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Tasteful Research

By Sean Henahan, Access Excellence

gee, proteins!WASHINGTON, D.C. (4/5/00)- The identification of genes associated with the bitter element of the sense of taste could lead to everything from better tasting medicines to better, safer pesticides. The research leading to the identification of these genes also suggests a taste of things to come from human genome screening initiatives.

Researchers at Harvard Medical School scoured the current database of genetic sequences of the nearly completed Human Genome Project, as well as the genome of the mouse, in an effort to find the genes that code for receptors that sense bitter-tasting chemicals. They found a family of genes that produce the proteins that encode G-protein-coupled receptors (GPCRs).These proteins are made in the 30,000-50,000 taste receptor cells that make up the taste buds covering the tongue.

The discovery could lead to the development of substances that block these receptors, which could help to produce medicines that are better tasting. At the other end of the spectrum, it should be possible to exploit these genes in the production of otherwise nontoxic pesticides that simply taste terrible to bugs, the researchers note.

The many types of G-proteins perform a variety of functions throughout the body. They were discovered by Alfred D G. Gilman, who received the 1994 Nobel Laureate in Medicine (with Martin Rodbellfor) for his work in describing the role of these proteins in signal transduction in cells. Research by Dr. Robert Margolskee, Mount Sinai School of Medicine, suggested that receptors for both bitter and sweet chemicals were associated with a common G-protein, known as gustducin. Gustducin is thought to be the essential link in sending the bitter signal from taste buds to the brain.

Building on this work, the Harvard team set out to find the location of the gene that produces this GPCR. After first finding a potential location for a taste-related GPCR in a mouse genome, they were able to screen through the human genome to find a corresponding region on human chromosome 12. They focused on that region, using the Human Genome Sequence (HGS) database at the National Center for Biotechnology Information to identify genes that specify receptors related to known GPCRs. This work revealed an impressive cluster of potential taste-receptor genes.

The Harvard research complements similar work being done by a group at the University of California, San Diego led by Dr. Charles Zuker. Working on a parallel track, Zuker's lab also identified genes that encode proteins that function as bitter taste receptors.

Only last year, Zuker and others reported the discovery of two genes, T1R1 and T1R2, that had most of the characteristics expected of taste receptor genes. The genes resembled other known sensory receptor genes and were expressed in the appropriate places inside taste receptor cells on the tongue and palate. But Zuker believed that two receptors seemed far too few to handle the huge number of chemicals that produce sweet and bitter substances. What's more, T1R1 and T1R2 generally were not found in the same places as gustducin, the coupling protein critical in sending the bitter signal from taste buds to the brain. So the search for a missing the family of taste receptors that coupled with gustducin continued.

The researchers focused on a specific interval of DNA on one human chromosome that was known to be associated with the ability to taste the bitter compound PROP (6-n-propylthiouracil). They identified a likely looking receptor sequence in that stretch of DNA, and showed that it belonged to a family of some 80 genes, which they dubbed T2Rs. Like T1R1 and T1R2, the T2R genes were selectively expressed in taste receptor cells, but there was even better news.

"If you look at the expression of this new family, you find that every cell that expresses one of these receptors is a gustducin-expressing cell," says Zuker.

The researchers then screened libraries of mouse genes in a search for the mouse versions of the new gene family. Mice are used in studying taste because strains have been bred with the inborn ability to taste or not taste certain bitter substances. Studies of these mice have pinpointed a cluster of gene positions on mouse chromosome six that are associated with the tasting of a number of bitter substances. Sure enough, gene mapping revealed a set of the GPCR genes on top of that bitter cluster. Subsequent research confirmed that three of the receptors specifically signaled in response to bitter taste,.

Taste vs. Olfaction

The new research may help explain the molecular logic behind the taste system and how it differs from the olfactory system. The olfactory system is designed to recognize a wide range of odors and to discriminate one odor from another. Each olfactory neuron expressing only one of the 1,000 or so olfactory receptor genes.

Taste is a different matter, especially where bitter compounds are concerned. Virtually every naturally occurring toxin tastes bitter, "so bitterness clearly evolved with the sole purpose of warning you against the ingestion of toxic substances," says Zuker. The important thing is to recognize and reject anything bitter, not to get hung up on distinctions among different compounds. Indeed, experimental evidence indicates that humans are unable to discriminate one bitter substance from another. Interestingly, while olfaction is associated with one receptor per cell, taste is associated with many receptors per cell.

Zuker believes that the T2R family of genes represents at least a subset of bitter taste receptors. The next step will be tracing pathways from receptor cells to the brain, generating "knockout" mice that lack T2Rs and studying their taste deficits, and searching for more gustducin-linked receptors. "This study will help scientists decipher the mechanisms behind how humans taste and allow them to discover ways to modulate the sense of taste so as to enhance the human taste experience," he says.

Sweet Tooth

Taste receptor research is not all focused on bitter flavors. Other researchers, including a group at the Monell Chemical Senses Center in Philadelphia, are hunting for the genes responsible for the perception of sweet flavors. Chemosensory research has also become a hot field in the biotech world. A handful of new companies, including San Diego-based Ambryx, Inc., are focusing all of their research efforts on the discovery and commercialization of products relevant to taste and olfaction. Beyond better-tasting medicines, other potential uses for this research might extend to fragrances, foods, cosmetics, therapeutics, household products as well as agricultural, and industrial applications.

Recent research on this subject appeared in the April 6, 2000, issue of Nature and in the March 17, 2000, issue of the journal Cell.


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