Chloride ion evokes taste sensation by binding to the extracellular ligand-binding domain of sweet/umami taste receptors

Abstract

The taste sensation of salt is multifaceted: table salt (NaCl) at low concentrations is perceived as a preferable taste through the salty taste receptor, while that at higher concentrations is perceived as an aversive taste through distinct pathways. In addition, Cl⁻ is also thought to participate in taste sensation through a currently unknown mechanism. Here we describe a Cl⁻ -ion binding and the response of taste receptor type 1 (T1r), a receptor family composing sweet/umami receptors. The T1r2a/T1r3 heterodimer from medaka fish, an amino-acid taste receptor and the sole T1r member whose structure has been solved, exhibited a specific Cl⁻-binding in the vicinity of the amino-acid-binding site in the ligand-binding domain (LBD) of T1r3. Notably, the Cl⁻-binding site is likely conserved among T1r3 from other species, including humans. The Cl⁻-binding at the site is considered to organize the structures of the amino-acid binding site and heterodimer interface. Indeed, the Cl⁻-binding was found to induce a conformational change of T1r2a/T1r3LBD at sub-mM to low-mM concentrations in a similar manner to canonical taste substances. In order to address the physiological significance of the Cl⁻ action on T1r, single fiber responses from mouse taste nerves connected to T1r-expressing taste cells were investigated. As a result, a Cl⁻ application increased impulse frequencies, which were inhibited by a lingual application of a T1r-specific blocker. These results suggest that the Cl⁻ evokes taste sensations by binding to T1r, underlying a reported “sweet” taste sensation by table salt at a low concentration.