The T1R3 subunit of the sweet taste receptor is activated by D2O in transmembrane domain-dependent manner.

Deuterium oxide (D2O) is water in which the heavier and rare isotope deuterium replaces both hydrogens. We have previously shown that D2O has a distinctly sweet taste, mediated by the T1R2/T1R3 sweet taste receptor. Here, we explore the effect of heavy water on T1R2 and T1R3 subunits. We show that D2O activates T1R3-transfected HEK293T cells similarly to T1R2/T1R3-transfected cells. The response to glucose dissolved in D2O is higher than in water. Mutations of phenylalanine at position 7305.40 in the transmembrane domain of T1R3 to alanine, leucine, or tyrosine impair or diminish activation by D2O, suggesting a critical role for T1R3 TMD domain in relaying the heavy water signal.