The peripheral cholecystokinin receptors

Silvente-Poirot, Sandrine; Dufresne, Marlène; Vaysse, Nicole; Fourmy, Daniel

doi:10.1111/j.1432-1033.1993.tb18061.x

Cited by 125 publications

(94 citation statements)

References 233 publications

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“…Pharmacological studies have shown that chemically distinct molecules such as peptides, peptoids, and non-peptides can bind to the CCK1R with very close affinities (8,9). On the other hand, within each chemical family of CCK1R ligands, compounds having close structures are agonists, partial agonists, or antagonists, indicating that appropriate modifications within the pharmacophore switches an agonist to an antagonist and vice versa.…”

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

“…The wide spectrum of biological functions regulated by the CCK1R makes it a candidate target for a therapeutic approach in a number of diseases related to nutrient assimilation. This led a number of academic and pharmaceutical research groups to design specific and highly potent agonists and antagonists for this receptor (8,9).…”

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

“…The CCK1R and CCK2R can exist in several conformational states, which bind CCK with high, low, and very low affinities, respectively, and share the functional coupling to phospholipase C, via binding to heterotrimeric GTP-binding protein(s) (5-7). CCK1R-mediated effects include control of gallbladder contraction, pancreatic exocrine secretion, gastric emptying and gut motility, and satiety (8,9). The wide spectrum of biological functions regulated by the CCK1R makes it a candidate target for a therapeutic approach in a number of diseases related to nutrient assimilation.…”

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

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The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

Escrieut

Gigoux

Archer

et al. 2002

Journal of Biological Chemistry

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105

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The cholecystokinin (CCK) receptor-1 (CCK1R) is a G protein-coupled receptor, which mediates important central and peripheral cholecystokinin actions. Our aim was to progress in mapping of the CCK1R binding site by identifying residues that interact with the methionine and phenylalanine residues of the C-terminal moiety of CCK because these are crucial for its binding and These new and important insights will serve to better understand the activation process of CCK1R and to design or optimize ligands.

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Section: Cholecystokinin (Cck)mentioning

confidence: 99%

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

Section: Cholecystokinin (Cck)mentioning

confidence: 99%

See 1 more Smart Citation

The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

Escrieut

Gigoux

Archer

et al. 2002

Journal of Biological Chemistry

Self Cite

105

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“…While the CCK1 receptor is highly selective towards cholecystokinin vs. gastrin, the CCK2 receptor binds the 2 agonists with similar high affinities. 2 Both are G-protein coupled receptors with extrinsic tyrosine kinase activity. They activate many intracellular mediators classically described in the regulation of mitogenesis by growth factors.…”

mentioning

confidence: 99%

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Mathieu

Clerc

Portolan

et al. 2005

Intl Journal of Cancer

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In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis. ' 2005 Wiley-Liss, Inc.Key words: G protein coupled receptors; CCK2 receptor; precancerous conditions; gastrin; transdifferentiation; experimental animal model; developmental gene Peptides of the cholecystokinin (CCK)/gastrin family are present in the gastrointestinal tract where they are known to physiologically regulate gallbladder and bowel motility, pancreatic and gastric secretion as well as growth and trophicity of gastrointestinal epithelial mucosa. 1 Two receptors that mediate the actions of cholecystokinin and gastrin have been pharmacologically classified as CCK1 and CCK2 receptors on the basis of their binding affinity for their natural ligands. While the CCK1 receptor is highly selective towards cholecystokinin vs. gastrin, the CCK2 receptor binds the 2 agonists with similar high affinities. 2 Both are G-protein coupled receptors with extrinsic tyrosine kinase activity. They activate many intracellular mediators classically described in the regulation of mitogenesis by growth factors. 3 Mitogen-activated protein kinases, ERK1/2, Jun kinase and p38MAPK, as well as the phosphatidylinositol 3-kinase (PI3K) and early responsive genes (c-fos, c-myc and c-jun), are known targets of gastrin. 4-7 Several groups including ours, have documented the contribution of Src and focal adhesion kinase (Fak) families' tyrosine kinases upstream the activation of these pathways. 4,8 The role of gastrin and CCK2 receptors as positive regulators of proliferation of normal...

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“…Gastrin increases interleukin isoforms, IL-1β and IL-8 secretion, resulting in inflammatory process and subsequently cancer (16). Notably, peptide CCK selectively binds to CCK-A, while gastrin binds with equal affinity to both CCk-A and CCk-B receptors (17). CCK-A is over 500-fold more selective towards CCK than gastrin, while CCK-B/gastrin receptor has equal affinity for both CCK and gastrin.…”

Section: Introductionmentioning

confidence: 99%

Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Ponnusamy

Lattmann

Lattmann³

et al. 2016

Oncology Reports

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Abstract. Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genome-wide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.

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The peripheral cholecystokinin receptors

Cited by 125 publications

References 233 publications

The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

The Biologically Crucial C Terminus of Cholecystokinin and the Non-peptide Agonist SR-146,131 Share a Common Binding Site in the Human CCK1 Receptor

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

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