A taste for umami


Chaudhari and colleagues identify the taste receptor for l-glutamate, also known as umami, found in protein-rich foods. The protein they describe is a new G-protein-coupled receptor that corresponds to a truncated form of the metabotropic glutamate receptor mGluR4.


Molecular biologist have been trying for many years to clone taste receptors and identify their ligands. Now at last, they seem to have succeeded. Chaudhari and colleagues have identified a receptor for umami, the taste corresponding to l-glutamate1. The umami receptor is a G-protein-coupled receptor, which binds extracellular glutamate and signals through a G protein to regulate the level of intracellular cAMP and the firing of taste receptor cells.

Until recently, the textbook wisdom was that humans could detect four primary tastes: sweet, bitter, salty and sour. Yet as early as 1908, Kikunae Ikeda at the Tokyo Imperial University had identified l-glutamate as the principal source of a fifth taste. This taste quality, which cannot be mimicked by any combination of the other four tastes, Ikeda called ‘umami’. Taste researchers have long been aware of Ikeda's work, but it is only recently that umami has gained widespread recognition in the West, perhaps in part because of the increasing popularity of oriental food2. Monosodium glutamate (MSG), of course, is widely used as a flavoring additive in Asian cuisine, but the most abundant amino acid, glutamate, is also an important nutrient, and it is presumably for this reason that some animals have evolved the ability to taste it. Free glutamate is found in many protein-rich foods, including meat, milk and seafood (Fig. 1); it is particularly concentrated in aged cheese. Rats and humans can both recognize the taste of glutamate, and for adult humans the detection threshold is about 0.7 mM (ref. 3).

Figure 1

Umami is an important flavor constituent of many protein-rich foods.

The key to further advance in understanding taste perception will be the identification of taste receptors. Salty and sour tastes are produced by small cations such as Na+, K+ and H+, which affect the activity of taste receptor cells directly, either by contributing to current flow through ion channels or by modulating channel conductances4. In contrast, sweet, bitter and umami are all thought to depend on the activation of G-protein-coupled receptors (GPCRs), but until now, none of these receptors has been definitively identified. A report last year described two new GPCRs, TR1 and TR2, that are expressed in taste buds. They were suggested to be candidates for sweet and bitter receptors, but at present there is no functional evidence for this proposal5,6.

Chaudhari and colleagues1 have provided such evidence for what seems to be the umami receptor. The molecule they describe is a new GPCR that corresponds to a truncated form of the metabotropic glutamate receptor mGluR4, which they term ‘taste-mGluR4’. The mGluR4 receptor was originally described in the brain, where it responds to extracellular glutamate by downregulating the second messenger cAMP. This receptor is expressed on presynaptic terminals of both glutamatergic and GABAergic neurons, where it mediates glutamate-dependent regulation of neurotransmitter release7. In addition, mGluR4 is expressed in taste tissue, making it an obvious candidate for the umami receptor. However, one problem with this idea is that glutamate activates mGluR4 at micromolar concentrations, far below the taste threshold.

Chaudhari and colleagues have now resolved this puzzle by showing that rat taste tissue also expresses an alternative transcript of mGluR4 (which may arise by differential transcription and/or splicing), in which the first 300 amino acids of the amino (N) terminus are absent. They go on to show that this isoform, when expressed in a cultured cell line, can transduce a response to extracellular glutamate, over a concentration range that is consistent with it being the umami taste receptor.

The loss of the N terminus would be predicted to decrease the receptor's affinity for glutamate. The sequence of mGluR4 is homologous to that of bacterial amino-acid binding proteins, for which crystal structures are available. Based on this homology, the N terminus of mGluR4 is predicted to form a ‘clamshell’ structure, in which the two halves of the shell are connected by a hinge, forming a cleft in which glutamate can bind8,9,10 ( Fig. 2). The high-affinity binding site has been mapped by site-directed mutagenesis of the mGluR4 sequence, with the hydroxyl groups of Ser 159 and Thr 182 predicted to form hydrogen bonds with glutamate (or its agonists) and Arg 78 to provide electrostatic attraction. These highly conserved residues lie within the first half of the shell structure, and mutating any of them to alanine causes a major (over 95%) reduction in glutamate binding10.

Figure 2: The mGluR4 protein is a seven-transmembrane receptor, and the N terminus of the brain isoform (center) forms a ‘clamshell’ structure, homologous to bacterial amino-acid-binding proteins (left), which contains the high-affinity binding site for glutamate.

The taste isoform (right) is truncated at the N terminus.

Given the importance of these N-terminal residues, which are absent in the taste isoform, how can the truncated taste variant of mGluR4 recognize glutamate at all? Presumably it must contain an additional binding site, of lower affinity than the one at the N terminus. It is unclear whether a similar site exists in the brain isoform, but it is interesting to note that one of the bacterial amino-acid-binding proteins was proposed to contain a second binding site on the opposite side of the cleft from the first site8. It remains to be determined whether glutamate binds to the taste mGluR4 isoform at the corresponding site or at some other position, either in the extracellular domains or in the bundle of seven helices that span the membrane.

By expressing the two isoforms in a cultured cell line, Chaudhari and colleagues1 show that activation of the taste isoform (as measured by the reduction in intracellular cAMP) requires a much higher concentration of glutamate than does the brain isoform. This was not due to any difference in the level of expression of the two isoforms on the cell surface, so it seems likely to reflect a reduced affinity for glutamate. This would be consistent with the truncation of the presumed high-affinity binding site, but it will be important to confirm the difference in affinities by direct binding measurements. Certainly, it would make sense for the umami receptor to have a lower affinity, given the high concentrations of glutamate that exist in certain foods. The concentrations required to activate the receptor are also in the same range as the known behavioral detection threshold (about 100 micromolar in juvenile and 1 mM in adult rodents).

A skeptic might still argue that taste-mGluR4 is not a taste receptor but is instead involved in synaptic transmission or some other function of taste tissue, but several further lines of evidence are consistent with a role in taste transduction. First, the authors confirm that taste-mGluR4 is activated by the glutamate agonist l-AP4, which to rats is indistinguishable from glutamate itself11. As with glutamate, the concentrations of l-AP4 required to produce a cAMP response are consistent with the known taste thresholds in rats. Second, the same group has previously shown by in situ hybridization that mGluR4 expression in taste tissue is concentrated in the taste buds themselves, and that about 40% of buds are positive for the label. Although the probe used in that study did not distinguish between the two isoforms, which may both be present in taste tissue, it is significant that neither isoform was detected outside the taste buds, either by in situ hybridization or by RT-PCR assays11.

Finally, the effect of mGluR4 activation in cultured cells is to decrease cAMP levels, and glutamate is known to reduce cAMP in isolated taste buds (X. Zhou & N. Chaudhari, Chem. Senses 22, 834, 1997). Although the experiments on taste buds were performed under somewhat artificial conditions—the baseline concentration of cAMP was raised by treatment with forskolin—they nevertheless seem to reflect the normal process of taste transduction. For instance, the effect of glutamate was enhanced by inositol monophosphate, which, like other ribonucleotides that are found in meat and other umami foods, enhances the taste of glutamate2,3,4.

How does the decrease in cAMP modulate membrane potential and cause the taste receptor cell to signal the presence of ligand? Electrophysiological recordings of isolated taste cells from the posterior part of the tongue have shown two types of responses to l-glutamate12. Most cells (60%) respond with a sustained hyperpolarization, possibly due to closure of nonselective cation channels. A few cells (4%) respond with a transient depolarization, probably due to the opening of such channels.

It seems likely that the sustained hyperpolarizing response is what leads to taste signaling, because l-AP4, an agonist that also evokes the taste of umami, also caused the sustained response but not the transient depolarization. This suggests a model in which glutamate triggers a decrease in cAMP, resulting in the closure of cyclic nucleotide-gated channels13 and hyperpolarization of taste receptor cells. This would be analogous to visual transduction, in which photons trigger the breakdown of cGMP, resulting in closure of cGMP-gated cation channels and hyperpolarization of photoreceptors. In the case of taste receptors, it is still not known whether hyperpolarization modulates tonic release of transmitter, as it does in vertebrate photoreceptors, or whether it has some other effect such as inhibiting the response to other tastants.

An additional point of interest is that a small number of taste cells from the anterior part of the rat tongue have been found to respond to l-AP4 with a depolarization rather than a hyperpolarization14. The basis for this difference is unknown; perhaps they express channels that are closed rather than opened by cAMP15. The role of these cells in taste transduction is also unknown, but it is possible that they, rather than the hyperpolarizing cells, may be the real umami receptors.

Even though it cannot clarify all these issues, the paper by Chaudhari and colleagues is an important advance. The cloning of a taste receptor with an identified ligand should add meat to the field of taste research. Bon appétit!


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Lindemann, B. A taste for umami. Nat Neurosci 3, 99–100 (2000). https://doi.org/10.1038/72153

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