Distinct potency of compounds targeting the T1R3 subunit in modulating the response of human sweet and umami taste receptors

The heterodimeric G-protein-coupled receptors T1R2/T1R3 and T1R1/T1R3 have been identified as sweet and umami taste receptors, respectively, and both of these receptors share the T1R3 subunit. Previous research has indirectly indicated functional differences in the T1R3 subunit between the receptors. In this study, a comparative analysis was conducted on the responses of these receptors to substances acting on T1R3, standardizing the response measurement conditions for both. The results revealed significant differences in the modulatory effects of negative allosteric modulators (NAMs) and positive allosteric modulators (PAMs), that act on the transmembrane region of T1R3. Notably, (+/-)-lactisole, (+/-)-2,4-DP, and clofibric acid, which are sweet taste receptor inhibitors, also function as umami taste receptor inhibitors, albeit at concentrations approximately 6-10 times greater than those required for sweet taste inhibition. Additionally, cyclamate and NHDC, which are ago-PAMs of sweet taste receptors, did not activate the umami taste receptor at any concentration that significantly elicited sweet taste receptor responses. These results suggest that the binding modes of the substances to the T1R3 subunit of the sweet taste receptor and umami taste receptor are not entirely identical. The difference in the heterodimeric partners to T1R3 may account for their distinct modulation patterns of receptor function.