Genetic Discovery Paves Way to Decode Sense of Smell in Mammals

Duke University Medical Center geneticists have discovered new proteins that help the olfactory system in mammals organize properly. Thus the proteins are key to the ability of mammals, including humans, to detect and respond appropriately to chemicals in the environment via their sense of smell. The finding in mice paves the way for scientists to unravel the underlying code that allows the brain to interpret smells, according to the researchers.

Using genetic manipulations, the team found two proteins in mice that chaperone odorant receptors to the surface of olfactory nerves in the nose. Odorant receptors are the protein switches nestled in nerve cell membranes that trigger responses to specific volatile chemicals.

The discovery of the chaperone proteins reveals the first molecular components of the olfactory machinery that promotes proper targeting of olfactory receptors to the neuronal cell surface, said Hiroaki Matsunami, Ph.D., assistant professor of molecular genetics and microbiology at Duke. By taking advantage of the newly discovered components of the olfactory machinery, the Duke researchers have already begun tests to match the nearly 1,000 different mouse odorant receptors with the very specific chemical or chemicals to which they respond.

“In a fundamental way, the manner in which odorant receptors function remains a mystery due to technical difficulties that have largely prevented the necessary experiments,” Matsunami said. “The finding of these accessory proteins opens the door toward understanding the mechanisms underlying our sense of smell.”

Matsunami and his colleagues reported their results in the November 24, 2004, issue of the journal Cell. The work was supported by the National Institutes of Health and Duke University Medical Center.

Humans and other animals can detect and discriminate among thousands of volatile environmental chemicals. The sense of smell is essential for animals to detect food sources and potential toxins and to identify suitable mates. The sensory ability depends initially on olfactory nerve cells in the lining of the nose.

Scientists first identified olfactory receptors in mammals 10 years ago – a discovery that won the 2004 Nobel Prize in Physiology or Medicine. Each olfactory neuron bears only one type of olfactory protein receptor on its surface, forming the cellular basis for discrimination among smells, Matsunami explained. Mice have as many as 1,000 different odorant receptors, while humans – with a relatively poorer sense of smell – have 350 of the protein receptors for smell. However, the selectivity of those different receptors for chemical stimuli remains unclear, he added.

The researchers’ extensive search for proteins involved in delivering odorant receptor proteins to the surface of olfactory nerves revealed two proteins, which they named receptor transporting proteins one and two (RTP1 and RTP2). The researchers found that genes encoding the proteins were specifically active in olfactory neurons. Furthermore, RTP1 and RTP2 interact with olfactory receptor proteins and enhance their function, they found.

The researchers reported similar, although much weaker effects, for a third protein, which they called receptor expression enhancing protein one (REEP1).

To demonstrate the utility of the accessory proteins for elucidating the sense of smell, the team created cells with constantly high levels of RTP1, RTP2, REEP1, and another protein known to bind olfactory receptors. The enhancement of these protein levels made it possible for the researchers to induce the newly created cells to express odorant receptors at their surfaces. The team then tested the receptors’ response to various chemicals, including the fishy-smelling aliphatic acids and sweet-smelling coumarine and piperonal.

Through these experiments, the researchers identified seven new olfactory receptors that respond to different chemical odorants included in their test panel. The initial results further suggest that the ability to discriminate among chemicals depends on a “combinatorial receptor code,” in which one receptor responds to multiple related odorants and one odorant activates multiple receptors, they reported. “These initial findings are just the beginning,” Matsunami said. “We have established a system that should allow the rapid identification of chemicals that stimulate olfactory neurons to provide a comprehensive understanding of the mammalian sense of smell.”

The research team included Harumi Saito, Momoka Kubota, Richard Roberts and Qiuyi Chi, all of Duke.