Unraveling the biochemistry of sweet and umami tastes.

T aste is an important part of everyone’s daily life. Sweet taste is particularly important as evidenced by the fact that wars have been fought and people have been enslaved over sugar, the prototypical sweet stimulus (1). Savory taste, often referred to as umami (delicious in Japanese), is also important, its prototypical stimulus being monosodium glutamate (MSG). Despite the importance of these taste sensations to our daily enjoyment of life, until the late 1980s, the biochemical pathways that mediate them were largely unknown. Then, for sweet taste, evidence began to accumulate that it must be by G protein-coupled receptor (GPCR)-mediated. More specifically, it was generally believed to be mediated by several GPCRs because the findings of biochemical, electrophysiological, and psychophysical experiments could only be easily explained by a plurality of receptors (2, 3). And this expectation was supported by the fact that multiple subtypes of GPCRs commonly exist for other important signal molecules (e.g., acetylcholine, norepinephrine, dopamine, serotonin, etc.). Then, in the early 2000s, a breakthrough occurred, dramatically increasing the understanding of both sweet and umami tastes. Nelson et al. (4) reported the discovery of the rat sweetener receptor. In a functional assay, they showed that all substances that rats generalize to sucrose taste are mediated by a single receptor, which is a heterodimer of two GPCRs, T1R2 and T1R3. Further, they showed that umami taste is also mediated by a heterodimer of the two GPCRs T1R1 and T1R3. T1R1, T1R2, and T1R3 are members of the small family of class C GPCRs. The most studied members of the class C GPCRs are the homodimeric metabotrophic glutamate (mGluR), heterodimeric -aminobutyric acid type B (GABABR), and homodimeric extracellular calcium receptors, which have recently been reviewed (5). Interestingly, the umami and sweetener receptors are 50% identical in that they share the common subunit T1R3. This rat receptor discovery was quickly followed by a report of parallel findings on the human system by Li et al. (6). Again, it was surprising to see that the single human heterodimeric sweetener receptor, often written as T1R2 T1R3, responded to all structural types of sweeteners tested and did so in a manner consistent with expectation from sensory experiments. Class C GPCRs are unique in that they possess very large N-terminal Venus flytrap-like domains (VFDs). In the case of metabotrophic glutamate receptor 1, it has been demonstrated that its VFD closes on binding glutamate just as expected (7). This precedent, and the fact that the sweetener and umami receptors contain the common subunit T1R3, leads to the expectation that sweeteners likely bind in the VFD of T1R2 and glutamate likely binds in the