Structure and Developmental Expression of the Mouse CCK-B Receptor Gene

Lay, Jean M.; Jenkins, Casey; Friis‐Hansen, Lennart; Samuelson, Linda C.

doi:10.1006/bbrc.2000.2875

Cited by 31 publications

(32 citation statements)

References 31 publications

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“…A concentration of 10 nM is able to cause a significant down-regulation of SP, whereas a concentration of 1 M completely reversed SP expression to basal levels. Because the effective inhibitory concentration of devazepide is well below the IC 50 for CCK B , along with the very low expression of CCKB receptors in mouse pancreas, we suggest that caerulein acts through CCK A receptors to mediate the up-regulation of SP (Lay et al, 2000;Dufresne et al, 2006).…”

Section: Discussionmentioning

confidence: 86%

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Koh

Tamizhselvi²,

Bhatia³

2009

J Pharmacol Exp Ther

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The neuropeptide substance P (SP) has emerged to be an important proinflammatory mediator in acute pancreatitis (AP). The presence of substance P and its receptor, neurokinin-1 receptor (NK1R) has been shown in the pancreas and the pancreatic acinar cells. In this study, we investigated the unexplored mechanisms that mediate SP and NK1R expression using an in vitro AP model. Pancreatic acinar cells were obtained from pancreas of male Swiss mice. Isolated cells were treated with caerulein to mimic secretagogue pancreatitis. A concentration-dependent study that subjected the cells to 60 min of stimulation by caerulein showed that SP and the transcript from its gene preprotachykinin-A (PPT-A), and NK1R were up-regulated at a supraphysiological concentration of 10 Ϫ7 M. A concentration-dependent study on intracellular kinases, extracellular signal-regulated kinase (ERK1/2), and cJun N-terminal kinase (JNK) and also transcription factors nuclear factor-B (NF-B) and activator protein-1 (AP-1) showed that they were activated when the caerulein concentration was 10 Ϫ7 M. Inhibition of JNK reversed the up-regulation of PPT-A, SP, and NK1R. However, inhibition of ERK1/2 reversed the up-regulation of NK1R but not of PPT-A and SP. Furthermore, we found that specific ERK1/2 and JNK inhibitors reduce NF-B and AP-1 activity. Taken together, our results suggest that supraphysiological concentrations of caerulein up-regulate the expression of SP and NK1R in pancreatic acinar cells, and the signaling molecules that are involved in this up-regulation include ERK1/2, JNK, NF-B, and AP-1.Acute pancreatitis (AP) is the rapid onset of inflammation of the pancreas. The severity of the disease varies widely, because mild forms of acute pancreatitis are self-limiting and the more severe forms could result in multiple organ dysfunction. It is thought that the initiating event of AP is the injury of enzyme-secreting pancreatic acinar cells (Bhatia, 2005). Injured tissue releases cytokines and chemokines, which then leads to a worsening of inflammatory response. The pathophysiology of AP has largely been determined using cellular and animal models of AP. The endogenous hormone cholecystokinin (CCK) or its amphibian ortholog caerulein is often used to induce experimental AP. The concentration of caerulein that mimics physiological concentration is reported to be 10 Ϫ10 M, whereas a supraphysiological concentration of 10 Ϫ7 M is often used to mimic AP in cellular models (Thrower et al., 2008).The binding of substance P (SP) to its receptor, neurokinin-1 receptor (NK1R), was found to be crucial in determining the outcome of AP (Pandol et al., 2007). SP belongs to the tachykinin neuropeptide family and is derived from the product of preprotachykinin-A (PPT-A) gene. SP is mainly produced by neural cells, but other cell types, such as mouse pancreatic acinar cells, are known to express both SP and NK1R (Tamizhselvi et al., 2007). Stimulation of pancreatic acinar cells with SP was found to up-regulate the production

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Section: Discussionmentioning

confidence: 86%

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Koh

Tamizhselvi²,

Bhatia³

2009

J Pharmacol Exp Ther

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“…Although the expression of CCK2R mRNA was reported and related to modulation of rat cholangiocyte function by gastrin, there is until now no other evidence for the presence of CCK receptors in the liver (174, 270,546). The role of CCK as a stimulant for small bowel and colon growth is unclear.…”

Section: Liver and Intestinementioning

confidence: 99%

“…The role of CCK as a stimulant for small bowel and colon growth is unclear. The majority of reports suggest that the normal colon does not appear to express CCK2R, with the exception of detection by RT-PCR in the mouse colon (270). To date, there is also insufficient evidence for the presence of CCK2R in the small intestine.…”

Section: Liver and Intestinementioning

confidence: 99%

Cholecystokinin and Gastrin Receptors

Dufresne

Seva²,

Fourmy³

2006

Physiological Reviews

419

418

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Cholecystokinin and gastrin receptors (CCK1R and CCK2R) are G protein-coupled receptors that have been the subject of intensive research in the last 10 years with corresponding advances in the understanding of their functioning and physiology. In this review, we first describe general properties of the receptors, such as the different signaling pathways used to exert short- and long-term effects and the structural data that explain their binding properties, activation, and regulation. We then focus on peripheral cholecystokinin receptors by describing their tissue distribution and physiological actions. Finally, pathophysiological peripheral actions of cholecystokinin receptors and their relevance in clinical disorders are reviewed.

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“…is expressed in the murine colon (30), but the precise location of expression has not been defined. Using quantitative RT-PCR (qRT-PCR) analysis, we confirmed that CCK2R was highly expressed in the stomach and, as expected, expressed at much lower levels in the small intestine and colon in 6-week-old WT FVB/N mice ( Figure 1B).…”

Section: Cck2r Is Expressed In the Murine Colonic Crypts And Upregulamentioning

confidence: 99%

“…With the identification and characterization of CCK2R (29), the receptor was demonstrated to have a negligible affinity for nonamidated gastrins (10). CCK2R has been shown to be widely expressed, with transcripts most abundant in the brain and stomach but also detectable in the colon, kidney, ovary, and pancreas (30)(31)(32). It has been shown that overexpression of CCK2R can mediate growth-promoting effects on pancreatic cells both in vitro (33) and in vivo (34).…”

Section: Introductionmentioning

confidence: 99%

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Jin

Ramanathan²,

Quante³

et al. 2009

J. Clin. Invest.

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Hyperproliferation of the colonic epithelium, leading to expansion of colonic crypt progenitors, is a recognized risk factor for colorectal cancer. Overexpression of progastrin, a nonamidated and incompletely processed product of the gastrin gene, has been shown to induce colonic hyperproliferation and promote colorectal cancer in mice, but the mechanism of pathogenesis has not been defined. Cholecystokinin-2 receptor (CCK2R) is the primary receptor for cholecystokinin (CCK) and amidated gastrin. Here, we show that Cck2r was expressed in murine colonic crypts and upregulated in the transgenic mice that overexpress human progastrin. Murine deletion of Cck2r abrogated progastrin-dependent increases in colonic proliferation, mucosal thickness, and β-catenin and CD44 expression in the colon tumor. In addition, either deletion or antagonism of Cck2r resulted in the inhibition of progastrin-dependent increases in progenitors expressing doublecortin and CaM kinase-like-1 (DCAMKL1), stem cells expressing leucine rich repeat-containing G protein-coupled receptor 5 (LgR5), and colonic crypt fission. Furthermore, in the azoxymethane mouse model of colorectal carcinogenesis, Cck2r deletion in human progastrin-overexpressing mice resulted in markedly decreased aberrant crypt foci formation and substantially reduced tumor size and multiplicity. Taken together, these observations indicate that progastrin induces proliferative effects, primarily in colonic progenitor cells, through a CCK2R-dependent pathway. Moreover, our data suggest that CCK2R may be a potential target in the treatment or prevention of colorectal cancer.

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Structure and Developmental Expression of the Mouse CCK-B Receptor Gene

Cited by 31 publications

References 31 publications

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Cholecystokinin and Gastrin Receptors

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

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Structure and Developmental Expression of the Mouse CCK-B Receptor Gene

Cited by 31 publications

References 31 publications

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Cholecystokinin and Gastrin Receptors

Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice

Contact Info

Product

Resources

About

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH₂-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells