Of the five senses, taste seems to be the one that we take personally. People will identify themselves as having a “sweet tooth” as opposed to being a “salt junky”. Many cultures are defined on the basis of their traditional cuisine–we often are more familiar with a country’s basic dishes than we are with its politics. The question of taste even spills over into non-nutritional areas–to have “good taste” implies a level of intelligence and sophistication to be admired and emulated.

Although taste may seem to be the one sense that developed strictly for our own amusement, it was in fact an essential tool in the survival of primordial humans. Most of the toxic substances in the world taste bitter, while the most highly nutritious substances are sugar-rich carbohydrates that taste sweet. Experts believe that our sense of taste developed to help early humans determine which foods were safe to ingest and which should be avoided.

Of the five senses, the molecular mechanism underlying taste perception remains the most mysterious. Whereas the proteins and nerve paths involved in vision and hearing are very well described, as are many of the molecules involved in the sense of touch and of smell, the molecules of taste perception have until recently remained stubbornly hidden. Since deficits in taste perception are associated with many disorders, such as hypertension, diabetes, malnutrition and obesity, an understanding of the molecular basis of taste perception could provide valuable clues toward the treatment and management of these disorders. Also, it is well known that the ability to perceive certain tastes declines as a person ages. As the demographics of the United States population shifts toward an older age group, increased knowledge of the taste system could mean a greater quality of life for a substantial portion of our society.

Despite the vast range of compounds that can stimulate the taste system, scientists have found that we perceive only five basic tastes: salty, sweet, sour, bitter, and umami, the taste associated with monosodium glutamate (MSG). In mammals, the cells that bind to tastant molecules are called taste receptor cells, and they are found in papillae, the tiny outgrowths that cover the surface of the tongue. Within the papillae, taste receptor cells are organized into bulb-shaped clusters called taste buds. The classic model of taste perception was that different areas of the tongue respond to different tastes. For example, it was once thought that the receptors for salt were mainly located at the front of the tongue, whereas those for bitter tastes were located toward the back of the tongue. It is now known that taste buds responding to each taste modality are found in all areas of the tongue. When taste cells sense a particular tastant molecule, this information is translated chemically to the nearby cranial nerves, which in turn carry the information to the brain.

One question that has been of particular interest to taste researchers is the molecular identity of the taste receptors. Determining the identity of these molecules is an important first step in understanding our ability to distinguish between sweet and bitter tastes. Many of the mysteries of taste perception could be clarified through the identification of the taste receptor molecules.

Determining the molecular identity of taste receptor cells proved to be a challenging problem. The sensory tissues involved in taste perception–mainly the tongue, the palate and the tissue lining the throat–are difficult to work with, because they contain such a relatively low density of receptor cells. The receptor for umami (MSG) was discovered in 1996. Researchers found this receptor by looking for a new protein that structurally resembled other proteins known to bind glutamate. However, there was no similar strategy available for finding receptors that could bind the chemically diverse range of bitter and sweet compounds.

The past two years have seen exciting developments in the field of taste perception. Advanced techniques in cloning along with our ever-increasing understanding of the human genome have led to the discovery of new families of taste receptors. This article will focus on two of the most recent developments: the discovery of a family of receptors shown to respond to bitter tastes, and the cloning of the capsaicin receptors, a family of molecules which allow us to taste the heat from chili peppers. We will conclude with a little speculation into where these new studies could lead in the future.

The End Of The Bitter Pill?
As discussed earlier, we perceive most of the toxic molecules in the world as tasting bitter. The ability to detect these bitter substances was an essential tool for survival for early humans, just as it is for many animals living in the wild today.

In 1999, groups led by Charles Zuker at the University of California, San Diego and by Nicholas Ryba at the NIH cloned a small family of two receptors called T1R1 and T1R2. To clone these molecules, the two groups compared the genetic activity from cells in the tongue that are involved in taste perception to other cells in the tongue which do not respond to tastants. The researchers found hundreds of extra genes within the taste-sensing cells, and by sifting through each of these genes they found one that resembled the gene for the previously cloned umami receptor. They named this new gene T1R1. They then turned to a search of the genetic database to clone T1R2.

Although the group did not functionally determine the taste modality–sweet, bitter, sour, or salt–to which these receptors respond, they thought that two molecules was probably too few to account for the perception of the wide variety of sweet and bitter compounds encountered by the taste system every day. The group turned their attention to looking for receptors that modulate the perception of bitter substances.

Previous studies have shown that the ability to taste a bitter substance called 6-n-propyl-2-thiouracil (PROP) is hereditary in humans, and that this ability maps to a particular region of the human genome. The Zuker and Ryba groups hypothesized that the ability to taste PROP may stem from differences in the bitter taste receptor. They examined the region of the genome known to affect the PROP taste, looking particularly carefully for proteins that resemble the taste receptors they had cloned the previous year.

In the March 2000 issue of the journal Cell, the groups were able to pronounce their success. They cloned a family of proteins which they named “T2R,” consisting of approximately 20 receptors; using a statistical model the researchers predict that there may be a total of 50 to 80 receptors in this family.

The scientists presented functional evidence that the T2R proteins are bitter taste receptors in a second paper in the same issue of Cell. They showed that the mouse version of one of the T2R receptors (mT2R5) was directly activated by the bitter substance cycloheximide. A human receptor (hT2R4) and a mouse receptor (mT2R8) both respond to the bitter substances danotrium and PROP. The researchers further showed that defective T2R receptors from mice responded poorly to cycloheximide. All these results together indicate that the T2R family of genes does indeed represent bitter taste receptors.

There is a great deal of structural variability within the T2R bitter taste receptors, and the researchers hypothesize that this diversity could reflect the wide range of bitter substances that we can taste. Interestingly, the researchers found that individual taste cells express many different members of the T2R family. Thus, a single taste cell can respond to a wide variety of bitter substances, but the cellular response is identical for all of the substances. This might mean that our perception of the taste of each of those substances is the same. This idea corresponds well to psychophysical studies of bitter sensitivity, which have shown that humans perceive a wide range of bitter substances as having the same bitter taste.

The cloning of these bitter taste receptors is an important step in determining the cellular basis of taste, and the knowledge of the genes that code for these receptors will allow scientists to study the way taste perception is formed during development.

If You Can’t Take The Heat…
Bite into a hot pepper and the tears that jump into your eyes and the heat that engulfs your tongue have all the hallmarks of pain. As it turns out, the receptors in the tongue that allow us to sense the spiciness of a chili pepper are in fact pain receptors. Capsaicin is the substance in chili peppers that provides their spicy hot taste. For centuries, capsaicin has been used to enliven the favorite dishes of a number of cultures. In the past few years, capsaicin has also been a tool in the study of treatments for chronic pain.

In 1997, David Julius and his colleagues at the University of California, San Francisco cloned the molecule that is responsible for our (at times) rather violent response to chili peppers. The hot pepper receptor, officially named the vanilloid receptor subtype I (VR1), belongs to a class of proteins known as ion channels. When these proteins are stimulated, they change their shape in such a way that a water-filled pore is exposed. Ions, such as potassium and calcium, are usually barred from crossing the cell’s lipid membrane, but once ion channels open, the ions are able to cross the membrane easily through the water-filled pore. Julius and his colleagues were able to measure the activation of the hot pepper receptor by using calcium indicator dyes to monitor the amount of calcium the hot pepper receptor allows into cells.

Julius’s group found that the receptor activated when exposed to capsaicin. A similar level of activation was seen when they exposed the receptor to extracts from a habanero pepper. In what is perhaps one of the more colorful figures in ion channel literature, the group was able to show that the hot pepper receptor responds differently to extracts from different kinds of peppers. The Thai green pepper produces a smaller response from the receptor than is seen from the habanero, and the Poblano verde pepper did not stimulate the receptor at all. Scoville units are used to rate the “hotness” of peppers. On this scale, the habanero is one of the strongest peppers. In contrast, the Poblano verde is 100-300 times less potent. A reasonable conclusion from the Julius study was that these receptors respond to certain threshold levels of capsaicin concentration, or in terms of Scoville units, to certain levels of “spiciness”.

The burning quality of hot pepper perception prompted the researchers to study the effects of temperature on the receptor’s activation. They found that raising the temperature to levels that can cause pain (45oC) activated the receptors. This result was one of the clues that the capsaicin receptor may be a pain receptor.

Julius and his colleagues extended their investigation of the capsaicin receptor by creating a genetically-altered knockout mouse that no longer expressed the hot pepper receptor. In the April 14, 2000 issue of the journal Science, the group reports that these mice are less able to sense high levels of heat than their normal counterparts. This is a definitive piece of evidence that the hot pepper receptor transmits information about bodily pain.

The discoveries of the Julius group have opened an exciting new chapter in the study of both sensory perception in the tongue and of the transmission of pain signals. The knowledge of a molecular target for these sensations will lead to greater understanding of pain, and hopefully, new treatments for chronic pain.

The Future
These are exciting times for the taste field. Molecular targets for tastant molecules could lead to gastronomical delights unknown to us now. Perhaps more importantly, the ability to block the bitter taste, for example, could ease some of the suffering of the chronically ill by eliminating the bitter taste of their medicines. Nutritionists may also use our growing understanding of taste perception to make eating “healthy” more enjoyable. In a country where obesity is a concern, this ability could have far-reaching benefits.

The capsaicin receptor offers hope to the researchers working to treat the chronically ill. Knowing the identity of the molecule will at the very least increase our understanding of the way pain signals are transmitted to the brain. Researchers are hopeful that such understanding will one day lead to drugs that are able to block these pain signals. The chili pepper receptor could thus be significant step in easing the suffering of millions.

References:
Adler, E. et al. March 17, 2000. “A novel family of Taste Receptors.” Cell. 100:693-702.

Caterina, M.J. et. al. April 14, 2000. “Impaired nociception and pain sensation in mice

lacking the capsaicin receptor. Science. 288: 306-313.

Caterina, M.J. et al. October 23, 1997. “The capsaicin receptor: a heat-activated ion

channel in the pain pathway.” Nature. 389: 816-824.

Chandrashekar, J. et al. March 17, 2000. “T2Rs function as bitter taste receptors.” Cell. 100:703-711.

Dulac, Catherine. March 17, 2000. “The physiology of taste, vintage 2000.” Cell. 100:607-610.

Herness, M.S. and Gilbertson, T.A. 1999. “Cellular mechanisms of taste transduction.” Annu. Rev. Physiol. 61:873-900.