Specific patterns in the nasal passageway that determine which olfactory neurons are associated with which particular odors have remained a mystery for scientists. The human nose has millions of these olfactory neurons grouped into hundreds of different neuron types. And each of these neuron types expresses only one odorant receptor in one region of the brain, allowing that specific odor to be sensed.

Now, researchers from UC Riverside and Stanford University have identified a braking mechanism in these olfactory neurons that helps generate an astonishing diversity of sensors in the nose.

As an example, the researchers said when a person smells a rose, only the neurons that express a specific odor receptor for the chemical emitted by the rose are activated. This in turn activates a specific region in the brain, allowing the person to sense the odor. Each smell activates a different group of neurons and also a different area of the brain.

In their study, the researchers focused on the olfactory receptor for detecting carbon dioxide in the fruit fly (Drosophila). Doing so, they identified a large multi-protein complex in olfactory neurons, called MMB/dREAM, that plays a role in selecting the carbon dioxide receptors to be expressed in specific neurons.

The researchers found that a molecular mechanism first blocks the expression of most olfactory receptor genes in the fly's antennae. This mechanism, which the team say acts like a brake, relies on repressive histones - proteins that tightly wrap DNA around them. This mechanism, which is found in all insects and mammals, keeps olfactory receptor genes repressed.

Anandasankar Ray, an assistant professor of entomology at UC Riverside, said his team wanted to find out how they could release this braking mechanism "so that only the carbon dioxide receptor is expressed in the carbon dioxide neuron while the remaining receptors are repressed."

While working with researchers at Stanford, the researchers were able to realize this goal. In essence, the team "found that the MMB/dREAM multi-protein complex can act on the genes of the carbon dioxide receptors and de-repress the braking mechanism - akin to taking the foot off the brake pedal. This allows these neurons to express the receptors and respond to carbon dioxide."

In explaining how this braking mechanism works, Ray said it is easiest to image a typewriter. When no keys are pressed, a "brake" holds the letter bars away from the paper. However, when a key is pressed, the "brake" is overcome and the letter bar associated with the key pressed is allowed to strike the paper. And just like typing only one letter in one spot is important for each letter to be recognized, so too does expressing one receptor in one neuron allow different sensor types to be generated in the nose.

Ray added that if this so-called "brake" was not in place, "a single cell would express several receptors and there would be no diversity in sensor types."

With this area being demystified, Ray noted that the next step is to "answer a fundamental question in neurobiology: How do we generate so much cellular diversity in the nervous system?"

The team plans to further examine the receptor-braking mechanism in the fruit fly in other organism like mosquitoes. They also plan to examine other receptors in the fruit fly to explain what de-represses each one.

Through their studies, the team also discovered that the activity of the MMB/dREAM complex in the fruit fly can alter levels of the carbon dioxide receptor and modulate the level of response to carbon dioxide.

"If you dial down the activity of the complex, you also dial down the expression of the carbon dioxide receptors, and the flies cannot sense carbon dioxide effectively," Ray said in a statement.

"What's particularly encouraging is that this complex is highly conserved in mosquitoes as well, which means that we may be able to dial down the activity of this complex in mosquitoes using genetic strategies, and potentially lower the ability of mosquitoes to sense carbon dioxide, used by them to find human hosts. Because carbon dioxide receptors are so well conserved in mosquitoes, we expect that the regulatory mechanism we discovered in Drosophila may also be acting on mosquito carbon dioxide receptors," he said.

Interestingly, unlike fruit flies, which use receptors on their antennae to sense carbon dioxide, mosquitoes use their maxillary palps (small structures near their mouthparts) to sense carbon dioxide. Specifically, two unique proteins (E2F2 and Mipl20) have been detected that could "explain why Drosophila expresses carbon dioxide receptors in the antennae while the mosquito expresses them in its maxillary palp," said Ray.

Study results appear in the Nov. 15 issue of Genes & Development. The research was funded by a grant from the Whitehall Foundation.