Disease relevance of CCK

• All the effects of CCK depended on a pertussis toxin-dependent G protein [1].
• CCK mRNA was restricted predominantly to Ewing sarcomas (9 of 11) and leiomyosarcomas (5 of 10) [2].
• The overexpression of CCK1 receptors in a subset of human neuroendocrine tumors may provide a molecular basis for efficient targeting of these tumors with radiolabeled CCK analogs [3].
• Polymorphism or mutations in the CCK receptors may be involved in type 2 diabetes mellitus and obesity [4].
• Some data suggest that cholecystokinin (CCK) receptor agonists stimulate the growth of colon cancer [5].
• Baseline and nutrient-stimulated plasma CCK concentrations were higher in critically ill patients compared with healthy subjects (p < .001) [6].

Psychiatry related information on CCK

• 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].
• There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD) [8].
• Results obtained with CCK receptor antagonists in animal studies have been highly variable, and clinical trials with several of these compounds in anxiety disorders have been unsuccessful so far [9].
• OBJECTIVE: To determine whether polymorphisms of CCK and CCK receptor genes are associated with hallucinations in white PD subjects [10].
• Cholecystokinin (CCK) plays an important role in the regulation of postprandial gastric motor activity which was found to be abnormal in duodenal ulcer patients [11].

High impact information on CCK

• We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions [12].
• An increasing body of evidence supports the concept that opioid and CCK peptides may interact to control food intake, but the evidence is more suggestive than conclusive [13].
• Cholecystokinin peptides have been isolated in both the brain and gastrointestinal tract, and changes in concentration in the brain and in plasma have been shown to vary with feeding [13].
• Malabsorption due to cholecystokinin deficiency in a patient with autoimmune polyglandular syndrome type I [14].
• Impaired cholecystokinin secretion in bulimia nervosa [15].

Chemical compound and disease context of CCK

• 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 [5].
• No immunoreactivity was obtained either in the cerebral ganglion or in the alimentary tract with antibodies to leu-enkephalin, met-enkephalin, CCK, growth hormone, ACTH, CLIP and GIP [16].
• In severe cholecystitis, CCK contractile effect was reduced by the serotonin receptor antagonist methysergide [17].
• The stimulatory effect of CCK on meningioma cell growth was completely abolished by a CCK-B specific receptor antagonist, L-365,260 [18].
• Cholecystokinin (CCK) and its analogs, the opioid peptides beta-endorphin and FK33824, TRH analogs, and several dipeptides exhibit potent anticonvulsant properties in chemical, electroshock, and genetic model screens [19].

Biological context of CCK

• Food intake and plasma CCK concentrations were assessed, and subjects scored their feelings of hunger and fullness in paired experiments [7].
• This inhibitory effect was observed at doses of RC-160 similar to those necessary to occupy the sst5 recombinant receptor and to inhibit CCK-induced cell proliferation [1].
• CCK also activated both phosphorylation and activity of p42-MAP kinase; these effects were inhibited by KT 5823 [1].
• The two receptor isoforms may contribute to functional differences in gastrin- and CCK-mediated signal transduction [20].
• A synthetic DNA based on the known amino acid sequence of the brain/gut peptide cholecystokinin (CCK) was synthesized [21].

Anatomical context of CCK

• CONCLUSIONS: The sub-types of receptors for CCK in the human pancreas and gallbladder are different [22].
• Hitherto, little information on characteristics of CCK receptors in the human pancreas was available [22].
• BACKGROUND/AIMS: The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is still controversial [23].
• RESULTS: Specific bindings for CCK were visualized in pancreatic tissue and the smooth muscle layer of the gallbladder [22].
• BACKGROUND & AIMS: Exogenous cholecystokinin (CCK) decreases lower esophageal sphincter (LES) pressure and increases transient LES relaxations (TLESRs) in humans [24].

Associations of CCK with chemical compounds

• In loxiglumide-treated subjects there was a 4-5-fold elevation in plasma CCK levels [7].
• METHODS: Acini isolated from human pancreas were treated with CCK receptor agonists, CCK-8 and gastrin, and an agonist for m3 muscarinic acetylcholine receptors (m3 AchR), carbachol [25].
• The response to CCK was inhibited in a competitive manner by the addition of the benzodiazepine analog, MK-329 [26].
• CCK treatment induced an increase of intracellular cGMP concentrations, but concomitant addition of LY 83583 virtually suppressed this increase [1].
• Identification of the two amino acids was achieved by dynamics-based docking of CCK in a refined three-dimensional model of CCK-AR using, as constraints, previous results that demonstrated that Trp-39/Gln-40 and Met-195/Arg-197 interact with the N terminus and the sulfated tyrosine of CCK, respectively [27].
• EWS/FLI1 knockdown in A673 and SK-PN-DW Ewing cells using two different doxycycline-inducible EWS/FLI1-specific shRNA vectors down-regulated CCK mRNA expression and diminished the levels of secreted CCK, showing that CCK is a EWS/FLI1 specific target gene in Ewing cells [28].
• Partial intraclass correlation showed an independent correlation of plasma CCK with free fatty acids (r(ic) = -0.377, P < 0.001) but not with serum insulin (r(ic) = 0.077, P = 0.32) [29].

Physical interactions of CCK

• Identification of two amino acids of the human cholecystokinin-A receptor that interact with the N-terminal moiety of cholecystokinin [30].
• Using the NOE-generated intermolecular contact points, extensive MD simulations of CCK-8 bound to the CCK2 receptor were carried out [31].
• G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family [32].
• Endogenous CCK appears to interact with direct cholinergic stimulation at the pancreatic PP cell and the gastric D-cell but not at pancreatic acinar and antroduodenal smooth muscle cells [33].
• Serotonin and gastrin/cholecystokinin-like immunoreactive neurons in the larval retrocerebral complex of the blowfly Calliphora erythrocephala [34].

Regulatory relationships of CCK

• Somatostatin analogue RC-160 inhibited CCK-induced stimulation of cell proliferation but it did not potentiate the suppressive effect of the inhibitors LY 83583 and KT 5823 [1].
• 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 [35].
• The aldosterone response to CCK and pentagastrin was suppressed by a CCK2-R antagonist, but not by a CCK1-R antagonist [36].
• The cholecystokinin gene is abundantly co-expressed with gastrin-releasing peptide, enkephalin and neuropeptide Y genes in a clonal human neuroepithelioma cell line [37].
• BACKGROUND: Alpha-amidated gastrin promotes the growth of nontransfected pancreatic cell lines expressing the gastrin/cholecystokinin (CCK)-B receptor [38].

Other interactions of CCK

• No significant intergroup differences were noted in postprandial levels of Nt and CCK [39].
• These actions seem mediated by extrasphincteric CCK-A receptors that override a direct contractile effect of CCK on the LES muscle [24].
• Issues considered include, the effects of systemic injection of CCK on consummatory and operant feeding, the role of the vagus nerve, the effects of CCKB receptor antagonists, and the neuroendocrine responses to exogenous CCK [40].
• CCK-8 markedly stimulated colony formation in GLC19 cells in a dose-dependent manner in the nanomolar range, whereas over the same concentration range, gastrin had no effect on clonal growth [35].
• Cortical Sources of CRF, NKB, and CCK and Their Effects on Pyramidal Cells in the Neocortex [41].

Analytical, diagnostic and therapeutic context of CCK

• METHODS: CCK receptors were localized by in vitro receptor autoradiography with 125I-[Leu15]gastrin-I and 125I-[D-Tyr-Gly, Nle(28,31)]-CCK 26-33 in stomach and gallbladder [42].
• 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 [8].
• We determined whether cortical levels of CCK might be similarly affected in AD by dissecting postmortem brain samples from 14 histologically confirmed cases of AD and 17 age-matched controls and measuring CCK and somatostatin by radioimmunoassay [43].
• However, future investigations using CCK receptor antagonists with better pharmacokinetic characteristics and animal models other than those validated with the classical anxiolytics benzodiazepines may permit a more precise evaluation of the potential of these compounds as anti-anxiety agents [9].
• In the present study we have evaluated gastrin and CCK gene expression in a group of primary human tumors, including neuronal, renal, and myogenic stem cell tumors, using in situ hybridization techniques [2].

References