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Is Calcium-Sensing Receptor a New Molecular Target toward Improving Gastrointestinal Health? Hua Zhang† and Yoshinori Mine*,‡ †
Guelph Food Research Centre, Agriculture and Agri-Food Canada, 93 Stone Road West, Guelph, Ontario N1G 5C9, Canada Department of Food Science, University of Guelph, Guelph, Ontario N1G 2W1, Canada domain. In addition to this extracellular binding domain, CaSR is also comprised of characteristic seven transmembrane helices of GCPRs and a cytoplasmic carboxyl terminus. To further understand the role of CaSR in intestinal homeostasis and health, we investigated the allosteric modulation of CaSR. CaSR has evolved diverse and dynamic mechanisms that regulate receptor expression, trafficking, and desensitization. Interactions with other signaling molecules allow for the coordination of various signaling pathways rather than on−off switches. Accordingly, intestinal CaSR can adopt different allosteric agonist-mediated conformational changes, which allow for regulation of distinct cellular signaling pathways and control over a broad range of physiological activities, e.g., digestion, absorption, energy metabolism, secretion, motility, and immune homeostasis. This suggests that CaSR exerts multiphasic effects on the modulation of gut health. Therefore, a better understanding of the non-calciotropic actions of CaSR and its response to different extracellular stimuli, especially AAs he gastrointestinal tract (GIT) is an organ system that and oligopeptides, is critical to fully explore the role of CaSR as takes the form of a continuous passageway going from the a chemosensor and its contribution to maintaining gut integrity mouth to the intestine within humans and animals and has for and immune balance. primary functions those of food digestion, nutrient absorption, Emerging evidence showed that non-nutritional biological and waste excretion. Within the GIT, the intestinal epithelium activity of dietary AAs and oligopeptides, owing to their CaSR represents the structure that directly interacts with a variety of allosteric agonism, provides the spotlight on a new area of exogenous substances derived from ingested foods or symbiotic functional food research.1 An increased amount of AAs and microflora; hence, the GIT acts as both a physical and chemical peptides is accumulated during the protein digestion process, barrier to impede the entry of pathogens, harmful antigens, and which may lead to activation of CaSR and initiate the digestive toxins. The intestinal barrier system consists of multiple layers, processes, even under a relatively low concentration of calcium i.e., mucosa, submucosa, muscularis, and serosa, within which in the GIT. Therefore, CaSR agonistic AAs and oligopeptides are embedded the lymphatic system, blood vessels, and glands. are potentially involved in regulating intestinal ingestion, Disturbance in the homeostasis of the intestinal microenvirondigestion, and secretion. Current literature supports the ment may lead to impaired barrier integrity, disruption of local observation that CaSR expressed along the GIT confers ecological niches, and also disruption of the metabolic balance increased sensitivity to kokumi taste and stimulates the between resident microorganisms and lead to persistent secretion of stomachic gastrin, mucous, and intestinal immune responses that normally dampen intestinal inflammacholecystokinin (CCK) in response to AAs, e.g., L-phenyltion. All of the above processes are initiated and controlled by a alanine, and peptides, e.g., γ-glutamyl peptides and soybean complex of the gut chemosensing system, in which a variety of β51−63 peptide stimulation.1,2 Similarly, a recent study cellular receptors, including pattern recognition receptors documented that CaSR was involved in the modulation of (PRRs) and G-coupled protein receptors (GCPRs), act as intestinal fluid secretion through enhanced colonic absorption intestinal chemosensors. Those chemosensors are located of short-chain fatty acids (SCFAs) resulting from the colonic within the GIT and have a role the transmission of nutrients fermentation of dietary fibers and, as such, may modulate and the provision of immunomodulatory signals. diarrheaic responses.3 All in all, the above findings suggest that One of the major chemosensors is the extracellular calcium intestinal CaSR plays an essential role in maintaining gut sensing receptor (CaSR), which is widely distributed along the functions and promoting gut health in response to agonistic GIT and accessary organs. Its primary role is to sense variations nutrients or metabolites. in extracellular calcium concentration; however, more importantly, CaSR has the ability to sense a broad range of nutrients, e.g., amino acids (AAs), oligopeptides, polyamines, Received: March 4, 2018 and ions, owing to its extracellular venus fly trap (VFT) ‡
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© XXXX American Chemical Society
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DOI: 10.1021/acs.jafc.8b01150 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
Figure 1. Proposed mechanism underlying the anti-inflammatory effects of CaSR as a result of sensing dietary AAs or peptides in the intestinal milieu. Allosterically activated CaSR induces an adaptor protein, β-arrestin-2, to coordinate with TAB1 or Dvl, thereby suppressing TNF-α- or Wntinduced pathways.
formation of TAB1/2 and TAK-1 complex and, therefore, interferes with TNF-α-activated mitogen-activated protein kinases (MAPKs) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) pathways.5 In this, the intestinal inflammation is eventually suppressed to restore compromised intestinal barrier function and immune homeostasis. Elucidation of the mechanisms responsible for the anti-inflammatory action of CaSR agonistic AAs or peptides will help toward the development of bioactive dietary compounds, which will improve gut health (Figure 1). In our recent study using a dextran sodium sulfate-induced mouse colitis model, we reported that γ-glutamyl peptide supplementation was implicated in the regulation of the Wnt signaling pathway. We subsequently verified that activation of CaSR using γ-glutamyl peptide could enable β-arrestin-2 to interact with Wnt/β-catenin signaling in a HT-29 cell model and increased Wnt5a secretion (in preparation for publication). Besides, the interaction between Wnt/β-catenin signaling and peroxisome proliferator-activated receptor (PPAR)-γ is involved in development of different chronic diseases, such as colon cancer and type 2 diabetes.8 Activation of PPAR-γ induces adipogenesis in adipose tissue to improve insulin sensitivety. Therefore, CaSR may be a potential therapeutic target for treatment of metabolic disorders through regulating Wnt/β-catenin signaling pathways. The aforementioned findings suggest that dietary CaSR agonistic AAs or peptides
Elucidation of the mechanisms by which CaSR agonists, such as dietary AAs and peptides, preserve intestinal barrier integrity and maintain gut homeostasis will allow for the development of effective dietary strategies to improve overall gut health. Our recent findings demonstrated that AAs and peptides had significant anti-inflammatory activities, hence leading to protection of intestinal barrier functions.4−7 A number of studies have reported that a variety of AAs or oligopeptides, including γ-glutamyl peptides, polylysine, protamine, and tryptophan, were able to block tumor necrosis factor (TNF)α-induced inflammatory responses in both Caco-2 and HT-29 cell lines through allosteric activation of CaSR. As a result of these two cell lines being typical in vitro models of the intestinal barrier and CaSR being widely expressed in these two cell lines, they are propitious to study the intestinal chemosensing mechanism. However, the molecular mechanism underlying the anti-inflammation action of CaSR-agonistic AAs or peptides remains unknown. We afterward reported that tryptophan or γglutamyl peptides triggered allosteric activation of CaSR, leading to β-arrestin-2 recruitment.4,5 β-Arrestins are important scaffold proteins involved in bridging different signaling pathways to mediate a collaborative network of cellular responses. In our hands, CaSR activation was shown to be associated with recruitment of β-arrestin-2 ensued by the interaction with transforming growth factor (TGF)-β activated kinase (TAK)-1 binding protein (TAB)-1, which blocks the B
DOI: 10.1021/acs.jafc.8b01150 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
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Journal of Agricultural and Food Chemistry
recognition receptor; GCPR, G-coupled protein receptor; VET, venus fly trap; Cao2+, extracellular calcium; SCFA, short-chain fatty acid; CCK, cholecystokinin; TGF-β, transforming growth factor-β; TAK-1, TGF-β activated kinase-1; TAB, TAK-1 binding protein; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells; PPAR-γ, peroxisome proliferator-activated receptor; NOD, nucleotide-binding domain; NLR, leucine-rich repeatcontaining receptor
may augment CaSR sensing ability to accelerate its subsequent cellular responses and modulate its trafficking and signaling with other receptor-mediated pathways; this constitutes an essential mechanism to ensure the integrated and simultaneous modulation of various cellular activities and functions. In recent studies using an intestinal epithelium CaSRdeficient mouse model, solid evidence was provided that validates the essential role of CaSR in maintaining overall intestinal homeostasis.9 The absence of intestinal epithelial CaSR expression led to a defective mucosal barrier, showing increased intestinal permeability and systemic dissemination of gut microbiota, which triggered innate immune responses. The persistent chronic inflammation rose from the prolonged exposure to luminal content and the induced over-reactive innate immune responses. This study also showed that CaSRdeficient mice present severe colonic inflammation when encounter with colitic damage. The same study reported that a dysbiosis of the gut microbiota and significant upregulation of PRRs [e.g., toll-like receptors (TLRs), nucleotide-binding domains (NODs), and leucine-rich repeat-containing receptors (NLRs)] were attributed to CaSR deficiency, suggesting that CaSR plays a critical role in regulating microbial sensing and homeostasis. Increasing evidence already supports the observation that disruption in intestinal symbionts and loss of immune tolerance could enhance the risks of developing a myriad of disorders. Therefore, CaSR represents a promising therapeutic target in the treatment of intestinal inflammatory disorders. In summary, CaSR has notable implications in the maintenance of gut homeostasis via direct control of gut epithelial integrity, immunity, and host−microbe symbiosis. However, first the molecular mechanisms by which CaSR exerts functional cooperativity in cell signaling transduction in response to allosteric agonists, e.g., AAs or oligopeptides, remains obscure. Second, knowledge on the binding affinity of dietary AAs or peptides with CaSR and relevant CaSR-induced distinct cellular signaling pathway activation is still scarce. Lastly, it is important to investigate the role of intestinal CaSR in the integrated regulation of PRR-mediated innate immune responses according to the ability of CaSR in sensing nutrients (e.g., AAs and peptides derived from foods or microbial metabolites) and resident symbionts. Because CaSR may be able to abrogate PRR-induced cellular inflammatory responses, further studies are warranted to explore potential crosstalk between these two receptor-mediated signaling pathways. When the above knowledge gaps are addressed, the nonnutritional biological function of dietary AAs and oligopeptides, regarded as CaSR agonists, will be further elucidated and the associated health benefits will be manifested.
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REFERENCES
(1) Zhang, H.; Hu, C.-A. A.; Kovacs-Nolan, J.; Mine, Y. Bioactive dietary peptides and amino acids in inflammatory bowel disease. Amino Acids 2015, 47 (10), 2127−2141. (2) Ohsu, T.; Amino, Y.; Nagasaki, H.; Yamanaka, T.; Takeshita, S.; Hatanaka, T.; Maruyama, Y.; Miyamura, N.; Eto, Y. Involvement of the calcium-sensing receptor in human taste perception. J. Biol. Chem. 2010, 285 (2), 1016−1022. (3) Tang, L.; Peng, M.; Liu, L.; Chang, W.; Binder, H. J.; Cheng, S. X. Calcium-sensing receptor stimulates Cl−- and SCFA-dependent but inhibits cAMP-dependent HCO3− secretion in colon. Am. J. Physiol.: Gastrointest. Liver Physiol. 2015, 308 (10), G874−G883. (4) Mine, Y.; Zhang, H. Calcium-sensing receptor (CaSR)-mediated anti-inflammatory effects of L-amino acids in intestinal epithelial cells. J. Agric. Food Chem. 2015, 63 (45), 9987−9995. (5) Zhang, H.; Kovacs-Nolan, J.; Kodera, T.; Eto, Y.; Mine, Y. γGlutamyl cysteine and γ-glutamyl valine inhibit TNF-α signaling in intestinal epithelial cells and reduce inflammation in a mouse model of colitis via allosteric activation of the calcium-sensing receptor. Biochim. Biophys. Acta, Mol. Basis Dis. 2015, 1852 (5), 792−804. (6) Mine, Y.; Zhang, H. Anti-inflammatory effects of poly-L-lysine in intestinal mucosal system mediated by calcium-sensing receptor activation. J. Agric. Food Chem. 2015, 63 (48), 10437−10447. (7) Zhang, H.; Kodera, T.; Eto, Y.; Mine, Y. γ-Glutamyl valine supplementationinduced mitigation of gut inflammation in a porcine model of colitis. J. Funct. Foods 2016, 24, 558−567. (8) Lecarpentier, Y.; Claes, V.; Vallee, A.; Hebert, J. Interactions between PPAR gamma and the canonical Wnt/beta-catenin pathway in type 2 diabetes and colon cancer. PPAR Res. 2017, 2017, 5879090. (9) Cheng, S. X.; Lightfoot, Y. L.; Yang, T.; Zadeh, M.; Tang, L.; Sahay, B.; Wang, G. P.; Owen, J. L.; Mohamadzadeh, M. Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses. FEBS Lett. 2014, 588 (22), 4158−4166.
AUTHOR INFORMATION
Corresponding Author
*Telephone: 1-519-824-4120, ext. 52901. Fax: 1-519-824-6631. E-mail:
[email protected]. ORCID
Yoshinori Mine: 0000-0002-3567-5556 Notes
The authors declare no competing financial interest.
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ABBREVIATIONS USED CaSR, calcium-sensing receptor; GIT, gastrointestinal tract; AA, amino acid; TNF-α, tumor necrosis factor; PRR, pattern C
DOI: 10.1021/acs.jafc.8b01150 J. Agric. Food Chem. XXXX, XXX, XXX−XXX
