Contact: Wayne Little
Dr. Nicholas Ryba from the National Institute of Dental and Craniofacial Research (NIDCR) and Dr. Charles Zuker from the Howard Hughes Medical Institute and the University of California at San Diego have established a long-term collaboration to investigate the sense of taste. Last year, their groups reported the identification of the first two strong candidate taste receptors: TR1 and TR2. Their work describing and characterizing the new T2R taste receptors is reported in two articles in the March 17 issue of Cell.
According to Dr. Ryba, "We now have the means to really start to investigate how taste works, not just in the tongue but also what happens in the brain." Dr. Mark Hoon from the NIDCR, a co-author of the study, adds, "These results significantly enhance our understanding of bitter taste and provide clues about how the sensation of bitter might protect animals from many poisons." Drs. Zuker and Ryba are continuing their studies not only to dissect the basis of taste perception but also to identify compounds that might be used to modify the human sensation of bitter.
The investigators found the first of the bitter receptors by focusing on a region of human chromosome 5 that was known to affect the ability of certain individuals to detect a bitter compound. They found a gene that coded for a protein of the right size and shape to be a taste receptor. From there they discovered many closely related genes clustered on chromosomes 5, 7, and 12. Similar genes were also found on mouse chromosomes 6 and 15.
While other studies have identified a few potential taste receptor candidates, this is the first to discover an entire family of molecules that passed the rigorous biological criteria needed to confirm them as taste receptors.
The tongue is peppered with taste buds, which contain the cells that allow us to detect and distinguish salty, sour, sweet and bitter sensations. As expected, the T2R receptors were only found in the cells that are present in the physical confines of taste buds. Further evidence confirming the new family of molecules as taste receptors came from test tube studies. When receptor genes were introduced into experimental cells, the cells reacted only with bitter compounds. Furthermore, individual receptor molecules appeared very discriminating in their taste for bitter. A receptor that reacted with one form of bitter essentially ignored compounds that looked different. This phenomenon, say Zuker and Ryba, helps explain why there are up to 80 different bitter receptors. No single receptor could possibly recognize the many appearances of bitter.
Cell cultures and sections of rat tongue provide strong evidence that the molecules in question are indeed bitter receptors, but the ultimate tests lie with living organisms. Two strains of mice, bitter "tasters" and "non-tasters," were found to have distinct differences in the gene for a bitter receptor. The genetic variation translated into structural changes involving five of the 298 amino acids making up the receptor. This seemingly subtle difference in receptor structure determined whether or not the mice could recognize a bitter chemical.
While humans can identify a wide range of bitter compounds, they all taste pretty much the same. This observation may be explained by another discovery in Ryba and Zuker's study. Individual cells that discern bitter were found to have many different bitter receptors on the surface. Hoon explains, "The cellular signal caused by activation of any one receptor would likely be identical to the stimulation of another receptor by a different bitter compound. Since the receptors are all found in the same cell, the nerve connecting this cell to the brain gets the same message no matter which T2R is activated." Therefore, a single taste cell may bind many structurally different bitter molecules, but the brain cannot tell the difference. This finding suggests that over the course of mammalian evolution there was no selective advantage to discriminate among the nuances of bitter. Rather, survival was aided by simply recognizing and avoiding bitter's many forms.
In addition to Drs. Zuker, Ryba and Hoon, other authors of the study were Dr. Elliot Adler from the National Institute of Dental and Craniofacial Research; Drs. Ken Mueller, Jayaram Chandrashekar and Wei Guo from the Howard Hughes Medical Institute and the Departments of Biology and Neurosciences, University of California at San Diego; and Dr. Luxin Feng from Aurora Biosciences, La Jolla, California.