Calcimimetic acts on enteric neuronal CaSR to reverse cholera toxin-induced intestinal electrolyte secretion

Tang, Lieqi; Jiang, Lingli; McIntyre, Megan E.; Petrova, Ekaterina; Cheng, Sam X.

doi:10.1038/s41598-018-26171-4

Cited by 13 publications

(10 citation statements)

References 75 publications

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“…In fact, 7 mM Ca 2+ is significantly better than 2 μM AC-265347 in abrogating fluid secretion (Figure 4). These results confirm CaSR activation and are similar to what has been observed in the colon (Cheng, 2012; Tang et al, 2018).…”

Section: Discussionsupporting

confidence: 91%

Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine

et al. 2019

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Background The calcium-sensing receptor (CaSR) has been localized and characterized in numerous tissues throughout the body. In the mammalian gastrointestinal tract, the CaSR is known to act as a nutrient sensor and has recently been found to play a role in intestinal fluid and electrolyte balance. This study aims to demonstrate the functionality of the CaSR as a modulator of fluid secretion and absorption along the small intestine. Methods Small intestine regions (proximal, middle, and distal) were isolated from Sprague Dawley rats and loaded into an ex vivo intestinal perfusion device that provides independent intraluminal and extraluminal (serosa/basolateral) perfusion. The regions were perfused with 5 and 7 mM of Ca 2+ , both in the presence and absence of forskolin (FSK), a potent secretagogue. Control experiments were conducted with intraluminal perfusate containing standard Ringer-HEPES buffer with a physiological concentration of Ca 2+ (1 mM). A second set of comparison experiments was performed with intraluminal perfusates containing AC-265347, a CaSR activator and agonist, in the presence of FSK. In all experimental conditions, the intraluminal perfusate contained fluorescein isothiocyanate (FITC)-inulin, a nonabsorbable fluorescent marker of secretion and/or absorption. Intraluminal fluorescence signal was utilized as a measure of water movement at the start of the experiment and every 15 min for 90 min. Results Under physiological conditions, increasing the concentration of Ca 2+ in the luminal perfusate reduced intestinal fluid secretion in all regions. At a Ca 2+ concentration of 7 mM, net fluid absorption was observed in all regions. In the presence of FSK, 5 mM Ca 2+ significantly decreased fluid secretion and 7 mM Ca 2+ abolished FSK-induced fluid secretion. Intraluminal perfusion with 5 mM Ca 2+ was as effective as AC-265347, in reducing secretagogue-induced fluid hypersecretion in the proximal and middle regions. Conclusion This study concludes that apical CaSR is active along the small intestine. Its activation by Ca 2+ and/or calcimimetics reduces fluid secretion in a dose-dependent manner, with higher Ca 2+ concentrations, or application of a calcimimetic, leading to fluid absorption. We furthermore show that, in the presence of FSK, receptor activation abates FSK secretagogue-induced fluid secretion. This presents a new therapeutic target to address secretory diarrheal illnesses.

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Section: Discussionsupporting

confidence: 91%

Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine

et al. 2019

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“…The CaSR is expressed along the entire gastrointestinal tract in parietal and G cells of stomach gastric glands (Ray et al, 1997;Busque et al, 2005;Feng et al, 2010;Engelstoft et al, 2013), epithelial and enteroendocrine cells of the small and large intestine (Liou et al, 2011;Wang et al, 2011;Cheng et al, 2014;Alamshah et al, 2017), and neurons of the submucosal and myenteric plexuses of the enteric nervous system (ENS) (Geibel et al, 2006;Cheng, 2012;Tang et al, 2018). In the gastrointestinal tract, the CaSR functions as a nutrient sensor, binding not only Ca 2+ , Mg 2+ , and other cations but also L-amino acids and dipeptides and polypeptides (e.g., glutamyl dipeptides, poly-L-lysine).…”

Section: F Calcium-sensing Receptor In the Gastrointestinal Tractmentioning

confidence: 99%

“…In the gastrointestinal tract, the CaSR functions as a nutrient sensor, binding not only Ca 2+ , Mg 2+ , and other cations but also L-amino acids and dipeptides and polypeptides (e.g., glutamyl dipeptides, poly-L-lysine). The CaSR is involved in regulation of gastric acid and hormone secretion, nutrient absorption, intestinal fluid homeostasis, energy metabolism, cellular differentiation and proliferation, motility and enteric nerve activity, maintenance of gut microbiota, immune homeostasis, and intestinal inflammation (Dufner et al, 2005;Ceglia et al, 2009;Geibel and Hebert, 2009;Feng et al, 2010;Brennan et al, 2014;Cheng et al, 2014;Tang et al, 2016bTang et al, , 2018Alamshah et al, 2017;Sun et al, 2018).…”

Section: F Calcium-sensing Receptor In the Gastrointestinal Tractmentioning

confidence: 99%

“…2 ) secretion in the colon is finetuned by the CaSR (Tang et al, 2015). However, it seems that the neurogenic secretory responses in the intestinal epithelium are mediated mainly by the CaSR expressed in the ENS and not in the epithelium (Geibel et al, 2006;Cheng, 2012;Tang et al, 2018). Because abnormalities of the ENS affect the severity of intestinal inflammation and contribute to the pathogenesis of inflammatory bowel disease (Margolis et al, 2011), the CaSR could be a potential therapeutic target.…”

Section: F Calcium-sensing Receptor In the Gastrointestinal Tractmentioning

confidence: 99%

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International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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“…The CaSR is expressed in many organs of the body, where it affects very different processes, such as neuronal differentiation [7], vessel tone and blood pressure [8], skin wound healing [9] insulin secretion [10,11] among many others [3]. In the gastrointestinal tract the CaSR regulates secretion of gastrointestinal hormones such as gastrin and cholecystokinin [12,13], controls fluid absorption [14], represses electrolyte secretion through the modulation of the enteric nervous system [15] and modulates intestinal barrier function and inflammation [16].…”

Section: Introductionmentioning

confidence: 99%

Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

Iamartino

Elajnaf

Gall

et al. 2020

Preprint

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The calcium-sensing receptor (CaSR) is a ubiquitously expressed multifunctional G protein-coupled receptor. Several studies reported that the CaSR plays an anti-inflammatory and anti-tumorigenic role in the intestine, and that it is down-regulated during colorectal carcinogenesis. We hypothesized that intestine-specific positive allosteric CaSR modulators (type II calcimimetics) could be used for the treatment of intestinal pathologies. Therefore, the aim of this study was to determine the effect of pharmacological stimulation of CaSR on gene expression in vitro and on tumor growth in vivo. We stably transduced two colon cancer cell lines (HT29 and Caco2) with lentiviral vectors containing either the CaSR fused to GFP or GFP only. Using RNA sequencing, RT-qPCR experiments and ELISA, we determined that CaSR over-expression itself had generally little effect on gene expression in these cells. However, treatment with 1μM of the calcimimetic NPS R-568 increased the expression of pro-inflammatory factors such as IL-23α and IL-8 and reduced the transcription of various differentiation markers in the cells over-expressing the CaSR. In vivo, neither the presence of the CaSR nor p.o. treatment of the animals with the calcimimetic cinacalcet affected tumor growth, tumor cell proliferation or tumor vascularization of murine HT29 xenografts. In summary, CaSR stimulation in CaSR over-expressing cells enhanced the expression of inflammatory markers in vitro, but was not able to repress colorectal cancer tumorigenicity in vivo. These findings suggest potential pro-inflammatory effects of the CaSR and type II calcimimetics in the intestine.

show abstract

Calcimimetic acts on enteric neuronal CaSR to reverse cholera toxin-induced intestinal electrolyte secretion

Cited by 13 publications

References 75 publications

Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine

Activation of the Calcium Sensing Receptor Decreases Secretagogue-Induced Fluid Secretion in the Rat Small Intestine

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Effects of pharmacological calcimimetics on colorectal cancer cells over-expressing the human calcium-sensing receptor

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