T1R3 subunit of the sweet taste receptor is activated by D ₂ O in transmembrane domain-dependent manner

Deuterium oxide (D ₂ O) is a water molecule in which both hydrogens are replaced by the heavier and rare isotope deuterium. We have previously shown that D ₂ O has distinct sweet taste, which is mediated by the T1R2/T1R3 sweet taste receptor. Here we explore the effect of heavy water on T1R2 and T1R3 subunits. We show that D ₂ O activates T1R3 transfected HEK293T cells similarly to T1R2/T1R3 transfected cells. The response to glucose dissolved in D ₂ O is higher than to glucose dissolved in water. Mutations of Phenylalanine at position 730 ^5.40 in the transmembrane domain of T1R3 to Alanine, Leucine or Tyrosine, impair or diminish activation by D ₂ O, suggesting a critical role for T1R3 TMD domain in relaying the heavy water signal.