Posts tagged olfactory receptors
Articles and news from the latest research reports.
Cat and Mouse: A Single Gene Matters
When a mouse smells a cat, it instinctively avoids the feline or risks becoming dinner. How? A Northwestern University study involving olfactory receptors, which underlie the sense of smell, provides evidence that a single gene is necessary for the behavior.
A research team led by neurobiologist Thomas Bozza has shown that removing one olfactory receptor from mice can have a profound effect on their behavior. The gene, called TAAR4, encodes a receptor that responds to a chemical that is enriched in the urine of carnivores. While normal mice innately avoid the scent marks of predators, mice lacking the TAAR4 receptor do not.
The study, published April 28 in the journal Nature, reveals something new about our sense of smell: individual genes matter.
Unlike our sense of vision, much less is known about how sensory receptors contribute to the perception of smells. Color vision is generated by the cooperative action of three light-sensitive receptors found in sensory neurons in the eye. People with mutations in even one of these receptors experience color blindness.
“It is easy to understand how each of the three color receptors is important and maintained during evolution,” said Bozza, an author of the paper, “but the olfactory system is much more complex.”
In contrast to the three color receptors, humans have 380 olfactory receptor genes, while mice have more than 1,000. Common smells like the fragrance of coffee and perfumes typically activate many receptors.
“The general consensus in the field is that removing a single olfactory receptor gene would not have a significant effect on odor perception,” said Bozza, an assistant professor of neurobiology in the Weinberg College of Arts and Sciences.
Bozza and his colleagues tested this assumption by genetically removing a specific subset of olfactory receptors called trace amine-associated receptors, or TAARs, in mice. Mice have 15 TAARs. One is expressed in the brain and responds to amine neurotransmitters and common drugs of abuse such as amphetamine. The other 14 are found in the nose and have been coopted to detect odors.
Bozza’s group has shown that the TAARs are extremely sensitive to amines — a class of chemicals that is ubiquitous in biological systems and is enriched in decaying materials and rotting flesh. Mice and humans typically avoid amines since they have a strongly unpleasant, fishy quality.
Bozza’s team, including the paper’s lead authors, postdoctoral fellow Adam Dewan and graduate student Rodrigo Pacifico, generated mice that lack all 14 olfactory TAAR genes. These mice showed no aversion to amines. In a second experiment, the researchers removed only the TAAR4 gene. TAAR4 responds selectively to phenylethylamine (PEA), an amine that is concentrated in carnivore urine. They found that mice lacking TAAR4 fail to avoid PEA, or the smell of predator cat urine, but still avoid other amines.
“It is amazing to see such a selective effect,” Dewan said. “If you remove just one olfactory receptor in mice, you can affect behavior.”
The TAAR genes are found in all mammals studied so far, including humans. “The fact that TAARs are highly conserved means they are likely important for survival,” Bozza said.
One idea is that the TAARs may make animals very sensitive to the smell of amines. Humans may have TAAR genes to avoid rotting foods, which become enriched in amines during the decomposition process. In fact, the TAARs may relay information to a specific part of the brain that elicits innately aversive behavior in animals.
Bozza’s lab has recently shown that neurons in the nose that express the TAARs connect to with a specific region of the olfactory bulb — the part of the brain that first receives olfactory information. This suggests that the TAARs may elicit hardwired responses to amines in mice, and perhaps humans.
“We hope this work will reveal specific brain circuits that underlie instinctive behaviors in mammals,” Bozza said. “Doing so will help us understand how neural circuits contribute to behavior.”
Genetic Engineering Alters Mosquitoes’ Sense of Smell
In one of the first successful attempts at genetically engineering mosquitoes, HHMI researchers have altered the way the insects respond to odors, including the smell of humans and the insect repellant DEET. The research not only demonstrates that mosquitoes can be genetically altered using the latest research techniques, but paves the way to understanding why the insect is so attracted to humans, and how to block that attraction.
“The time has come now to do genetics in these important disease-vector insects. I think our new work is a great example that you can do it,” says Leslie Vosshall, an HHMI investigator at The Rockefeller University who led the new research, published May 29, 2013 in the journal Nature.
In 2007, scientists announced the completion of the full genome sequence of Aedes aegypti, the mosquito that transmits dengue and yellow fever. A year later, when Vosshall became an HHMI investigator, she shifted the focus of her lab from Drosophila flies to mosquitoes with the specific goal of genetically engineering the insects. Studying mosquitoes appealed to her because of their importance as disease carriers, as well as their unique attraction to humans.
Vosshall’s first target: a gene called orco, which her lab had deleted in genetically engineered flies 10 years earlier. “We knew this gene was important for flies to be able to respond to the odors they respond to,” says Vosshall. “And we had some hints that mosquitoes interact with smells in their environment, so it was a good bet that something would interact with orco in mosquitoes.”
Vosshall’s team turned to a genetic engineering tool called zinc-finger nucleases to specifically mutate the orco gene in Aedes aegypti. They injected the targeted zinc-finger nucleases into mosquito embryos, waited for them to mature, identified mutant individuals, and generated mutant strains that allowed them to study the role of orco in mosquito biology. The engineered mosquitoes showed diminished activity in neurons linked to odor-sensing. Then, behavioral tests revealed more changes.
When given a choice between a human and any other animal, normal Aedes aegypti will reliably buzz toward the human. But the mosquitoes with orco mutations showed reduced preference for the smell of humans over guinea pigs, even in the presence of carbon dioxide, which is thought to help mosquitoes respond to human scent. “By disrupting a single gene, we can fundamentally confuse the mosquito from its task of seeking humans,” says Vosshall. But they don’t yet know whether the confusion stems from an inability to sense a “bad” smell coming from the guinea pig, a “good” smell from the human, or both.
Next, the team tested whether the mosquitoes with orco mutations responded differently to DEET. When exposed to two human arms—one slathered in a solution containing 10 percent DEET, the active ingredient in many bug repellants, and the other untreated—the mosquitoes flew equally toward both arms, suggesting they couldn’t smell the DEET. But once they landed on the arms, they quickly flew away from the DEET-covered one. “This tells us that there are two totally different mechanisms that mosquitoes are using to sense DEET,” explains Vosshall. “One is what’s happening in the air, and the other only comes into action when the mosquito is touching the skin.” Such dual mechanisms had been discussed but had never been shown before.
Vosshall and her collaborators next want to study in more detail how the orco protein interacts with the mosquitoes’ odorant receptors to allow the insects to sense smells. “We want to know what it is about these mosquitoes that makes them so specialized for humans,” she says. “And if we can also provide insights into how existing repellants are working, then we can start having some ideas about what a next-generation repellant would look like.”
(Source: hhmi.org)
Scientists Identify Critical Link In Mammalian Odor Detection
Researchers at the Monell Center and collaborators have identified a protein that is critical to the ability of mammals to smell. Mice engineered to be lacking the Ggamma13 protein in their olfactory receptors were functionally anosmic – unable to smell. The findings may lend insight into the underlying causes of certain smell disorders in humans.
“Without Ggamma13, the mice cannot smell,” said senior author Liquan Huang, PhD, a molecular biologist at Monell. “This raises the possibility that mutations in the Ggamma13 gene may contribute to certain forms of human anosmia and that gene sequencing may be able to predict some instances of smell loss.”
Odor molecules entering the nose are sensed by a family of olfactory receptors. Inside the receptor cells, a complex cascade of molecular interactions converts information to ultimately generate an electrical signal. This signal, called an action potential, is what tells the brain that an odor has been detected.
To date, the identities of some of the intracellular molecules that convert odor information into an action potential remain a mystery. Suspecting that a protein called Ggamma13 might be involved, the research team engineered mice to be lacking this protein and then tested how the ‘knockout’ mice responded to odors.
Importantly, because the Ggamma13 protein plays critical roles in other parts of the body, the Ggamma13 ‘knockout’ was confined exclusively to smell receptor cells. This specificity allowed the researchers to characterize the effect of Ggamma13 deletion on the olfactory system without interference from changes in other tissues.
Both behavioral and physiological experiments revealed that the Ggamma13 knockout mice did not respond to odors. The findings were published in The Journal of Neuroscience.
In behavioral tests, control mice with an intact sense of smell were able to detect and retrieve a piece of buried food in less than 30 seconds. However, mice lacking Ggamma13 in their olfactory cells required more than 8 minutes to perform the same task. Both sets of mice were able to quickly locate the food when it was placed in plain sight.
A second set of experiments measured olfactory function on a physiological level. Using olfactory tissue from knockout and control mice, the researchers recorded electrical responses to 15 different odors. Responses from the Ggamma13 knockout mice were greatly reduced, suggesting that the olfactory receptors of these mice were unable to translate odor signals into an electrical response.
Together, the findings demonstrate that Ggamma13 is essential for mammals to smell odors and extend the current understanding of how olfactory receptor cells communicate information about odors to the brain. Future studies will seek to identify how Ggamma13 interacts with other molecules within the olfactory receptor.
“Loss of olfactory function can greatly reduce quality of life,” said Huang. “Our findings demonstrate the significant consequences when just one molecular component of this complex system does not function properly.”
(Source: monell.org)