Tastes of Life

October 2014 THE MONELL CONNECTION The Newsletter of the MONELL CENTER THE NEWSLETTER OF THE MONELL CENTER TASTES Alberto Ruggieri/ Illustration Source OF LIFE We perceive the world with five senses, but it is “Taste is even more important than we only one — taste — that internalizes our experiences previously knew, because how well you in the most visceral manner of them all. taste – or don’t taste – something might predict how well those same receptors Imagine biting into a crisp apple, rich with the fragrance of fall. function in other parts of the body,” sug- The faint tang puckers your tongue against gests geneticist Danielle Reed, PhD. your teeth, sugars and acids dribble across taste receptors on your tongue, Using cross-disciplinary approaches that and a wave of nervous and hormonal sig- span genomics, immunology, microbiolo- nals sweeps through your mouth, brain, gy, neuroscience, and other fields, Monell and gut. taste researchers are looking beyond the tongue to identify the fundamental func- Outside the mouth, taste receptors in tions of extra-oral taste receptors in the the stomach, intestines, and pancreas all health – or disease – of the entire body. sense and respond to chemical signals from food. Surprisingly common in non- Gut alimentary organs as well, extra-oral taste Sensation receptors play myriad roles in cancer drug responses, sperm fertility, sinus Although humans detect many different infections, and more. molecules that elicit five distinct tastes Continued from cover page [bitter, sweet, salty, sour, and umami The end result of this intracellular cascade (savory)], all these inputs are perceived allows the taste cell to announce a gustato- through a limited number of taste receptor ry sensation to the brain. types found in the tongue’s taste buds. Twenty-two years ago, molecular neurobi- Sweet and umami taste receptors arise ologist Robert Margolskee, MD, PhD, and from different combinations of receptor his colleagues discovered gustducin and proteins in the T1R family. Like old-fash- identified it as being specifically expressed ioned Tinkertoys, connecting T1R mole- in taste bud cells. More recently, Margolskee cules in different combinations makes and others showed that T1R and T2R taste taste receptors that are sensitive to singu- receptor proteins are expressed in sweet, lar taste qualities. The sweet receptor, for umami, and bitter-sensing taste receptor example, is a combination of T1R2+T1R3, cells in both rodent and human guts. while another version, which merges T1R1 and T1R3, is sensitive to glutamate and a These gut taste receptor cells helped to few other molecules and thus conveys explain a long-standing mystery concern- umami taste in humans. ing the physiology of sugar metabolism. Researchers have known for several The distantly related T2R family contains decades that glucose in the gut acts much about 25 receptor proteins in humans, more effectively than intravenous glucose each sensitive to one or more bitter-tast- to increase plasma insulin levels. But, pre- ing molecules. When a T1R or T2R recep- cisely how or why was poorly understood. Nogueras Paola tor is activated by a taste molecule, it Robert F. Margolskee triggers a taste cell-expressed G-protein, Solving the puzzle “started with the real- called gustducin, which then sets off a sig- ization that the small intestine senses naling cascade within the taste bud cells. sugars using something that we had been studying for a number of years in oral taste cells: the combination of T1R2 and T1R3 receptor proteins,” says Margolskee. trast, glucose administered intravenously Glucose in the gut, they found, activates bypasses the gut and thus cannot activate sweet taste receptor cells in the intestine these cells to secrete the insulin-releasing to trigger hormonal signals that stimulate hormones. the pancreas to secrete insulin. In con- “The oral cavity’s taste receptor cells are gatekeepers, controlling ingestion,” says Margolskee. “I think it's appropriate to consider the entire digestive tract from a systems point of view, to see how different Pancreatic islet ß parts of this system are specialized for dif- cells contain both ferent physiological responses.” insulin (red) and the taste receptor Starting protein T1R2 Elsewhere (green). To detect a given molecule, whether in the mouth or elsewhere in the body, it makes evolutionary sense for the body to re-pur- pose the same receptors, according to geneticist Alexander Bachmanov, PhD. With regard to understanding how we detect salty taste, still an unsolved mys- Yan Li Yan tery, this logic led scientists such as 1 Bachmanov to begin the hunt for salt- sensing taste cells by studying sodium- specific ion channels that are nearly ubiquitous in other parts of the body. “Sodium levels are strictly regulated inside the body, so cells need to have a way to detect it,” says Bachmanov. “Since sodium is also the stimulus for salty taste, it’s logical that taste cells would use the same mechanism.” The search focused on a sodium channel known as ENaC (epithelial Na+ channel), which helps control salt con- centrations within kidney and lung. Since several cardiovas- cular diseases are linked to disorders in renal sodium transport, drugs to modulate or block ENaC activity are readily available. Scientists found that applying these pharmacological blockers of ENaC activity reduced Nogueras Paola Danielle Reed rodents’ responses to salty tastes. The most direct evidence for ENaC as a salty taste receptor came from experi- ments using ‘knockout’ mice engineered ing sensitivity to sweet taste under differ- Alexander Bachmanov to lack a specific gene that encodes a por- ent nutritional circumstances. tion of this channel. Because ENaC is so important throughout the body, it was Peter Peter Olson With regard to salt, Bachmanov notes that impossible to knock out all the channels there likely is more than one mechanism without killing the mice. But Bachmanov for salt taste detection. He speculates that found a way to knock out only the tongue’s there is also a more general receptor for ENaC channels; when he did, the mice no non-sodium mineral salts, such as potas- longer could sense the taste of salt. sium, which also are regulated throughout the body. This second mechanism cur- “Putting all this together suggested that rently remains unknown; Bachmanov sug- the same channel that transports and reg- gests that looking at mineral regulation in ulates sodium in our internal organs may other parts of the body just might help be responsible for taste bud cells being solve this part of the mystery. able to detect sodium,” says Bachmanov. Essential A similar approach recently increased to Health understanding of sweet taste when Margolskee’s team found that several Being cued-in to fundamental cellular sig- sugar sensors from intestine and nals like glucose or salt is one reason pancreas also are present in the tongue’s extra-oral taste receptors are required for T1R2+T1R3 sweet-sensing taste cells. They life itself. “It makes perfect sense to me,” speculate that these ‘nontraditional’ sweet says Reed. “We are talking about mole- taste receptors may play a role in regulat- cules that are essential to health. You can 2 not survive without glucose, without salt. most sensitive to the bitter taste of PTC And, at least without warning labels, you were also most able to launch an immune also will not survive if you cannot detect defense against invading bacteria in the poisons, which often are bitter.” nose. At Monell, Reed studies how tiny genetic Taking this one step further, the group variations in taste receptors can add up to reported in a study published this year big health consequences. She has shown that small differences in the genetic that a small swap in the gene sequence of a sequence of T2R38 can change an individ- taste receptor protein can change a per- ual’s susceptibility to upper respiratory son’s taste sensitivity. For example, tract infections. changing three amino acids of the T2R38 bitter receptor gene makes the difference Using the T2R38 findings as a jumping off between people who are very sensitive to point, Reed now plans to develop ways to the nasty bitterness of phenylthiocar- study approximately 15,000 sites in the bamide (PTC) and those who are very human genome sequence and find vari- insensitive. Surprisingly – or at this point, ants of the T2R receptors. The goal, she maybe not so – it turns out that T2R38, says is “to see how the cacophony of bacte- along with nearly two-thirds of all bitter rial signals in the airways might be moni- Nogueras Paola receptors, is also expressed in our airways. tored by more than just this one bitter Hong Wang receptor and how people might differ.” If What are they doing there? To answer so, perhaps a quick taste test may someday this question, Reed, University of be all that’s needed to predict a person’s Pennsylvania otolaryngologist Noam susceptibility to some bacterial infections Cohen, MD, PhD, and their colleagues and perhaps even guide treatment looked at patients who suffer from chronic options. sinus infections. They found that the T2R38 receptors in the human nose had a Widespread function in recognizing bacterial signals— Receptors and that genetic variations in these receptors could control immune responses to Noting that many immune genes are also bacteria in the nose. Patients who were expressed in taste cells, “we want to see what these immune factors are doing in the taste system and how that relates to the development of taste disorders,” says molecular biologist Hong Wang, PhD. Wang’s background studying immune mediators and the chemical senses has helped her merge the two seemingly disparate research areas. Inflammation disrupts a cell’s internal chemistry; Wang suspects that this disruption may underlie taste disorders associated with infections or autoimmune disorders.

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