Discovery of a molecular receptor for a fifth taste.
ONE OF THE HOLY GRAILS OF PHYSIOLOGY is finally in our hands. For decades physiologists sought to explain how the cells of the gustatory papillae detect taste molecules. It was supposed that the surface of these cells contains proteins called receptors, to which the taste molecules attach themselves, but these receptors proved to be elusive. Attempts to extract them from papillary cells in solution were unsuccessful because receptors form a weak bond with taste molecules. Compensating for this experimental difficulty is a physiological advantage: If the bond were strong, receptors would be stimulated for long periods of time by a single molecule, and the resolution of individual tastes would be low. In that case gastronomes would be forced to savor their food in slow motion. Focusing on the phenomenon of weak molecular bonds, in February 2000 physiologists at the University of Miami identified one of the sought-after receptors, associated with the taste called umami.
It was long believed that the mouth is capable of detecting only four tastes, but the matter had been examined only cursorily. In 1908, Kikunae Ikeda at the Imperial University of Tokyo established that glutamate (the ionized form of an amino acid, glutamic acid) produced a particular sensation that was neither salt, sugar, sour, or bitter. After decades of struggle against conventional wisdom the notion of a fifth taste came to be accepted, in large part on account of the growing popularity in Western countries of Asian cuisine, which uses a great deal of monosodium glutamate. Moreover, it was shown that even animals detect this taste, perhaps because glutamate is present in many foods that are rich in proteins (which are chains of amino acids), such as meat, milk, and seafood. The detection of tastes is important because it signals satiety. One does not cease eating because one’s stomach is full; one stops because the brain, alerted by the sensory system, notifies the organism that a sufficient quantity of food has been consumed.
From Mouth to Brain
In searching for glutamate receptors, Nirupa Chaudhari and his colleagues at the University of Miami took as their starting point the results obtained ten years earlier by Annick Faurion at the Laboratoire de Neurobiologie Sensorielle in Massy. Because glutamate is a neurotransmitter, which is to say a molecule that is exchanged between neurons in the brain (on being released by one nerve cell it binds to a receptor on the surface of a neighboring nerve cell), it seemed reasonable to scrutinize taste cells in the mouth for molecules analogous to neuronal receptors.
Building on Faurion’s insight, Chaudhari and his colleagues looked for receptors paired with G-proteins—that is, with proteins embedded in the taste cell membrane that transmit the message detected by the receptor, which, projecting from the cell surface, is exposed to the extracellular medium. They made a surprising discovery: a truncated form of a neuronal protein known as a metabotropic glutamate receptor, or mGluR4.
Searching for Receptors
In the brain this neuronal receptor is activated by very weak glutamate concentrations. Unmodified, it would be completely saturated by the large quantities of glutamate present in the mouth when we taste certain dishes. Chaudhari and his colleagues concluded that the abbreviation of the protein’s structure probably was an adaptation to the function of taste. Examining the receptor that is synthesized in the gustatory tissues of the rat, they found that it had lost the first 300 amino acids found in its neuronal counterpart and that in this truncated form it binds very weakly to glutamate. Moreover, the glutamate concentrations needed to activate it are similar to the perception thresholds measured in rats (a threshold perception being defined as the weakest concentration to which an animal is sensitive).
Why does the shortening of the protein’s amino acid sequence reduce its affinity for glutamate? The University of Miami physiologists observed that the taste molecule strongly resembles a particular bacterial protein, extensively studied by crystallography, that has two bonding sites for glutamate. Truncation seems to have eliminated the more sensitive one of the two.
Is the protein they discovered the receptor for the umami taste? After all, the possibility could not automatically be excluded that the new protein transmits neural (rather than sensory) information from the gustatory cells to the brain. Confirmatory evidence is substantial. First of all, the mGluR4 protein is activated by other sapid molecules that rats do not distinguish from glutamate. This was not surprising because Faurion had observed that the tongue and brain react similarly to these molecules. Moreover, the truncated mGluR4 protein is synthesized only in the gustatory papillae. Finally, neither the complete nor truncated form of the mGluR4 protein has been detected elsewhere in the mouth than in the gustatory papillae.
This discovery raises many questions. Is truncated mGluR4 the only receptor for the umami taste? Is it involved in the perception of other tastes? Do receptor cells each bear only a single type of receptor? The result obtained by Chaudhari and his team seems to be the first of a series; physiologists have found other molecules of the same class that also seem to be taste receptors. Knowing the structure of the mGluR4 protein makes it possible to use molecular modeling systems to determine which molecules attach themselves to it. The computer-assisted design of completely new sapid molecules, further expanding the number of tastes, may not be far off.