RESUMEN
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 heterodimer 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.
Humans perceive taste when proteins called taste receptors on the surface of the tongue are activated by molecules of food. These receptors turn on nerve cells that send signals the brain can read as sweet, sour, salty, bitter, or umami, depending on which receptor was activated. Most animals with backbones share the same five types of taste receptors. In food, salty flavors are usually the result of adding table salt, which has two components: a sodium ion and chloride ion. The main taste receptors that signal to the brain that a food is salty become activated when they bind to the sodium ion. However, some studies have shown that salt is also perceived as sweet when eaten in minuscule amounts. It is poorly understood why this happens, but it is possible that the chloride half of salt drives the sweet taste. In 2017, scientists worked out the structure of a taste receptor from a fish, that is equivalent to the sweet receptor in humans. Curiously, one part of this receptor, known as T1r2a/T1r3LBD, was bound to a chloride ion. This prompted Atsumi, Yasumatsu et al. to think about the 'sweet' taste of salt, leading them to take a closer look at T1r2a/T1r3LBD and whether chloride could indeed activate it. Atsumi, Yasumatsu et al. used structural biology techniques to examine T1r2a/T1r3LBD and found evidence that the receptor might be binding chloride. Further biophysical experiments confirmed that chloride does indeed bind to the receptor, and that it also causes it to change shape. Usually, changes in shape are hallmarks of receptor activation, suggesting that chloride may activate T1r2a/T1r3LBD. Next, Atsumi, Yasumatsu et al. checked whether chloride could stimulate the neurons that signal when food tastes sweet, by using an approach known as electrophysiology to measure the activity of these neurons in mice. The results showed that the neurons became active when a solution containing small amounts of chloride was placed on the mouse's tongue. This activity went away when a compound that can block the receptor's activity was delivered alongside the chloride. Additionally, when mice were given a choice of plain water or water containing chloride, they seemed to prefer the latter. This confirmed that mice recognized the sweetness of chloride via the activation of sweet taste receptors and neurons. Based on these findings, Atsumi, Yasumatsu et al. propose that small amounts of salt may taste sweet because the chloride ions in the salt activate sweet taste receptors and their linked neurons. Their results also suggest that animals sense salt in many ways, likely because balanced salt levels are essential for the body to work properly. Future experiments on human taste receptors may reveal how these pathways help assess salt levels in humans.