Disease relevance of CCKBR

• In pancreatic cancer cells, a gastrin autocrine loop involving the CCKBR was suggested [1].
• Furthermore, Gly-G stimulates growth of human gastric cancer cell lines, possibly through a receptor other than the CCK-B or CCK-A receptor [2].
• Gastrin mRNA measured by in situ hybridization was present in most CCK-B receptor-positive small cell lung cancers, breast tumors, and ovarian tumors, representing the molecular basis of a possible autocrine growth regulation of these tumors [3].
• CCK-B/gastrin receptors were found frequently in medullary thyroid carcinomas (92%), in small cell lung cancers (57%), in astrocytomas (65%), and in stromal ovarian cancers (100%) [3].
• CCK-A and CCK-B receptors were not frequently found in these tumors, except for leiomyosarcomas [4].

Psychiatry related information on CCKBR

• However, no evidence of allelic association was found between the polymorphic repeat of the CCKBR gene and either panic disorder or schizophrenia (P = 0.186 and 0.987, respectively) [5].
• However, the CCK-A and CCK-B receptor-mediated interactions of this neuropeptide with mesencephalic dopaminergic regulation of motivation for locomotor activity have the potential to interfere with the behavioural outcome from routine exploratory activity tests [6].
• The effects of the CCKB-receptor agonist pentagastrin, a synthetic analogue of the cholecystokinin tetrapeptide (CCK-4), were studied in seven patients suffering from obsessive compulsive disorder (OCD) and seven healthy controls [7].
• GV-150013, a selective CCK-B receptor antagonist, was found to increase REM sleep, as well as non-REM sleep, and therefore total sleep (non-REM + REM) mainly in aged rats [8].
• OBJECTIVE: The anxiogenic and panicogenic effects of peripheral administration of the cholecystokinin-B receptor agonist pentagastrin and placebo were evaluated in patients with generalized anxiety disorder and normal comparison subjects [9].

High impact information on CCKBR

• The canine and human CCK-B/gastrin receptors share 90% amino-acid identity and have similar agonist affinities [10].
• The development of potent and selective antagonists for CCK-A (MK-329) and CCK-B (L-365,260) receptors now allows these issues to be addressed [11].
• These results suggest that endogenous CCK causes satiety by an agonist action on CCK-B receptors in the brain [11].
• The CCK-A antagonist MK-329 and the CCK-B antagonist L-365,260 increased food intake in partially satiated rats and postponed the onset of satiety; however, L-365,260 was 100 times more potent than MK-329 in increasing feeding and preventing satiety [11].
• Expression of CCK-B receptors was detected in all tissues arising from pancreas and in most extrapancreatic tissues and tumors [12].

Chemical compound and disease context of CCKBR

• We used HT-29 human colon cancer cells, expressing CCK receptors, to test the antiproliferative effects of several antagonists of CCK-A and/or CCK-B and their possible synergism with melatonin [13].
• We utilized intravenous infusions of pentagastrin, a selective CCK-B receptor agonist, and studied behavioral and cardiovascular responses in 10 patients with panic disorder and 10 normal controls [14].
• The effects of the cholecystokinin-B (CCK-B) receptor antagonist CI-988 on symptoms elicited by the cholecystokinin tetrapeptide (CCK4) were studied in DSM-IIIR patients with panic disorder [15].
• The stimulatory effect of CCK on meningioma cell growth was completely abolished by a CCK-B specific receptor antagonist, L-365,260 [16].
• Several lines of evidence implicate the cholecystokinin B receptor (CCKBR) and the A2a adenosine receptor (A2aAR) in the etiology of panic disorder [17].

Biological context of CCKBR

• These results present for the first time the identification of the amino acid sequence of the CCKBR conferring the majority of the selectivity for gastrin [18].
• Displacement experiments using [125I]-BH-CCK and various agonists and antagonists identified binding sites with typical CCKBR pharmacology [19].
• The CCKBR and ITGbeta2 loci define the ends of the linkage groups on Chromosomes (Chro) (SSC) 9p and 13qter, respectively [20].
• Recently, a dinucleotide repeat, (CT)(n), in the 5' regulatory region of the CCKBR gene was reported to be associated with panic disorder in Canadian samples [5].
• CCK-B receptor: chemistry, molecular biology, biochemistry and pharmacology [21].

Anatomical context of CCKBR

• The radiolabeled conjugate showed specific binding to both cell lines overexpressing CCKBR [22].
• In rodent's pancreas, the CCKAR were observed on acinar cells as well as on islet's alpha and beta cells; in six other species, the CCKAR were present only on alpha and beta cells with the CCKBR always present on delta cells [1].
• In situ hybridization indicated the presence of m3 Ach receptor and insulin mRNA but not CCK-A or CCK-B receptor mRNAs in adult human pancreas [23].
• The human pancreas predominantly expresses CCK-B receptors, whereas only CCK-A receptors were localized in the human gallbladder muscle [24].
• These results show that gastrin acts as a direct growth factor through gastrin/CCKB receptors and demonstrate, for the first time, that these peptides can stimulate the proliferation of cells outside the gastrointestinal tract [25].

Associations of CCKBR with chemical compounds

• Both CCK-8 and gastrin I markedly augmented phosphoinositide hydrolysis and cytosolic free calcium levels in the CHO transfectants, indicating that the cloned CCK-B receptor could functionally couple with intracellular signaling molecules [26].
• Substitution of Phe347 in TM-VI with alanine produced a mutant receptor that displays the same affinity and selectivity as the wild-type receptor for agonists, but a slightly increased affinity for the selective CCKB antagonist L-365,260 [27].
• Ser82 was further changed into Asp, Thr, or Ala to determine the specificity of this position in Gs coupling by the CCK-BR [28].
• Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin [13].
• Intravenous injection of the cholecystokinin (CCK)-B receptor agonist, pentagastrin, produces robust, dose-dependent release of adrenocorticotropin (ACTH) and cortisol, supporting the hypothesis that CCK-B agonists pharmacologically activate the hypothalamic-pituitary-adrenal (HPA) axis [29].

Physical interactions of CCKBR

• Using the NOE-generated intermolecular contact points, extensive MD simulations of CCK-8 bound to the CCK2 receptor were carried out [30].
• Our study has identified the presence of CCKB/gastrin receptor isoforms in different cellular locations and may help toward understanding the complex autocrine and intracrine pathways mediated by gastrin peptides [31].
• Using surface plasmon resonance analysis, we identified a highly conserved ITIM motif, containing the tyrosine residue 438, located in the C-terminal intracellular tail of the CCK2R which directly interacts with the SHP-2 SH2 domains [32].
• Taken together, these results suggest that the CCK2 receptor is coupled to two G proteins and that Phe347 and the cluster of basic residues K333/K334/R335 probably play a key role in Gq protein stimulation leading to inositol phosphate production but not in activation of the G protein coupled to phospholipase A2 [33].

Co-localisations of CCKBR

• By immunofluorescence, the CCKB receptor colocalizes with the islets' somatostatin delta cells, confirming what was previously shown in other species, as well as on ductal cells [34].

Regulatory relationships of CCKBR

• This segment could account for 100 of the expected 300-fold lower affinity of gastrin-17-I observed for the control CCKAR compared to the control CCKBR [18].
• These data indicated that CCK-8 and potent CCK analogs induced [Ca2+]i mobilization in the Human JURKAT T cell line through the CCKB/gastrin receptor type [35].
• Gastrin stimulates gastric acid secretion through direct activation of CCK-B/gastrin receptors on parietal cells and indirectly through release of histamine from ECL cells [36].
• To this aim, the CCK2 receptor was stably expressed into a glucagon-producing pancreatic islet cell line, and a glucagon-reporter fusion gene was transiently transfected in this new cellular model [37].
• SRC regulates constitutive internalization and rapid resensitization of a cholecystokinin 2 receptor splice variant [38].

Other interactions of CCKBR

• Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin [26].
• Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors [3].
• Cholecystokinin (CCK)-A and CCK-B receptors are highly homologous members of the seven transmembrane domain G-protein-coupled receptor superfamily [39].
• Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies [40].
• A series of healthy and tumoral colon samples, the associated hepatic metastases and four colonic cell lines were examined for gene expression of the 2 isoforms of the CCK-B receptor and the CCK-C receptor using reverse transcription-polymerase chain reaction [41].

Analytical, diagnostic and therapeutic context of CCKBR

• Using site-directed mutagenesis in this segment of the CCKBR, we identified a sequence of 5 amino acids in the second extracellular loop responsible for this 100-fold selective loss in gastrin affinity [18].
• Nude mice bearing control and CCKBR-overexpressing A431 xenografts were used as an in vivo model [22].
• RT-PCR revealed CCKBR transcripts in proximal tubules (MCT cells) and in mesangium (MMC) [19].
• Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder [42].
• In addition, CCK-A and CCK-B receptors were evaluated in the same group of tumors with receptor autoradiography [4].

References