Disease relevance of Cckar

• The plasma cholesterol levels, daily food intake, and body weight were not significantly different between CCK-AR(+/+) and (-/-) mice [1].
• Targeted disruption of the murine cholecystokinin-1 receptor promotes intestinal cholesterol absorption and susceptibility to cholesterol cholelithiasis [2].
• In contrast to OLETF rats, CCK-AR(-/-) mice have normal total daily food intake and do not develop obesity [3].
• METHODS: CCK-AR gene expression was determined by Northern transfer analysis in gallbladders with or without gallstones [4].
• We have modified the promoter of cholecystokinin type A receptor (CCKAR), named CCK/Mpd, which possesses a relatively high activity in pancreatic cancer cells as compared with normal cells [5].

Psychiatry related information on Cckar

• Thus, this increased frequency in open-arm entries for CCK-AR(-/-) mice was interpreted to be due to an increase in locomotor activity, rather than to a reduction in anxiety [6].
• Furthermore, PP secretion in response to CCK-8 showed a similarity with that of insulin in terms of dose- and time-response characteristics as well as sensitivity to CCKA-receptor antagonism [7].

High impact information on Cckar

• Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor [8].
• The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight [8].
• We concluded that helices VI and III of the CCK1R are functionally linked through the CCK1R agonist binding site and that positioning of the C-terminal ends of peptidic agonists toward Phe(330) of helix VI is responsible for extent of phospholipase C activation through Galpha(q) coupling [9].
• Computational simulations predicted that residue 121 affected orientation of the C-terminal end of CCK, thus suggesting that the molecular complex with a reduced inositol phosphate production observed with the mutated CCK1R resembles that resulting from binding of JMV 180 to the WT-CCK1R [9].
• A chimeric protein consisting of the cholecystokinin receptor type A (CCKAR) and the green fluorescent protein (GFP) was used for studying receptor localization, internalization, and recycling in live cells in real time in four different cell lines [10].

Chemical compound and disease context of Cckar

• In the human CHP212 and IMR32 neuroblastoma cell lines, which constitutively express the CCK1 receptor, SR146131 behaved as a partial agonist on intracellular calcium release and inositol monophosphate formation [11].
• It is concluded that the CCK-A receptor antagonist, loxiglumide, has therapeutic and/or prophylactic effects on acute pancreatitis in various models of experimental acute pancreatitis [12].

Biological context of Cckar

• We have cloned the mouse CCK-A receptor gene (Cckar), determined its nucleotide sequence, and analyzed its expression [13].
• The CCK-A receptor is involved in satiety, food intake and behavior, whereas the B receptor is involved in anxiety [14].
• Daily energy intake and expenditure were significantly greater in CCK-BR(-/-) and CCK-AR(-/-)BR(-/-) mice than CCK-AR(-/-) and wild-type [CCK-AR(+/+)BR(+/+)] mice [14].
• The CCKA receptor gene (Cckar) mapped to mouse Chromosome (Chr) 5, in tight linkage with the DNA marker D5Bir8 [15].
• We conclude that intestinal lipid activates the vagal afferent pathway, decreases gastric acid secretion, and delays gastric emptying via a CCK1R-dependent mechanism [16].

Anatomical context of Cckar

• Cckar is widely expressed in the gastrointestinal system (pancreas, gallbladder, intestine, colon and stomach), as well as in brain and kidney [13].
• D2R expression in the nucleus accumbens was significantly lower in the CCK-BR(-/-) mice and was significantly higher in CCK-AR(-/-) mice than in wild-type mice [17].
• AIMS: To determine pancreatic functions in a CCK-A receptor deficient mouse mutant generated by gene targeting in embryonic stem cells [18].
• In addition to ICC, circular smooth muscle cells at the tip of the comma-shaped sphincter muscle, but not elsewhere, also exhibited strong, membrane-bound CCKAR immunoreactivity [19].
• In the rat, cells that display strong CCKAR immunoreactivity and fit the morphological description of interstitial cells of Cajal (ICC) were found in the distal sphincter muscle and in the circular muscle of the proximal duodenum [19].

Associations of Cckar with chemical compounds

• Differences in ethanol ingestion between cholecystokinin-A receptor deficient and -B receptor deficient mice [17].
• Based on the evidence of interaction between CCK and dopamine, we had found previously that the CCK-AR gene -81A/G polymorphism was associated with alcohol dependence [17].
• CONCLUSION: The CCK-A receptor is important for pancreatic exocrine secretion, but not essential for maintaining glucose concentration and pancreatic growth in mice [18].
• Since asperlicin, a selective CCK-A receptor antagonist, may be regarded as a conformationally constrained 2-substituted-3-phenyl-4(3H)-quinazolinone, the progenitor of compound 3 (compound 2, 2-[2-(1H-indol-3-yl)ethyl]-3-phenyl-4(3H)- quinazolinone) might therefore represent a conformationally flexible pharmacophore of the natural product [20].
• In contrast, the selective CCKA receptor antagonist, devazepide, was inactive [21].

Regulatory relationships of Cckar

• Hypolocomotion induced by peripheral or central injection of CCK in the mouse is blocked by the CCKA receptor antagonist devazepide but not by the CCKB receptor antagonist L-365,260 [22].

Other interactions of Cckar

• Pretreatment with L364,714, the CCK1 receptor specific antagonist did not block COX-2 induction by gastrin [23].
• We demonstrate that although CCK-AR(-/-) mice show a similar dysregulation in meal size as OLETF rats, they do not have an elevation in DMH NPY mRNA expression levels [3].
• The present results demonstrate that the response of the gastric vagal afferent activity in CCK-A receptor deficient OLETF rats was more sensitive to intravenous administration of IL-1beta than was in control LETO rats [24].
• The effect of CGRP on food intake was not antagonized by the cholecystokinin A receptor antagonist, L364,718 [25].

Analytical, diagnostic and therapeutic context of Cckar

• Gastric emptying of whole egg, measured by nuclear scintigraphy in awake mice, was significantly faster in CCK1R(-/-) than CCK1R(+/+) mice [16].
• In order to identify the site(s) of action of CCK in the gastropyloric region, we performed immunohistochemistry using an antibody directed to the C-terminal region of the cholecystokinin A receptor (CCKAR) [19].
• Different effects of oral administration of synthetic trypsin inhibitor on the pancreas between cholecystokinin-A receptor gene knockout mice and wild type mice [26].
• We examined whether the treatment of hyperglycemia participates in a non-CCK-1-receptor-mediated mechanism of pancreatic regeneration after partial (30%) pancreatectomy (Px) with use of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model for type 2 diabetes mellitus without CCK-1 receptor gene expression [27].
• The development of a sensitive and specific enzyme immunoassay for FK480, a novel cholecystokinin type-A receptor antagonist, in human plasma [28].

References