Taste Researchers Savor Fruits Of Work In Stimulating Times

Researchers have been piecing together a more complex picture of the chemosensory experience of taste. Identifying new taste receptors on the surface of the tongue and elucidating the enzymatic steps in the signal-transduction pathways of taste are two areas in which biologists are engaged. Teasing apart the psychological and physical aspects of taste-an area of study called psychophysics-is yet another dimension to understanding how we taste food and drink. SCREENING MECHANISM: Andrew Spielman notes that the sense of taste helps animals select what food is safe, palatable, and nutritious. Of the five senses, taste is one of the least understood. In humans, hearing and vision are more developed than the senses of taste and smell, but the cellular machinery that relays gustatory and olfactory messages to the brain is the first line of defense for what we ingest, say chemosensory researchers. "We view taste primarily as a screening mechanism," says Andrew I. Spielman, an associate professor of oral medicine and pathology at the New York University College of Dentistry. Taste and smell help many types of higher animals screen what's safe to eat, what's palatable, and what's needed nutritionally. The sensation of taste also includes physical factors like temperature and texture. In fact, until recently researchers thought that fat had no taste and was detected only by its texture. But earlier this year, Tim Gilbertson, a neuroscientist at the Pennington Biomedical Research Center at Louisiana State University, showed evidence for a fat taste receptor (Notebook, The Scientist, Feb. 17, 1997, page 30). Because the neurophysiological and psychological data are accruing so quickly and because of the multimillion-dollar food and beverage industry's continuing interest in taste research, investigators say that this is a very stimulating time in which to work. "There's quite a lot of interest in taste research both from the academic world and from the industrial world," says Joseph Brand, associate director of the Monell Chemical Senses Center in Philadelphia. "Industry is particularly interested in masking bitter taste and enhancing salty taste." The signal transduction of bitter taste is complex and diverse: The taste of the same bitter compound may be transmitted to the brain by more than one route, and bitter substances with similar structures may share similar signaling mechanisms. "It's very exciting to be studying bitter taste right now because there are a number of conflicting ideas," says Brand. For the last eight years, Brand's lab and several others have been looking at what happens after a bitter-taste stimulus binds a receptor on the membrane of a taste-bud cell. Researchers say that there are at least two lines of reasoning-which may not necessarily be mutually exclusive-for what happens at this point. For a well-studied bitter compound called denatonium, one transduction pathway involves the activation of a G protein, in which its alpha or beta/gamma subunits, according to some researchers, might activate the enzyme phospholipase C. This G protein causes the buildup of a second-messenger molecule called IP3. Such accumulation eventually leads to shifts in cellular ion concentrations that cause the release of a neurotransmitter. Spielman, Brand, and others determined the cascade of events in the G-protein- and IP3-related pathway (A.I. Spielman et al., American Journal of Physiology, 270:C926-31, 1996). SECOND MESSENGERS: Robert Margolskee and colleagues identified gustducin, a molecule that might be important in bitter taste signal transduction. The other possible pathway involves a G protein called gustducin. Activation of gustducin causes a decrease in cyclic AMP, another type of second messenger, rather than an increase of IP3. Researchers have shown that the alpha subunit of gustducin can activate taste phosphodiesterase, while they surmise that the beta and gamma subunits could activate phospholipase C. Robert Margolskee, an associate professor of physiology and biophysics at Mount Sinai School of Medicine in New York, and colleagues identified gustducin (S.K. McLaughlin et al., Nature, 357:563-9, 1992). "We differ with Margolskee in the nature and importance of the second messengers that may be involved in bitter taste transduction," explains Spielman. "The similarities lie in the hypothesis that the denatonium signal transduction appears to be a receptor-mediated and a G-protein-mediated event. It is also possible that both pathways take place in the same cell at different times." "I think what we have are parallel lines of inquiry," says Margolskee. "There may be places where they conflict; there may be places where they overlap, and there may be places where they're identical." Last year, Margolskee's lab published a study on gustducin knockout mice (G. Wong et al., Nature, 381:796-800, 1996). "We found that behaviorally and electrophysiologically there were no differences in the knockout mice vs. their wild-type siblings in their response to salt compounds and sour compounds," says Margolskee. "But there were very pronounced differences in these animals' responses to bitter and sweet compounds." These studies demonstrate that gustducin is essential to the transduction of denatonium, which is intensely bitter to humans. RELISHING RESEARCH: The lab of Sue Kinnamon at Colorado State is shedding light on the molecular mechanisms of many types of taste sensations. The lab of Sue Kinnamon, an associate professor of anatomy and neurobiology at Colorado State University, also has evidence of a G-protein-mediated response in bitter taste transduction in an amphibian called a mudpuppy. This G protein, she says, is probably a third type of response to bitter taste. The four basic taste sensations of sweet, sour, salty, and bitter are well known, but scientists are currently in what they call a "friendly debate" over the likelihood of a mechanism for a fifth basic taste called umami. The term umami is "hard to translate from Japanese," says Brand. "Most of us translate it as 'delicious' or 'savory.' It's basically the taste of glutamate, more specifically the taste of monosodium glutamate [MSG], the Asian-dish additive that imparts a meat flavor." Tomatoes, meats, and cheese, especially parmesan, naturally contain a lot of glutamate. As with bitter-taste transduction, what happens after glutamate enters the mouth is under conjecture. In this case, it's the type of receptor on the taste-cell membrane that's in question. One type is called an ionotropic receptor, in which the receptor and a membrane ion channel are part of the same protein, or are closely associated. In this case, the binding of a taste stimulus simply opens the channel directly. Another type is called metabotropic, in which binding causes an enzymatic cascade to open or close an ion channel. Metabotropic receptors are G-protein-coupled receptors. John Teeter, an electrophysiologist at the Monell Center, has been studying umami taste for the last several years. A few years ago, Takashi Kumazawa, a postdoc working with Teeter and Brand, incorporated fragments of membranes from taste regions of the mouse tongue sensitive to glutamate into lipid bilayers that mimic the cell membrane. When they applied MSG to these bilayers, they measured an increase in electrical conductance, which was enhanced by guanosine monophosphate. These findings suggested that taste responses to MSG may be mediated by ionotropic receptors, perhaps similar to the class of glutamate neurotransmitter receptors activated by N-methyl-D-aspartate, or NMDA (J.G. Brand et al., Physiology & Behavior, 49:899-904, 1991; J.H. Teeter et al., "Amino acid receptor channels in taste cells," in Sensory Transduction, D.P. Corey, S.D. Roper, eds., Rockefeller University Press, 1992). Subsequent to this work, Nirupa Chaudhari, an associate professor of physiology and biophysics at the University of Miami School of Medicine, and Stephen D. Roper, a professor of physiology and biophysics also at Miami, discovered that rat taste-bud cells express a metabotropic glutamate receptor called mGluR4 (N. Chaudhari et al., Journal of Neuroscience, 16:3817-6, 1996). In this paper, they describe taste studies in which mice avoid both MSG and L-AP4, a ligand for mGluR4, indicating that mGluR4 may be a receptor that is, in part, accountable for the ability to taste MSG. Recent behavioral studies with genetic knockout mice lacking mGluR4 support this conclusion. "We have different views of the same subject," says Roper. "If mGluR4 turns out to transduce umami taste, it will be the first taste receptor to be identified at the molecular level. We think that there might be multiple mechanisms for the reception of glutamate. We have seen that NMDA receptors as well as the mGluR4 receptors are expressed in taste cells. But the unique thing about the mGluR4 receptor is that in the tongue, mGluR4 is expressed only in taste buds and not here, as is NMDA." Those involved in umami taste research agree that there's room for a cohesive hypothesis for glutamate transduction that incorporates both types of receptors. In fact, Weihung Lin, a Ph.D. student in Kinnamon's lab, recently found evidence for both ionotropic and metabotropic receptors in glutamate transduction, but do not have direct evidence that it's a taste response per se. "Now, all of a sudden, both for bitter and glutamate taste, when we thought that we had the bare essentials worked out six years ago, it's not so clear-cut," remarks Brand. Roughly 60 years ago, a chemical called phenylthiocarbamide, or PTC, was found to be tasteless to about 25 percent of the people tested, but bitter to the remaining 75 percent. After this discovery, many genetic studies have related PTC tasting to a number of food preferences. PROP (6-n-propylthiouracil), a chemical similar to PTC, is now used in psychophysical studies of taste. TIP OF THE TONGUE: At Yale, Laurie Lucchina, left, Valerie Duffy, on table, and Linda Bartoshuk study the biology of PROP tasting. Inset: Tongue of a PROP supertaster, left, and a PROP nontaster. Linda Bartoshuk, a professor of surgery at Yale University School of Medicine, has been working on PTC-PROP tasting since the 1970s. Her lab has found that there is a gradation of how bitter PROP tastes. Bartoshuk recalls that her team found a few subjects who reacted very strongly to PROP. "Around the lab we started calling them supertasters," she recalls. "To supertasters, bitters taste more bitter and sweets taste more sweet." With Inglis I. Miller, a taste researcher from the Bowman Gray School of Medicine in Winston-Salem, N.C., Bartoshuk and Valerie Duffy, then a doctoral student in her lab and now an assistant professor in the department of applied health sciences at the University of Connecticut, discovered that supertasters have more taste buds (L.M. Bartoshuk et al., Physiology and Behavior, 56:1165-71, 1994). "Now that we understand the logic to supertasting, we can go on and look at other substances like fat," says Bartoshuk. "Supertasters perceive more fattiness and sweetness in high-fat, high-sweet foods, and that's got to have some effect on them," says Bartoshuk. "[Duffy] did food preference studies, and lo and behold it turns out that women who are supertasters don't like sweet and don't like fat, but men who are supertasters do [V.B. Duffy et al., Chemical Senses Abstract, 20:688, 1995]." Another researcher on the Bartoshuk team is Laurie A. Lucchina, now a postdoctoral associate at Yale University School of Medicine. For her Ph.D. research she measured the effect of PROP perception on the nutritional status of 60 women aged 65 to 95 (L.A. Lucchina et al., Chemical Senses Abstract, 20:735, 1995). "Tasters were thinner and had better lipid levels, lower body mass index and weight, decreased percent body fat, and increased HDLs, the good cholesterol," explains Lucchina. "And behaviorally, tasters had a lower intake of high-fat dairy foods. The thinking is that supertasters get more bang for their taste buck. They may get more out of food, so may eat less." Bartoshuk cautions that the study populations in these and other experiments are homogeneous, and that more data are needed on men and non-white ethnic groups. "My guess is that PROP is likely to predict things in all of these groups because it's a sensory variable, but what it's going to correlate with will depend a lot on culture and experience. I see a huge picture unfolding, but there are still lots of holes in it," she concludes. FOR MORE INFORMATION: Professional Societies Association For Chemoreception Sciences (AChemS) c/o Panacea Associates 744 Duparc Circle Tallahassee, Fla.32312 Phone/Fax:(904)531-0854 E-mail: mmered@neuro.fsu.edu http://neuro.fsu.edu/achems/homepage.htm 700 members Executive Chair: Michael Meredith Journal: Chemical Senses Society for the Study of Ingestive Behavior 1111 Amsterdam Avenue New York, NY 10025 (212)523-4200 Fax:(212)523-4830 E-mail: hrk2@columbia.edu http://www.psy.jhu.edu/~gjs/ssib.html 600 members Executive Officer: Harry R. Kissileff Web Sites The ChemoReception Web, managed by Cambridge Sciences Abstracts, an information company in Bethesda, MD. http://moe.csa.com/crw/ Stephen Roper's Home Page http://chroma.med.miami.edu/physiol/mf/df/ff/Roper.html A 1993 study from Bartoshuk's lab on the relationship between PROP tasting and perception of ethyl alcohol suggested that tasters might be protected against alcoholism because ethyl alcohol is less palatable to them than it is to nontasters (L.M. Bartoshuk et al., Chemical Senses, 18:526-7, 1993). Prior to this study, Marcia Levin Pelchat, an associate member at the Monell Center, and Sarah Danowski, then a senior at Washington College in Chestertown, Md., found a possible genetic link between PROP-tasting and alcoholism (M.L. Pelchat, S. Danowski, Physiology & Behavior, 51:1261-6, 1992). Pelchat and Danowski, who recently finished her M.S. in psychology at the University of California, San Diego, were also involved in the 1993 ethyl alcohol study. Over the last 30 years, different studies have suggested that PTC nontasting might be a genetic marker for alcoholism. But the findings were mixed, notes Pelchat. "We looked at college students and had them fill out a paper-and-pencil test on alcoholism and also had them answer similar questions about their parents, so we could classify the subjects as alcoholics or nonalcoholics or as children of alcoholics or nonalcoholics," says Pelchat. "The critical group is nonalcoholic children of alcoholics, because they don't display alcoholic behavior but they presumably have the genetics. "Basically what we found is that nonalcoholic children of alcoholics were more likely to be nontasters of PROP than were children of nonalcoholics. This was evidence that suggested a genetic-marker explanation." But Pelchat notes that one recent paper failed to replicate these findings (H.R. Kramzler et al., Alcoholism: Clinical and Experimental Research, 20:1496-1500, 1996). However, this study included many non-Caucasian subjects. Outside of the Caucasian population there are few nontasters; therefore, PROP taste profiles might not be a good indicator of alcoholism for non-Caucasian groups, says Pelchat. "While the proportion of nontasters is higher than would be expected for children of alcoholics, it is by no means the case that everyone that's a nontaster is an alcoholic," she cautions. There may also be a genetic association between alcoholism and sweet taste, at least so far in mice. Working with two strains of inbred mice, Alexander Bachmanov, a Monell research associate, and Danielle Reed and R. Arlen Price, colleagues from the University of Pennsylvania, have found a correlation between an inherited preference for sweet solutions and a preference for alcohol (A.A. Bachmanov et al., Behavior Genetics, 26:563-73, 1996). The researchers conducted breeding studies to determine the genetic component of these preferences. From these studies they found two genes that influence the level of sweet preference. This work led to other investigations that related to preference for alcohol. "In genetic terms this is called a pleiotropic effect, where one gene affects more than one trait," explains Bachmanov. "Now we are doing the genetic mapping for these traits. We are trying to find chromosomal markers linked to both sweet and alcohol preferences to see whether they are affected by the same or different loci." "We do find alcohol-preferring and nonpreferring strains of mice," remarks Pelchat. "And when you look at their sensitivity to sweetness and bitterness, it does show the same kind of profile as PROP-tasters and nontasters. So the alcohol-avoiding strains seem to be more sensitive to bitter, and that sensitivity appears to have a genetic basis because you can breed for it." Although it's too early to understand all of the ramifications of these associations, she notes that the bitter-PROP-sweet taste and alcoholism work-as with other areas in the biology of taste-is coming together to form a nice package.

Taste Researchers Savor Fruits Of Work In Stimulating Times

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