KEYPOINTS：
○ The olfactory receptor of an insect is an ion channel. When odor molecules bind to olfactory receptors, ion channels open and ions flow in, causing action potentials.
○ The researchers studied the olfactory receptors of the stone borer and found that different odor molecules docked with the same pocket of the receptor. This is not the classic key-lock pattern, but a one-to-many combination.
They found that even changing the individual amino acids in the receptor pocket was enough to change the binding properties of the receptor pocket. This may explain why insects' olfactory receptors evolve so quickly and vary so much from species to species.
Written by | Jordana Cepelewicz
Compile the | Ah Shuo
Review | Lixia
Edit | Jiahui，EY
Source: nextquestion
Smell, not sight, is the most important sense of most animals. It allows animals to find food, avoid danger, and attract mates; it directs the animal's perception and directs its behavior; it determines how the animal interprets and responds to the vast amount of sensory information around it.
However, the sense of smell is also probably the most incomprehensible to our senses, in part because of the complexity of the information it inputs. What we think of as a single smell — the smell of coffee in the early morning, the smell of wet grass after a summer storm, the smell of shampoo or perfume — is often a mixture of hundreds of chemicals. For animals to detect and discern multiple odors that are essential for their survival, a limited number of receptors on their olfactory sensory neurons must somehow recognize large numbers of compounds. Therefore, a single receptor must be able to respond to many different, seemingly unrelated odor molecules.
Now, new research has taken a crucial and highly anticipated step in elucidating the initial stages of the olfactory process. In a preprint published online earlier this year, the Rockefeller university team provided for the first time a molecular view of olfactory receptors as they bind to odor molecules. Richard Benton, a biologist at the University of Lausanne in Switzerland who was not involved in the new study, said that since the discovery of olfactory receptors 30 years ago, "this has been a dream in the field."
The tentacles of fruit flies. 丨 Image source: Science Image of Fruit fly antenna from PS MicroGraphs
This result is very helpful in confirming how animals recognize and distinguish massive odors. It also elucidates key principles of receptor activity, which could have far-reaching implications for understanding the evolution of chemical perception, understanding how other nervous systems and processes work, and developing things like targeted drugs and repellents.
There are several hypotheses competing to explain how olfactory receptors achieve the necessary flexibility. Some scientists have proposed that the receptors respond to a single feature of the odor molecule, such as shape or size; the brain may then recognize an odor by synthesizing information from different receptors. Other researchers believe that each receptor has multiple binding sites that can dock with different kinds of compounds. But to figure out which of these ideas is correct, they need to see the actual structure of the receptor.
Cryo-EM structure of MhOR5 (olfactory receptor) of MhOR5 (lithophyllum olfactory receptor) is shown from the side (e) and top (f). 丨 Image source: https://doi.org/10.1101/2021.01.24.427933
Olfactory receptors of primitive insects
The Rockefeller team turned its focus to receptor interactions in stone borers. The stone borer is the most primitive insect in existence and has a particularly simple olfactory receptor system.
In insects, olfactory receptors are ion channels that are activated when odor molecules bind to them, causing action potentials. There are millions of such ion channels in insect species around the world, so olfactory receptors are probably the largest and most diverse family of ion channels in nature. Therefore, they must carefully balance commonality and specificity, both flexible enough to detect a large number of potential odors and selective enough to reliably identify important odors (which may vary significantly depending on the species or environment).
Researchers found an odor receptor in jumping bristletail. The olfactory system of this wingless insect is simpler and more primitive, making it an ideal test subject. 丨 Image source: Yasunori Koide
What is the mechanism that allows them to grasp such a good direction and evolve in this way? The traditional method of determining the three-dimensional molecular structure of proteins to study olfactory receptors is not ideal. Under the conditions required by these methods, olfactory receptors tend to fold incorrectly, behave abnormally, or become difficult to distinguish. But recent advances, particularly in imaging called cryo-electron microscopy, have allowed researchers to try new approaches.
They studied the structure of olfactory receptors in three different configurations: one is the receptor itself, one is bound to the common odor molecule eugenol (which smells like cloves), and the other is to bind to the insect repellent DEET. They then compared these structures, down to individual atoms, to understand how odor binding opens up ion channels, and how individual receptors identify chemicals that differ significantly in shape and size.
Cryo-EM density in the modeling area, from top to bottom: eugenol-binding structure, DEET binding structure, pre-binding structure of proteins.
The researchers found that although DEET and eugenol didn't have much in common as molecules, they both docked to the same location of the receptor. The position is a deep and simple pocket lined with many amino acids lined up on the inside, favoring the formation of loose weak interactions. Eugenol and DEET use different interactions to reside in the pocket. Further computational simulations showed that each molecule could bind in many different directions, and that many other kinds of odor compounds could bind to the receptor in a similar way. This is not a one-to-one lock key pattern, but a one-size-fits-many approach. (See diagram at the end of the paragraph)
Olfactory receptors "are making more comprehensive recognition of molecules, rather than just detecting any particular structural feature." Vanessa Ruta, author of the study, said, "It's a very different chemical logic." ”
When Ruta and her team changed the receptor pockets, they found that even mutations in a single amino acid were enough to alter their binding properties. This, in turn, is enough to affect the receptor's interaction with many compounds, completely resetting the object of action of the receptor. For example, enlarging the receptor pocket increases its affinity for DEET (the larger molecule) and reduces its affinity for eugenol (the smaller molecule). This may be because eugenol is smaller in size and doesn't fit well into larger receptor pockets). Such changes would also have downstream effects on the receptor's broader odor detection "odor-detecting palette," which the researchers did not identify.
The team's observations may explain why insects' olfactory receptors evolve so quickly and vary so much between species. Each insect may have evolved "its own unique receptors that are well suited to their specific chemical niches." ”
"This tells us that there's more to going on than the receptors interacting weakly with a bunch of ligands." Neurobiologist Bob Datta said. A response profile built around a single binding pocket can be fine-tuned. If the chemical composition of this receptor is changed more broadly, the process of evolution may be accelerated.
The structure of this receptor also confirms this view. Ruta and her colleagues found that the receptor is made up of four protein subunits that loosely bind to the central pore of the channel, like the petals of a flower. As receptors diversify and evolve, only the central region is conserved; the gene sequences that control the remaining receptor units are less restricted. This structural organization means that the receptor can adapt to a wide variety of diversity.
This slight evolutionary limitation at the receptor level can exert enormous selection pressure on downstream olfactory neural circuits: the nervous system needs good mechanisms to decode chaotic patterns of receptor activity. "In fact, the olfactory system has evolved to take arbitrary receptor activation patterns and give them meaning through learning and experience." Ruta said.
The diversity of sensory perception
Interestingly, however, the nervous system doesn't seem to be lightening the workload for itself. Scientists used to generally believe that all receptors on a single olfactory neuron belonged to the same category, while different classes of neurons were distributed in different processing areas of the brain. However, in two preprints published last November, the researchers reported that individual olfactory neurons in both flies and mosquitoes expressed multiple types of receptors.
Ruta's findings are far from illustrative of how olfactory receptors work. Insects use many other kinds of ion channel olfactory receptors, of which a large number are more complex and specific than those of the stone borer. In mammals, the olfactory receptor is not even an ion channel; it belongs to a completely different family of proteins.
"This is the first structure of odor recognition in any receptor of all species. But this may not be the only mechanism for odor recognition. Ruta said. Even so, she and other researchers believe that we can learn more about the general knowledge from the olfactory receptors of stone borers. Imagine, for example, how this mechanism could be applied to other receptors in an animal's brain—from receptors that probe neuromodulants like dopamine to receptors that are affected by various anesthetics.
She added that perhaps in other cases this flexible combination should also be considered. For example, a study published in march in the Proceedings of the National Academy of Sciences (PNAS) suggested that even a typical key-locked ion channel receptor may not be as strictly selective as scientists believe.
If many different kinds of proteins bind to receptors through some kind of flexible weak interaction within a pocket, then this principle can guide the rational drug design of various diseases, especially neurological diseases. At the very least, Ruta's research on the binding of DEET to insect olfactory receptors could provide new insights into the development of targeted mosquito repellents. Her findings actually shed light on the debate that has been going on for more than half a century about how DEET works. DEET is one of the most effective repellents, but scientists have not understood why— for example, whether it smells bad to insects or whether it impairs an insect's olfactory signals. Ruta and her colleagues' research proposes a different theory: DEET confuses insects by activating many different receptors, flooding their olfactory systems with meaningless signals.
"The mystery of chemical cognition is to use structure as a lens to study." Ruta said, "Structural biology is so beautiful, clear, and surprisingly explanatory. My lab does a lot of work in cell and systems neuroscience, and few experiments have been as explanatory as structures. ”
About the author
Jordan Cepelewicz
Jordana Cepelewicz is a biology columnist for Quanta magazine. Her writings on mathematics, neuroscience, and other disciplines have also appeared in Nautilus and Scientific American. She graduated from Yale University in 2015 with a bachelor's degree in mathematics and comparative literature.
This article is reprinted with permission from the WeChat public account "nextquestion".
original:
https://www.quantamagazine.org/secret-workings-of-smell-receptors-revealed-for-first-time-20210621/