Chloride ions evoke taste sensations by binding to the extracellular ligandbinding domain of sweet/umami taste receptors

Salt taste sensation is multifaceted: NaCl at low or high concentrations is preferably or aversively perceived through distinct pathways. Cl⁻ is thought to participate in taste sensation through an unknown mechanism. Here, we describe Cl⁻ ion binding and the response of taste receptor type 1 (T1r), a receptor family composing sweet/umami receptors. The T1r2a/T1r3 heterod-imer from the medaka fish, currently the sole T1r amenable to structural analyses, exhibited a specific Cl⁻ binding in the vicinity of the amino-acid-binding site in the ligand-binding domain (LBD) of T1r3, which is likely conserved across species, including human T1r3. The Cl⁻ binding induced a conformational change in T1r2a/T1r3LBD at sub-to low-mM concentrations, similar to canonical taste substances. Furthermore, oral Cl⁻ application to mice increased impulse frequencies of taste nerves connected to T1r-expressing taste cells and promoted their behavioral preferences attenuated by a T1r-specific blocker or T1r3 knock-out. These results suggest that the Cl⁻ evokes taste sensations by binding to T1r, thereby serving as another preferred salt taste pathway at a low concentration.