The extracellular calcium sensing receptor (CaSR) is a G-protein coupled receptor which is widely distributed along the gastrointestinal tract and accessary organs. Its primary role is to sense variations in extracellular calcium concentration, however, our recent research unlocked that CaSR exerts multiphasic effects on the modulation of gut health. Our findings demonstrated that specific amino acids (AAs) and peptides have significant anti-inflammatory activities, hence leading to protection of intestinal barrier functions. We have reported that a variety of AAs or oligopeptides, including γ-glutamyl peptides, poly-lysine, protamine, and tryptophan, are able to block tumour necrosis factor (TNF)-α-induced inflammatory responses in intestinal epithelial cells through allosteric activation of CaSR. We also reported that tryptophan or γ-glutamyl peptides trigger allosteric activation of CaSR leading to β-arrestin-2 recruitment. β-arrestins are important scaffold proteins involved in bridging different signalling 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 interaction with transforming growth factor (TGF)-β activated kinase (TAK)-1 binding protein (TAB)-1 which blocks the formation of TAB1/2 and TAK-1 complex, and therefore interfere with TNF-α-activated mitogen-activated protein kinase (MAPK)s and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. We also found that γ-glutamyl peptide supplementation was implicated in the regulation of Wnt signalling pathway. We subsequently verified that activation of CaSR using γ-glutamyl peptide could enable β-arrestin-2 to interact with Wnt/β-catenin signalling in a HT-29 cell model, and increased Wnt5a secretion. All in all, the above findings suggest that intestinal CaSR plays an essential role in maintaining gut functions and promoting gut health in response to agonistic nutrients or metabolites. Emerging evidences show non-nutritional biological activity of dietary AAs and γ-glutamyl peptide, owing to their CaSR allosteric agonist, provides the spotlight on a new area of functional food research.<br/>

New molecular target, calcium-sensing receptor (CaSR) toward to improving gastrointestinal health

256th National Meeting (2018)

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