Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice

Konno, Kohtarou; Takahashi-Iwanaga, Hiromi; Uchigashima, Motokazu; Miyasaka, Kyoko; Funakoshi, Akihiro; Watanabe, Masahiko; Iwanaga, Toshihiko

doi:10.1007/s00418-014-1281-3

Cited by 19 publications

(13 citation statements)

References 52 publications

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“…A recent paper found CCK1(A)R signaling via ␤-arrestin, extracellular signal-regulated protein kinase (ERK), the 90-kDa ribosomal S6 kinase (p90RSK), and Bad regulates the ␤-cell antiapoptotic effects of CCK in high-glucose conditions (44). The expression of CCK receptors in the pancreatic islet has been controversial, with several studies finding disparate results in different species and using different antibodies (5,11,23,25,28,43,48). There are many challenges with antibodies raised against G protein-coupled receptors, and sensitivity and specificity problems can lead to uncertainty in the results (10).…”

Section: E825mentioning

confidence: 99%

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

Lavine

Kibbe

Baan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Lavine JA, Kibbe CR, Baan M, Sirinvaravong S, Umhoefer HM, Engler KA, Meske LM, Sacotte KA, Erhardt DP, Davis DB. Cholecystokinin expression in the ␤-cell leads to increased ␤-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab 309: E819 -E828, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00159.2015.-Cholecystokinin (CCK) is a peptide hormone produced in the gut and brain with beneficial effects on digestion, satiety, and insulin secretion. CCK is also expressed in pancreatic ␤-cells, but only in models of obesity and insulin resistance. Whole body deletion of CCK in obese mice leads to reduced ␤-cell mass expansion and increased apoptosis. We hypothesized that islet-derived CCK is important in protection from ␤-cell apoptosis. To determine the specific role of ␤-cell-derived CCK in ␤-cell mass dynamics, we generated a transgenic mouse that expresses CCK in the ␤-cell in the lean state (MIP-CCK). Although this transgene contains the human growth hormone minigene, we saw no expression of human growth hormone protein in transgenic islets. We examined the ability of MIP-CCK mice to maintain ␤-cell mass when subjected to apoptotic stress, with advanced age, and after streptozotocin treatment. Aged MIP-CCK mice have increased ␤-cell area. MIP-CCK mice are resistant to streptozotocin-induced diabetes and exhibit reduced ␤-cell apoptosis. Directed CCK overexpression in cultured ␤-cells also protects from cytokineinduced apoptosis. We have identified an important new paracrine/ autocrine effect of CCK in protection of ␤-cells from apoptotic stress. Understanding the role of ␤-cell CCK adds to the emerging knowledge of classic gut peptides in intraislet signaling. CCK receptor agonists are being investigated as therapeutics for obesity and diabetes. While these agonists clearly have beneficial effects on body weight and insulin sensitivity in peripheral tissues, they may also directly protect ␤-cells from apoptosis.cholecystokinin; islet; ␤-cell; apoptosis; aging; streptozotocin TYPE 1 AND TYPE 2 DIABETES MELLITUS are both diseases of reduced ␤-cell mass. In type 1 diabetes, autoimmune destruction of ␤-cells results in an absolute ␤-cell mass deficit. In type 2 diabetes, obesity increases insulin resistance, resulting in a relative insulin deficiency. In patients with type 2 diabetes, ␤-cell mass is lost via increased ␤-cell apoptosis (7, 16). Therefore, there has been wide interest in the development of diabetes therapeutics that preserve ␤-cell mass and prevent ␤-cell apoptosis.Cholecystokinin (CCK) is a gastrointestinal peptide produced by duodenal I cells and secreted in response to fat and protein (31). CCK signals through two G protein-coupled receptors, the CCK1(A) receptor [CCK1(A)R] and the CCK2(B) receptor [CCK2(B)R]. In healthy and diabetic patients, CCK infusion increases insulin secretion and decreases glucose excursion after a meal, suggesting that CCK is a potential diabetes therapeutic (1, 2). CCK also increases satiety by ...

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Section: E825mentioning

confidence: 99%

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

Lavine

Kibbe

Baan

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…However, neither FXR agonist GW4064 nor Fex selective inducing intestinal FGF15 production was suppress the expression of Cyp7a1 in vitro, which indicating that LXR, but not FXR/FGF15 was the dominant transcriptional regulator of Cyp7a1 under the condition of CAV1 depletion [Gupta et al, ; Inagaki et al, ]. Cholecystokinin A receptor (CCKAR) [Konno et al, ], a major physiologic mediator of gallbladder smooth muscle contraction was also suppressed in lithogenic diet‐fed CAV1 −/− mice. Lack CCKAR may aggravate cholestasis, deteriorate gallbladder contraction, and hence accelerate gallstone formation [Miyasaka et al, ].…”

Section: Discussionmentioning

confidence: 99%

CAV1 Prevents Gallbladder Cholesterol Crystallization by Regulating Biosynthesis and Transport of Bile Salts

Jiang

et al. 2016

J of Cellular Biochemistry

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Cholesterol gallstone disease (CGD) is a hepatobiliary disorder which results from a biochemical imbalance in the gallbladder bile. Here we show that loss of CAV1 sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary cholesterol concentration and decreased biliary bile salt secretion in CAV1(-/-) mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. At the signaling level, the ERK/AP-1 pathway seems to mediate the effects of CAV1 on biliary BA homeostasis and might be developed as a therapeutic target for CGD. We propose that CAV1 is an anti-lithogenic factor and that the CAV1(-/-) mice may offer a convenient CGD model to develop therapeutic interventions for this disease. J. Cell. Biochem. 117: 2118-2127, 2016. © 2016 Wiley Periodicals, Inc.

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“…The specificity of rabbit anti-CCK antiserum to I cells in the duodenal epithelium and mucosal nerve plexus in the colon has been confirmed by immunostaining using the same antiserum, and the specificity of the antigen-antibody reaction in this study was confirmed by preincubation of the antiserum with the corresponding antigen. The CCKAR antibodies were raised in a rabbit and guinea pig, as reported previously (19). The specificity of these antibodies has been shown by the disappearance of the immunoreactivities in tissue sections from CCKAR-deficient mice.…”

Section: Methodsmentioning

confidence: 99%

“…Fluorescent in situ hybridization for CCK. Procedures for fluorescent in situ hybridization have been detailed elsewhere (19). Briefly, frozen sections~30 m thick were prepared from the paraformaldehyde-fixed kidneys, followed by inactivation of endogenous peroxidases with 1% H 2O2 (wt/vol).…”

Section: Methodsmentioning

confidence: 99%

Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis

Takahashi-Iwanaga

Kimura

Konno

et al. 2017

American Journal of Physiology-Renal Physiology

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The natriuretic hormone CCK exhibits its gene transcripts in total kidney extracts. To test the possibility of CCK acting as an intrarenal mediator of sodium excretion, we examined mouse kidneys by ) an in situ hybridization technique for CCK mRNA in animals fed a normal- or a high-sodium diet;) immuno-electron microscopy for the CCK peptide, ) an in situ hybridization method and immunohistochemistry for the CCK-specific receptor CCKAR;) confocal image analysis of receptor-mediated Ca responses in isolated renal tubules; and ) metabolic cage experiments for the measurement of urinary sodium excretion in high-salt-fed mice either treated or untreated with the CCKAR antagonist lorglumide. Results showed the CCK gene to be expressed intensely in the inner medulla and moderately in the inner stripe of the outer medulla, with the expression in the latter being enhanced by high sodium intake. Immunoreactivity for the CCK peptide was localized to the rough endoplasmic reticulum of the medullary interstitial cells in corresponding renal regions, confirming it to be a secretory protein. Gene transcripts, protein products, and the functional activity for CCKAR were consistently localized to the late proximal tubule segments (S2 and S3) in the medullary rays, and the outer stripe of the outer medulla. Lorglumide significantly diminished natriuretic responses of mice to a dietary sodium load without altering the glomerular filtration rate. These findings suggest that the medullary interstitial cells respond to body fluid expansion by CCK release for feedback regulation of the late proximal tubular reabsorption.

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Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice

Abstract: Information concerning the cellular localization of cholecystokinin (CCK)-1 receptors has been discrepant and remained scanty at ultrastructural levels. The present immunohistochemical study at

Cited by 19 publications

References 52 publications

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis

CAV1 Prevents Gallbladder Cholesterol Crystallization by Regulating Biosynthesis and Transport of Bile Salts

Intrarenal signaling mediated by CCK plays a role in salt intake-induced natriuresis

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