Disease relevance of CCKAR

• Furthermore, Gly-G stimulates growth of human gastric cancer cell lines, possibly through a receptor other than the CCK-B or CCK-A receptor [1].
• CCK1R and CCK2R may therefore serve as pharmacological targets in diabetes and obesity and genes encoding these receptors may be candidate genes in the pathogenesis of the diseases [2].
• CCK-A-receptor mRNA was detected in 5 out of 8 esophageal cancers (0.1-1 fg/microg), in 5 out of 8 gastric cancers (0.05-4.2 fg/microg) and in 5 out of 12 colon cancers (0.1-1 fg/microg RNA) [3].
• Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson's disease [4].
• We have measured the levels of mRNA for CCK-A and CCK-B/gastrin receptors using quantitative reverse transcription-polymerase chain reaction (RT-PCR) in primary digestive cancers and hepatic metastases [3].

Psychiatry related information on CCKAR

• RESULTS: Significant differences between patients with hallucination and controls were found in the allele frequencies at the -388 and -85 loci of the CCKAR gene (p = 0.0095, p = 0.0087, respectively), but these differences were not significant after Bonferroni correction for multiple testing [5].
• In this study, association analyses were re-examined between the polymorphisms of the promoter region of the CCKAR gene and patients with alcohol withdrawal symptoms, in addition to patients with alcoholic liver injury [5].
• However, a significant association was found between polymorphism at the -85 locus of the CCKAR gene and patients with hallucination, and especially patients with hallucination accompanying delirium tremens [5].
• Association of cholecystokinin-A receptor gene polymorphisms and panic disorder in Japanese [6].
• To further explore the role of CCK in humans, the effect on satiety and eating behavior of a specific CCK-receptor antagonist, loxiglumide, that preferentially inhibits peripheral (CCK-A) receptors was investigated [7].

High impact information on CCKAR

• 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 [8].
• However, it has not been established that endogenous CCK causes satiety or whether the response is mediated by peripheral-type (CCK-A) or brain-type (CCK-B) receptors [8].
• 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 [8].
• Of significance, CCK-A receptors were expressed selectively in all pancreatic adenocarcinomas, but not in any normal pancreas specimens [9].
• Southern blot analysis revealed no evidence of CCK-A receptor gene amplification or rearrangement in pancreatic adenocarcinomas [9].

Chemical compound and disease context of CCKAR

• CCK is a major mediator of the sensitisation of gastric perception by lipids in patients with functional dyspepsia as the CCK-A receptor antagonist dexloxiglumide markedly diminishes this effect [10].
• These results suggest that melatonin and CCK-A antagonists are useful for controlling human colon cancer cell growth in culture and in combined therapy significantly increases their efficiency [11].
• CCK-JMV-180 acts as an antagonist of the CCKA receptor in the human IMR-32 neuroblastoma cell line [12].
• A great interest is devoted to antagonists of the cholecystokinin type B (CCKB) receptor such as L-365,260, which reduces panic attacks in humans and to antagonists of the cholecystokinin type A (CCKA) receptor, such as L-364,718 which might be efficient in mental diseases [13].
• CCK administration caused a short-lived hypothermia, but interference with the action of endogenous CCK at CCK-A receptors was without effect on IL-1beta- or LPS-induced fever [14].

Biological context of CCKAR

• CONCLUSIONS: The data from the case control suggest that polymorphisms of the promoter region of the CCKAR gene do not play a major role in the pathogenesis of alcohol withdrawal symptoms or alcoholic liver injury [5].
• The human CCKAR gene maps to chromosome 4 [15].
• Investigation of quantitative trait loci in the CCKAR gene with susceptibility to alcoholism [5].
• In addition, patients displaying hallucinations showed a higher frequency of the homozygous genotype of the allele (GT)8 at the -388 locus of the CCKAR gene (p = .042) and homo- and heterozygous genotypes of the T allele at the -333 locus (p = .025), relative to other patients [16].
• These first molecular data identifying the agonist binding site of the human CCK-A receptor represent an important step toward the complete delineation of the agonist binding site and the understanding of the molecular mechanisms that govern differential activation of this receptor by CCK-related peptides [17].

Anatomical context of CCKAR

• The human pancreas predominantly expresses CCK-B receptors, whereas only CCK-A receptors were localized in the human gallbladder muscle [18].
• Conflictual data have been published as to whether CCKA, CCKB and CCKC receptors are, or are not, present in tumors of the central and peripheral nervous system (CPNS) in general, and in gliomas in particular [19].
• However, RT-PCR/Southern blotting showed the presence of CCK-A receptor mRNA in adult pancreas [20].
• Using autoradiography, high concentrations of CCK-A receptors were detected in the duodenal mucosa, although in the pancreas only CCK-B receptors were detected by this method [21].
• Mechanism of cholecystokinin-A- receptor antagonist on human pancreatic exocrine secretion. Localization of CCK-A receptor in the human duodenum [21].

Associations of CCKAR with chemical compounds

• First intracellular loop of the human cholecystokinin-A receptor is essential for cyclic AMP signaling in transfected HEK-293 cells [22].
• Discovery of 1,5-benzodiazepines with peripheral cholecystokinin (CCK-A) receptor agonist activity (II): Optimization of the C3 amino substituent [23].
• Analogs of the previously reported 1,5-benzodiazepine peripheral cholecystokinin (CCK-A) receptor agonist 1 were prepared which explore substitution and/or replacement of the C-3 phenyl urea moiety [23].
• The potency of the contraction induced by CCK-8, desulphated CCK-8, and gastrin-I, and the effect of the CCK-A (loxiglumide and SR 27897) and the CCK-B (YM022 and L-365 260) specific receptor antagonists were compared [24].
• In contrast, its enantiomer PD 140548 ((benzenebutanoic acid, beta-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2-[[(tricyclo[3.3.1.1(3,7] dec-2-yloxy)carbonyl]amino]propyl] amino],-[S-(R*,S*)) displayed the reverse selectivity (CCKA IC50 = 2.8 nM, CCKB IC50 = 260 nM) [25].

Physical interactions of CCKAR

• Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin [17].

Regulatory relationships of CCKAR

• 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 [26].
• Furthermore, the selective CCKA antagonist CAM-1481 inhibited the increase in [Ca2+]i induced by CCK-8 (half-maximal inhibitory concentration = 3 nM) in GLC19 but not in H510 cells [27].
• Gastrin stimulates growth of human colon cancer cells via a receptor other than CCK-A or CCK-B [28].
• CCK-B antagonists suppressed CCK-4-induced calcium mobilization more potently than CCK-A antagonist [29].
• The present work shows that both aminosteroids inhibit cholecystokinin-(26-33)-peptide amide (CCK-8)-induced phospholipase D activation equipotently in Chinese hamster ovary cells expressing the cholecystokinin-A receptor (CHO-CCK(A) cells) [30].

Other interactions of CCKAR

• It can therefore be expected that in humans bearing V365I mutation, decreases in CCK1 receptor expression and coupling efficiency may affect CCK-induced regulation of satiety [2].
• In contrast, CCK-A receptor antagonists inhibited the stimulatory effect of G-17 in SIIA cells, whereas CCK-B receptor antagonists had no effect [1].
• This occurs through activation of CCK-A receptors and is associated with an increased gastric luminal release of somatostatin [31].
• In contrast, LPC 1 responded with increased cell number to CCK-8S and decreased cell number to the CCK-A receptor antagonist devazepide [32].
• As for all G-protein-coupled receptors, docking of ligands into modeled CCK1R binding site should greatly help to understand intrinsic mechanisms of activation [33].

Analytical, diagnostic and therapeutic context of CCKAR

• These results describe for the first time the molecular cloning, expression and chromosomal localization of the human CCKA receptor [15].
• In the present study we employed polymerase chain reaction (PCR) on a series of 29 CNPS tumors, including 20 gliomas (17 astrocytic and 3 oligodendroglial tumors), 4 schwannomas and 5 meningiomas to investigate whether RNAs were present or absent in the case of these CCKA, CCKB and CCKC receptors [19].
• Northern blot analysis showed a strong signal for CCK-B receptor mRNA in adult pancreas, but no detectable signal for CCK-A receptor mRNA [20].
• Using fluorescence in situ hybridization, we determined that CCKAR maps to 4p15.1-p15 [34].
• Here, we describe the procedure we used to progressively build a structural model for the CCK1R, to integrated, and on the basis of site-directed mutagenesis data on its binding site [33].

References