LAUSR

Hydrogen to deuterium isotopic substitution has only a minor effect on physical and chemical properties of water and, as such, is not supposed to influence its neutral taste. Here we conclusively demonstrate that humans are, nevertheless, able to distinguish D 2 O from H 2 O by taste. Indeed, highly purified heavy water has a distinctly sweeter taste than same-purity normal water and can add to perceived sweetness of sweeteners. In contrast, mice do not prefer D 2 O over H 2 O, indicating that they are not likely to perceive heavy water as sweet. HEK 293T cells transfected with the TAS1R2/TAS1R3 heterodimer and chimeric G-proteins are activated by D 2 O but not by H 2 O. Lactisole, which is a known sweetness inhibitor acting via the TAS1R3 monomer of the TAS1R2/TAS1R3, suppresses the sweetness of D 2 O in human sensory tests, as well as the calcium release elicited by D 2 O in sweet taste receptor-expressing cells. The present multifaceted experimental study, complemented by homology modelling and molecular dynamics simulations, resolves a long-standing controversy about the taste of heavy water, shows that its sweet taste is mediated by the human TAS1R2/TAS1R3 taste receptor, and opens way to future studies of the detailed mechanism of action. Ben Abu, Mason and colleagues use molecular dynamics, cell-based experiments, mouse models, and human subjects to determine that, unlike ordinary water, heavy water tastes sweet to humans, but not mice. Mechanistically, this effect is mediated by the human TAS1R/TAS1R3 sweet taste receptor.