 1,4,5-triphosphate (1,4,5-IP3) and 1,2-diacylglycerol (DAG), leading to the release of intracellular Ca2+ and the activation
Site directed mutagenesis of the CCK-B receptor: characterization of residues involved in binding of ligands and functional coupling
In order to develop more specific and selective compounds, it is important to elucidate the molecular interactions involved in CCK receptor ligand binding. In contrast to the endogenous peptide ligands, nonpeptide antagonists often show substantial differences in affinity among species. These species-related differences in binding affinity often reflect differences in the primary structure of the receptors. Thus, although canine and human CCK-B receptors share ∼90% amino acid identity and have
CCK-B receptor heterogeneity
On the basis of the pharmacological data obtained receptor subtypes has been proposed to exist in the CCK family. However, despite extensive searching by hybridization screening of cDNA libraries from different tissues [reviewed in Wank (1995)], only two CCK receptors have been identified. Southern blot hybridization using human, guinea pig and rat DNA with either CCK-A or CCK-B receptor species-specific, full-length coding sequence probes under both high- and low-stringency conditions has also
Gastric acid secretion
Gastrin and CCK, which are two related peptides that share homology at their biologically active pentapeptidic C-terminal sequence, have been shown to stimulate gastric acid secretion in vitro. Thus, both peptides bind to receptor sites located on parietal (Magous et al., 1989) and induce an increase in phosphoinositide turnover (Roche and Magous, 1989; Chew and Brown, 1986) and an uptake in [14C]aminopyrine ([14C]AP) (an index of acid secretion in vitro) with the same efficacy and potency (
Conclusion
The peptide CCK exists in numerous brain and peripheral regions where it serves as a neurotransmitter and neuromodulator or hormone. The development of selective and highly potent agonists and antagonists has constituted a major breakthrough in the field of CCK research. Numerous data support the existence of physiological interactions between endogenous CCK system and other systems, as opioid or dopaminergic systems.
The obvious neuroanatomical association between dopamine and CCK continues to
Acknowledgements
The authors would like to thank C. Dupuis for typing the tables. All members of the laboratory and colleagues whose names appear in the references cited in this review are acknowledged. They thank Rhone-Poulenc-Rorer for their financial supports.
References (287)
- et al.
Antidepressant-type effects of endogenous enkephalins protected by systemic RB 101 are mediated by opioid δ and dopamine D1 receptor stimulation
Eur. J. Pharmac.
(1992) - et al.
The role of CCK, caerulein, and CCK antagonists in nociception
Pain
(1989) - et al.
Role of aromatic transmembrane residues of the δ-opioid receptor in ligand recognition
J. Biol. Chem.
(1996) - et al.
Novel constrained CCK-B dipeptoid antagonists derived from pipecolic acid
Bioorg. Med. Chem. Lett.
(1998) - et al.
Differential inhibitory/stimulatory modulation of spinal CCK release by μ and δ opioid agonists, and selective blockade of μ-dependent inhibition by κ receptor stimulation
Neurosci. Lett.
(1991) - et al.
Synthesis of conformationally constrained macrocyclic analogues of the potent and selective CCK-B antagonist CI-988
Tetrahedron
(1993) Neural basis of psychomotor stimulant and opiate reward: evidence suggesting the involvement of a common dopaminergic system
Behav. Brain Res.
(1986)- et al.
Role of a serine endopeptidase in the hydrolysis of exogenous cholecystokinin by brain slices
Neuroscience
(1989) - et al.
Catecholamine receptors: structure, function, and regulation
Recent Prog. Horm. Res.
(1993) - et al.
Potent, selective, water-soluble benzodiazepine-based CCK-B receptor antagonists that contain lipophilic carboxylate surrogates
Bioorg. Med. Chem. Lett.
(1995)
Cholecystokinin B receptor antagonism enhances the ability of a low dose of morphine to reduce c-Fos expression in the spinal cord of the rat
Neuroscience
Enzyme-resistant CCK analogs with high affinities for central receptors
Peptides
Release of intracellular Ca++ and elevation of inositol triphosphate by secretagogues in parietal and chief cells isolated from rabbit gastric mucosa
Biochim. Biophys. Acta
Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin
FEBS Lett.
Cholecystokinin–dopamine interactions
Trends Pharmac. Sci.
Biological actions of cholecystokinin
Peptides
The behavioral effects of CCK-8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat
Eur. J. Pharmac.
The selective CCK-B agonist, BC 264 injected in the antero-lateral part of the nucleus accumbens, reduces the spontaneous alternation behaviour of rats
Neuropharmacology
A two trial memory task with automated recording: study in young and aged rats
Brain Res.
Extension of a new two-trial memory task in the rat: influence of environmental context on recognition processes
Neurobiol. Learn. Memory
Cholecystokinin-A but not cholecystokinin-B receptor stimulation induces endogenous opioid-dependent antinociceptive effects in the hot plate test in mice
Neurosci. Lett.
Involvement of D2 dopaminergic receptors in the emotional and motivational responses induced by injection of CCK8 in the posterior part of the nucleus accumbens
Brain Res.
Heterogeneity of CCK-B receptors involved in animal models of anxiety
Pharmac. Biochem. Behav.
The selective CCK-B agonist, BC 264, impairs socially reinforced memory in the three-panel runway test in rats
Behav. Brain Res.
Synthesis and CCK-B binding affinities of cyclic analogues of the potent and selective CCK-B antagonist CI-988
Tetrahedron
Aspartate 196 in the first extracellular loop of the human VIP1 receptor is essential for VIP binding and VIP-stimulated cAMP production
Biochem. Biophys. Res. Commun.
Investigation on the metabolism of CCK8 analogues by rat brain slices
Neuropeptides
Occurrence of two cholecystokinin binding sites in guinea pig brain cortex
Biochem. Biophys. Res. Commun.
[3H]pBC 264, first highly potent and very selective radioligand for CCK-B receptors
Eur. J. Pharmac.
In vivo binding affinities of cholecystokinin agonists and antagonists determined using the selective CCK-B agonist [3H]pBC 264
Eur. J. Pharmac.
Effect of gastrin receptor blockade on endocrine cells in rats during achlorhydria
Gastroenterology
The origin of cholecystokinin terminals in the basal forebrain of the rat: evidence from immunofluorescence and retrograde tracing
Neurosci. Lett.
The use of a proline ring as a conformational restraint in CCK-B receptor “dipeptoids”
BioMed. Chem. Lett.
A novel short isoform of the D3 dopamine receptor generated by alternative splicing in the third cytoplasmic loop
J. Biol. Chem.
Cholecystokinin receptors mediate enhanced memory retention produced by feeding and gastrointestinal peptides
Peptides
A selective role for dopamine in the nucleus accumbens of the rat in random foraging but not delayed spatial win-shift-based foraging
Behav. Brain Res.
Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor
J. Biol. Chem.
The role of histidine 265 in antagonist binding to the neurokinin-1 receptor
J. Biol. Chem.
Pharmacological studies on CCK-B receptors in guinea pig synaptoneurosomes
Eur. J. Pharmac.
Co-localization of enkephalins and cholecystokinin in discrete areas of rat brain
Brain Res.
Characterization and visualization of cholecystokinin receptors in rat brain using [3H]pentagastrin
Peptides
CCK-8-related C-terminal tetrapeptides: affinities for central CCKB and peripheral CCKA receptors
Eur. J. Pharmac.
Evidence that CCK-B receptors mediate the regulation of exploratory behaviour in the rat
Eur. J. Pharmac.
Cholecystokinin in animal and human research on anxiety
Trends Pharmac. Sci.
Morphology of synapses formed by cholecystokinin-immunoreactive axon terminals in regio superior of rat hippocampus
Neuroscience
The CCK-B receptor antagonist, L-365,260, elicits antidepressant-type effects in the forced-swim test in mice
Eur. J. Pharmac.
Calcium oscillations in single cultured Chinese Hamster Ovary cells stably transfected with cloned human cholecystokinin (CCK)B receptor
Jpn. J. Pharmacol.
The probable arrangement of the helices in G protein-coupled receptors
EMBO J.
Type-A CCK receptors in CHP 212 neuroblastoma cells: evidence for association with G protein and activation of phosphoinositide hydrolysis
Mol. Pharmac.
A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non peptide antagonists
Nature (Lond.)
Cited by (154)
Emerging trends of receptor-mediated tumor targeting peptides: A review with perspective from molecular imaging modalities
2021, European Journal of Medicinal ChemistryCitation Excerpt :With highest capability of tumor uptake and broad spectrum applications, MG analogues were observed to show some drawbacks due to high renal involvement because of CCK8 (DYMGWMDF-NH2) sequence which causes nephrotoxicity as well as selectively high affinity for only CCK-2 receptor instead of CCK-1 receptor [95]. Sulphated CCK-8 (neuropeptide in brain; DY(SO3H)MGWMDF-NH2) peptide shows preferably high affinity in nanomolar concentrations for both CCK-1 and CCK-2 receptors [96–98]. Successful addition of histidine residue at first position reduces the kidney uptake by 2 folds, as study reported by Ref. [99] that HHEAYGWMDF peptide sequence was observed to possess high tumor-to-kidney ratio as compared to other MG peptide analogues so far reported in the literature [100].