Sweeteners interacting with the transmembrane domain of the human sweet-taste receptor induce sweet-taste synergisms in binary mixtures

Sweet enhancing effect of neohesperidin dihydrochalcone (NHDC) or cyclamate has been reported to be synergistic in human sensory tests. However, little is known about whether these synergisms are caused by the mechanism mediated by the human sweet-taste receptor. Here, we examined the sweetness intensity of sweet tastant mixtures by measuring the responses of cultured cells stably expressing the human sweet-taste receptor. The results showed that the cell response to sucrose was synergistically potentiated by the addition of NHDC or cyclamate. Moreover, a point mutation in the transmembrane domain of hT1R3 almost completely eliminated the enhancing effects of NHDC and cyclamate. These results suggest that ligand–receptor interactions in the transmembrane domain of hT1R3 are necessary for NHDC and cyclamate to elicit the synergistic potentiation of the receptor activation. Our results may provide the foundation of a molecular basis for receptor-based synergisms of sweet tastes in mixtures of diverse sweet substances.