Sweet proteins lysozyme and thaumatin are protein-type agonists for the calcium-sensing receptor

In addition to the maintenance of Ca2+ homeostasis, the calcium-sensing receptor (CaSR) is involved in many diverse physiological functions in the mammalian body. The receptor works as a kokumi taste receptor in taste buds and as a nutrient sensor in the gut, where it regulates the secretion of glycemic response and appetite-related hormones. To identify novel human CaSR (hCaSR) activators from food ingredients, we conducted a screening using a cell-based hCaSR assay. Hen egg-white lysozyme, which is a sweet protein, was found to be a novel orthosteric agonist of hCaSR with an EC50 value of 592 μM. Lysozyme hydrolysate was not able to activate hCaSR, thus suggesting that the protein structure of lysozyme is necessary for hCaSR activation. Thaumatin, which is another sweet protein, also activated hCaSR with an EC50 value of 71 μM. This is the first report that shows hCaSR activation by proteins with molecular weights exceeding 10,000 Da. These results provide a new avenue for the development of hCaSR activators, which could be applicable in food or drugs that modulate taste perception, appetite, or glucose tolerance, in addition to Ca2+ homeostasis. •A cell-based hCaSR assay system with hGα15 was established.•Sweet proteins lysozyme and thaumatin were identified as novel hCaSR agonists.•This is the first report that shows hCaSR activation by proteins.•These results provide a new avenue for the development of hCaSR activators.