Calcium-sensing receptor (CaSR) agonist R568 inhibits small intestinal motility of mice through neural and non-neural mechanisms

Guo, Yajie; Gao, Shengli; Jiang, Zucheng; Huang, Jinfang; He, Xiaoman; Jin, Ruijie; Sun, Shibo; Guo, Feifei; Gong, Yanling; Sun, Xiangrong

doi:10.1039/d1fo01988k

Cited by 7 publications

(5 citation statements)

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“…In the myenteric plexus of each animal, 30 ganglions were randomly selected, and the immunoreactive neurons in the colon were counted. The average number of neurons in each ganglion was obtained using ImageJ software ( Guo et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Melanin-concentrating hormone promotes anxiety and intestinal dysfunction via basolateral amygdala in mice

Zhang

et al. 2022

Front. Pharmacol.

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The limbic system plays a pivotal role in stress-induced anxiety and intestinal disorders, but how the functional circuits between nuclei within the limbic system are engaged in the processing is still unclear. In our study, the results of fluorescence gold retrograde tracing and fluorescence immunohistochemistry showed that the melanin-concentrating hormone (MCH) neurons of the lateral hypothalamic area (LHA) projected to the basolateral amygdala (BLA). Both chemogenetic activation of MCH neurons and microinjection of MCH into the BLA induced anxiety disorder in mice, which were reversed by intra-BLA microinjection of MCH receptor 1 (MCHR1) blocker SNAP-94847. In the chronic acute combining stress (CACS) stimulated mice, SNAP94847 administrated in the BLA ameliorated anxiety-like behaviors and improved intestinal dysfunction via reducing intestinal permeability and inflammation. In conclusion, MCHergic circuit from the LHA to the BLA participates in the regulation of anxiety-like behavior in mice, and this neural pathway is related to the intestinal dysfunction in CACS mice by regulating intestinal permeability and inflammation.

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Section: Methodsmentioning

confidence: 99%

Melanin-concentrating hormone promotes anxiety and intestinal dysfunction via basolateral amygdala in mice

Zhang

et al. 2022

Front. Pharmacol.

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“…[ 25,26 ] Furthermore, activation of CaSR in the AP causes side effects of nausea and malaise [ 27 ] and our group also observed that R568 injected into the AP inhibited gastric emptying and delayed gut transit time (unpublished observation). [ 4 ] To sum up, activation of CaSR in the AP does not exclusively facilitate the satiation process or post‐digestive satiety, the side effects such as gastrointestinal dysfunction, nausea, and malaise cannot be excluded to induced anorexia.…”

Section: Discussionmentioning

confidence: 99%

“…[2] CaSR is distributed widely in tissues and organs (e.g., gastrointestinal tract and brain) and participates in regulation of various physiological functions. [1,3,4] In the gastrointestinal tract, CaSR is expressed in epithelial cells, endocrine cells, and enteric nervous system, which is involved in regulating transportation of intestinal fluid, the immune response, hormone secretion, and gastrointestinal motility. [5] CaSR is also distributed in the brain, including the hippocampus, hypothalamus, area postrema (AP), cerebral cortex, and amygdala.…”

Section: Introductionmentioning

confidence: 99%

Activation of Calcium‐Sensing Receptor in the Area Postrema Inhibits Food Intake via Glutamatergic and GABAergic Signaling Pathways

Huang

Qian

et al. 2022

Molecular Nutrition Food Res

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Scope A high‐protein diet has become a popular way to lose weight. Calcium‐sensing receptor (CaSR) is activated by amino acids in addition to calcium ions. CaSR shows dense expression in the area postrema (AP), which participates in feeding regulation. The effect of CaSR in the AP on food intake and the potential mechanism involved is investigated. Methods and results Male C57BL/6 mice are used to observe the effect of R568 (agonist of CaSR) on food intake. Enzyme‐linked immunosorbent assay, immunofluorescence staining, and chemogenetics are used to explore the neural signaling involved. CaSR activation in the AP inhibited acute feeding; R568 increases the content of glutamate and γ‐aminobutyric acid (GABA) in the AP, whereas only glutamatergic neurons mediate the effect of R568. GABA‐A receptor and ionic glutamate receptor (N‐methyl‐D‐aspartate receptor [NMDAR]) in the paraventricular nucleus of hypothalamus (PVN) are involved in the effect of R568. Promotion of oxytocin (OT) synthesis in the PVN also participates in the effect of R568, and this mechanism is mediated by NMDAR in the PVN. Conclusion CaSR activation in the AP suppresses feeding, and AP–PVN glutamatergic and GABAergic signaling pathways are involved.

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“…The CaSR is a key molecule expressed in intestinal epithelial cells that plays a pivotal role in maintaining the integrity and balance of the epithelium while reducing the expression of inflammatory factors in the intestines (Cheng et al., 2014). Certain nutrients, such as chitosan (Huang et al., 2016), L ‐Trp (Guo et al., 2021; Ohsu et al., 2010), and γ‐glutamyl peptide (Zhang et al., 2015), have been demonstrated to bind to the CaSR and initiate intracellular immune responses, resulting in the alleviation of IBD. In the colon, CaSR activation regulates cell fate and demonstrates tumor‐inhibitory effects, making it a potential therapeutic target for autoimmune IBD and colon cancer treatment (Aggarwal et al., 2015; Yang et al., 2018).…”

Section: The Function and Mechanism Of Glutamine‐derived Peptidesmentioning

confidence: 99%

Glutamine‐derived peptides: Current progress and future directions

Yu,

Hu,

et al. 2024

Comp Rev Food Sci Food Safe

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Glutamine, the most abundant amino acid in the body, plays a critical role in preserving immune function, nitrogen balance, intestinal integrity, and resistance to infection. However, its limited solubility and instability present challenges for its use a functional nutrient. Consequently, there is a preference for utilizing glutamine‐derived peptides as an alternative to achieve enhanced functionality. This article aims to review the applications of glutamine monomers in clinical, sports, and enteral nutrition. It compares the functional effectiveness of monomers and glutamine‐derived peptides and provides a comprehensive assessment of glutamine‐derived peptides in terms of their classification, preparation, mechanism of absorption, and biological activity. Furthermore, this study explores the potential integration of artificial intelligence (AI)‐based peptidomics and synthetic biology in the de novo design and large‐scale production of these peptides. The findings reveal that glutamine‐derived peptides possess significant structure‐related bioactivities, with the smaller molecular weight fraction serving as the primary active ingredient. These peptides possess the ability to promote intestinal homeostasis, exert hypotensive and hypoglycemic effects, and display antioxidant properties. However, our understanding of the structure–function relationships of glutamine‐derived peptides remains largely exploratory at current stage. The combination of AI based peptidomics and synthetic biology presents an opportunity to explore the untapped resources of glutamine‐derived peptides as functional food ingredients. Additionally, the utilization and bioavailability of these peptides can be enhanced through the use of delivery systems in vivo. This review serves as a valuable reference for future investigations of and developments in the discovery, functional validation, and biomanufacturing of glutamine‐derived peptides in food science.

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Calcium-sensing receptor (CaSR) agonist R568 inhibits small intestinal motility of mice through neural and non-neural mechanisms

Abstract: Gastrointestinal motility (GI) disorder causes symptoms such as dyspepsia, abdominal distention, and constipation and severely affects the quality of life. The calcium (Ca2+)-sensing receptor (CaSR) expressed in the digestive tract...

Cited by 7 publications

References 35 publications

Melanin-concentrating hormone promotes anxiety and intestinal dysfunction via basolateral amygdala in mice

Melanin-concentrating hormone promotes anxiety and intestinal dysfunction via basolateral amygdala in mice

Activation of Calcium‐Sensing Receptor in the Area Postrema Inhibits Food Intake via Glutamatergic and GABAergic Signaling Pathways

Glutamine‐derived peptides: Current progress and future directions

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