Johns Hopkins scientists find brain's nose plug

February 04, 2002

Scientists from The Johns Hopkins University School of Medicine and elsewhere have found the brain's "nose plug" - the switch in the brain that lets us stop smelling something, even though the odor is still there.

"The ability to desensitize to odors is important for our well-being," says Randall Reed, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator and a molecular biologist and neuroscientist in the school's Institute for Basic Biomedical Sciences. "Odor adaptation is important in telling whether a scent is getting stronger or going away, and it prevents sensory overload. Understanding this process should help us figure out how adaptation affects our perception of odors."

Two papers published in the Dec. 8 issue of Science show that a protein called CNGA4 helps plug the "nose" of odor receptor cells -- neurons whose job is to detect smells and send that information to the brain as an electrical signal. The "nose" is really a channel in the neurons' membrane that opens when an odor is presented and closes as the neuron becomes desensitized to that smell.

By measuring the signals from these odor receptor cells in genetically engineered mice, Reed and his colleagues showed that mice lacking CNGA4 can't adapt to odors. Other scientists studied the molecule's behavior in laboratory-grown cells and reported that CNGA4 speeds up the "nose's" closing.

In normal mice, and in humans, the electrical signal from odor receptor neurons diminishes quickly over time, even when the odor is still present. Also, the neurons usually produce a much smaller electrical signal if exposed to the same odor twice in a short period of time, says Reed.

Using mice that were missing CNGA4, a protein they thought to be involved in odor sensitivity, Reed and his collaborators from the University of Maryland, Baltimore, found that mice without CNGA4 could sense odors but could not adapt to them. In these mice, the signal from the neurons stayed almost constant, and the response to an odor the second time was identical to that from the initial exposure.

"Adaptation and sensitivity are related, but CNGA4 clearly plays a bigger role in adaptation," says Reed. "We thought we knew what the protein did, but the gene knockout mouse showed us that we didn't. It showed us that the biggest impact of CNGA4 is on odor adaptation, not sensitivity."

In a separate study, Jonathan Bradley, a postdoctoral fellow in neuroscience in HHMI at Johns Hopkins, examined the electrical behavior of CNGA4 and the odor channel in isolated cells. The channel opens in response to one molecule (cAMP), letting charged calcium atoms inside the odor neuron. The channel closes as the calcium entering the cell turns around and inhibits it.

Bradley's experiments revealed that when CNGA4 is present, the odor channel closes within one second of opening. Without CNGA4, it takes 100 times longer for enough calcium to bind and close the channel, he reports.

"We came by CNGA4's involvement by our interest in what the channel is doing from a biology perspective, and they came at it from the biophysical side," says Reed. "It's really nice because we can refer to their detailed work about the mechanism, and they can refer to ours because we have generated the protein's biological effects. This is what science is about."

The scientists are now evaluating how the lack of CNGA4 affects the mouse's normal behavior and how exactly CNGA4 facilitates calcium binding, Reed says.
Co-authors with Reed are Steven Munger, formerly of Hopkins and now at the University of Maryland, Baltimore; Andrew Lane, Trese Leinders-Zufall and Frank Zufall of the University of Maryland, Baltimore; and Haining Zhong and King-Wai Yau of Johns Hopkins (Science, 294:2172-2175). Funding was provided by the Howard Hughes Medical Institute, the National Institute on Deafness and Other Communication Disorders, the National Institute of Neurological Disorders and Stroke, and the National Science Foundation.

Co-authors with Bradley, who was at the Ecole Normale Superiere in Paris, are Dirk Reuter, now with Sophion Bioscience in Denmark, and Stephan Frings of the Institute for Biological Information Processing in Juelich, Germany (Science, 294:2176-2178). Funding was provided by the Deutsche Forschungsgemeinschaft (German Research Partnership), European Community and the Centre Nationale de la Recherche Scientifique (CNRS, National Center for Scientific Research).

On the Web: (Dec. 7, 2001 issue)

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