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|77.4 - Summer 2004|
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Chemicals in Translation
From Odor Molecules to Smell
By Xueying Chen
|“After the people are dead, after the things are broken and scattered, taste and smell alone, more fragile but more enduring, more unsubstantial, more persistent, more faithful, remain poised a long time, like souls, remembering, waiting, hoping, amid the ruins of all the rest…” (from Swann’s Way)|
The sensitive boy narrator in Marcel Proust’s Swann’s Way gives arguably one of the best reminders of the enduring power of smell. His childhood impressions of his family and neighbors are all brought dazzlingly back to life years later by the smell of a madeleine cake dipped in tea. How does the olfactory system discriminate among such a wide range of odor molecules to recognize this lingering smell?From Odor Molecules to Olfactory Bulb
The discriminatory capacity of the olfactory system begins with the olfactory receptor neurons (ORN), the only neurons in the nervous system exposed directly to the external environment. ORNs reside in the olfactory epithelium of the nasal cavity and bind to odor molecules, deciphering the contained information into information accessible by the olfactory bulb. A pea-sized structure on the undersurface of the frontal lobe of the brain, the olfactory bulb sends input to the regions of the brain controlling the sense of smell. In this way, discrimination of odor molecules relies on three critical steps: transduction of the odor molecules by individual neurons, mapping of molecular information in neural space, and projection of signals from activated neurons to the olfactory bulb.Transduction of Odor Molecules
Odor molecules are grouped into general categories, such as floral, herbaceous, fruity, musky, and putrid. It has been suggested that each category has unique molecular determinants that form the fundamental informational unit of odor molecules, but it is a daunting task to understand the exact nature of odor molecule–receptor interactions.
The breakthrough finally came when olfactory transduction was found to be mediated by a G-protein-coupled secondary messenger system. G-protein-coupled receptors (GPCR) belong to a superfamily that includes rhodopsin — the light-sensitive pigment formed from retinal — and receptors for a variety of neurotransmitters, such as serotonin, dopamine, epinephrine, and histamine. To gain insight into the mechanisms of odor molecule–receptor interactions, studies often compare the binding of transmitter ligands to their designated receptors and their binding to other members of the GPCR superfamily. For example, adrenergic receptor responds to epinephrine, a hormone released in response to stress. Yet even with its individual function, it shares a consensus binding motif with many other members of the GPCR superfamily. Therefore, olfactory receptors appears to differentiate between odor molecules through the unique interactions between their ligand and binding pocket.
Gordon Shepherd, professor of neuroscience at the Yale School of Medicine, is a leading figure in the study of olfactory pathways. The Shepherd lab examined the differences between interactions of n-octanal — an aldehyde with a meaty smell — and its analogs with the binding pocket of rat 17 olfactory receptor (OR-17), n-octanal’s preferential receptor. The most important residues surrounding the binding pocket appear to be lysine 164 and aspartate 204 (LYS+ 164 and ASP- 204 in Figure 1). The positively charged lysine accounts for most of OR-17’s affinity for n-octanal, while the negatively charged aspartate generates a slight repulsion to balance the attractive force.
Figure 1. (Credit: Gordon Shephard)
Octanoic acid is a close analog of n-octanal, in which an aldehyde group is replaced by a carboxy. Despite the similarity between the two molecules, OR-17 exhibited no affinity for octanoic acid, suggesting high specificity of the receptor. Thus, Shepherd believes that aspartate 204 may determine odor specificity by means of selective repulsion. In this case, the electrostatic repulsion by aspartate 204 is much more pronounced for octanoic acid than for n-octanal, accounting for the low affinity of OR-17 for octanoic acid.Mapping of Molecular Information in Neural Space
During transduction, information contained in odor molecules is mapped in neural space onto a large population of ORNs residing in an extensive epithelial sheet. There has been much debate about whether the neurons expressing a given receptor and responding to a given odor are distributed randomly in the olfactory epithelium, or whether they are grouped in defined spatial patterns.
Recent eletrophysiological studies show that odors only educe localized responses in the olfactory epithelium; furthermore, there is little similarity between different regions in the olfactory epithelium in terms of their responses to odors. These studies indicate that ORNs in the olfactory epithelium are organized into different functioning zones, responding to a given odor molecule differently. Information contained in odor molecules is accordingly converted into activity maps by these ORNs.Organization of Information to the Glomerulus
In the brain’s olfactory region, sensory connections form within small groups of nerve cells called glomeruli. When responding to a given kind of odor molecule, a specific type of ORN exclusively targets a single glomerulus. In rabbits, there are 50 million sensory neurons and only 2,000 glomeruli, corresponding to a convergence ratio of 25,000:1. This considerable convergence of input processing enhances weak signals that otherwise would not be perceived by the glomerulus.
Specific targeting and convergence of each type of ORN produce odor maps at yet another level. The Shepherd lab used functional magnetic resonanace imaging (fMRI) to develop odor maps for the sensory processing of several aldehyde and ester compounds (Figure 2). Understanding this mapping of information contained in odor molecules at the glomerular layer of the olfactory bulb offers direct insight into how the brain perceives different types of odors.
Figure 2. Odor maps show that aldehydes with different carbon numbers can educe significantly different activity maps of ORNs. Red shows intense activity while blue shows low. (Credit: Gordon Shephard)
Neurons in the olfactory pathway have proved to be attractive models for studying how information is processed through interplays of the morphology of dendritic branching and the transduction of synaptic and sensory signals. The Shepherd lab is currently developing the Sense Lab Project, which constructs databases for receptors and neurons and facilitates the integration of these multidisciplinary data into computational models of neurons and neuronal currents.About the Author
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