Study: Nose doesn't smell like the eyes see

July 12, 2005

Johns Hopkins scientists have uncovered new details of how smelly things create signals in the nose that eventually go to the brain. The findings raise issues about how the process involved has been described for many years in biology textbooks.

The textbooks say that our sense of smell converts odors into brain signals just like our vision converts light into brain signals. But the new work shows that while a key protein pathway is used in both, it behaves quite differently in the nose than it does in the eye. The researchers' findings are published in the June 24 issue of Science.

"Most of the information about this pathway comes from studies of vision, and people just assumed it worked the same way elsewhere in the body," says King-Wai Yau, Ph.D., professor of neuroscience in Johns Hopkins' Institute for Basic Biomedical Sciences. "But instead of being a model for other systems in the body, our visual system is probably pretty unique."

At issue is the behavior of a huge family of proteins called G-protein-coupled receptors. When activated by light in the eye or a molecule in other settings, each G-protein-coupled receptor uses a similar switch -- the exchange of a tiny bit called GTP for a related bit called GDP on the aptly named G-protein -- to trigger the cell's response.

Since about 1980, scientists studying vision have understood that light activates a specific G-protein-coupled receptor (the light-detecting molecule rhodopsin) in cells called rods found at the back of the eye. They also know that, once activated by light, this particular receptor stays activated long enough to trigger the GTP-to-GDP switch on a large number of G-protein molecules, substantially amplifying the incoming signal.

"Because of this amplification, rods are extremely sensitive to light," says Yau. "Each cell is capable of signaling the absorption of a single unit, or photon, of light."

Because G-protein signaling is so well understood in the eye, Yau says that scientists just assumed that it would amplify signals in other systems and cells where it's important. Indeed, some scientists have claimed that G-protein-coupled receptors involved in detecting odors have similar amplification abilities and that, as a result, a single stinky molecule would produce a signal in odor-detecting cells as large as a single unit of light does in rods.

Trouble is, that conclusion has turned out to be wrong. "We found that most of the time, a single molecule does not trigger a response. And even when it does, the response we measured is about 100 times lower than reported for rods," says Vikas Bhandawat, lead author of the study and a graduate student in neuroscience at Johns Hopkins.

In his experiments, Bhandawat used a system developed by co-author Johannes Reisert, Ph.D., that allows precise measurement and control of the amount of odiferous molecules used to stimulate a single odor-detecting nerve cell from a frog, and precise, long-term measurement of the cell's response to the odors.

"If you don't know exactly how much of the odor is being used, or exactly how long the exposure lasts, then you can't figure out what a single odorant molecule does," says Bhandawat. "Johannes' system allows us to do just that."

The team's finding underscores the key difference between the eye's light-detecting system and the nose's odor-detecting system: the very nature of light and molecules.

"When light hits a rod and is absorbed, it's a one-time event -- the light disappears forever," says Yau. "In the nose, an odor molecule that's inhaled probably stays in the nasal mucus long enough to bind to and trigger a number of receptors, essentially enhancing its own signal."

G-protein-coupled receptors are involved in thousands of biological processes, from creating appropriate organizational cues during development to transmitting signals from hormones and other molecules in fully grown adults, and are present in creatures from the amoeba to plants and animals.

"We think the mode of receptor behavior in odor detection is more the norm for chemical-triggered G-protein pathways, which are by far the most common G-protein signaling pathways, than is what happens in the eye," says Yau. "The sense of smell needs to be sensitive, but amplification isn't the only way to improve sensitivity."

For example, the cells could have many copies of the receptor, or many cells could express the same receptor. These are most likely the reasons why mice and dogs have a heightened sense of smell compared to people, says Yau.
Authors of the paper are Bhandawat, Reisert and Yau, all of Hopkins. The research was funded by the National Institute on Deafness and Other Communication Disorders, the Human Frontier Science Program and the Howard Hughes Medical Institute.

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