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Olfaction - A Review

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Olfaction - Page 1

General Physiology of Olfaction

Trigeminal Sense in the Olfactory Epithelium

Olfaction - Page 2

The Odorant Binding Proteins

Odorant receptors

The Cellular Membrane

Olfaction - Page 3

G-Protein Coupled Receptors

^G-Proteins

The cAMP Transduction Cascade

Ion Protein Channels

Other Second Messengers in Olfaction - cGMP, IP3, NO, CO

Olfaction - Page 4

Chemical Olfactory Stimulation - Theories on Olfaction

The Steric Theory of Odor

The Vibrational Theory of Odor

Vibrational Induced Electron Tunneling Spectroscope Theory

Ribonucleotides as the Odorant carrier?

Olfaction - Page 5

Recent Events in Olfactory Understanding

A Combinatorial Process for odor Interpretation

Combinatorial Process Visualization

Human Olfactory Receptor Genes

Enantiomeric Specificity in the Olfactory bulb

Download this paper as a pdf file

Important Events in Olfactory Understanding

A Combinatorial Process for odor Interpretation:

In March 1999, Linda Buck and Bettina Malnic at Harvard Medical School, and Junzo Hirono and Takaaki Sato at the Life Electronics Research Center in Amagasaki, Japan appear to have unravelled the mystery of how can the nose can interpret a plethora of different odors.⁴⁴

It appears that the sense of smell in mammals is based on a combinatorial approach to recognizing and processing odors. Instead of dedicating an individual odor receptor to a specific odor, the olfactory system uses an "alphabet" of receptors to create a specific smell response within the neurons of the brain. As in language (or music), the olfactory system appears to use combinations of receptors (analogous to words or or musical notes, or to the way that computers process code) to greatly reduce the number of actual receptor types actually required to convey a broad range of odors.

As in genetic code where the four nucleotides (adenine, cytosine, guanine and thymine) allow the creation of a nearly infinite number of genetic combinatorial sequences, the findings of Buck et. al. provides the first confirmation that the nerves that constitute the mammalian olfactory system also use a combinatorial approach.

When an odor excites a neuron, the signal travels along the nerve cell's axon and is transferred to the neurons in the olfactory bulb. This structure, located in the very front of the brain, is the clearinghouse for the sense of smell. From the olfactory bulb, odor signals are relayed to both the brain's higher cortex, which handles conscious thought processes, and to the limbic system, which generates emotional feelings.

In the reported study, individual mouse neurons were exposed to a range of odorants. Using a technique called calcium imaging, the researchers detected which nerve cells were stimulated by a particular odor. (When an odorant molecule binds to its odor receptor, calcium channels in the membranes of the nerves open and calcium ions pour inside. This generates an electrical charge that travels down the axon as a nerve signal. Calcium imaging measures this influx of calcium ions). Using this technique, it was shown that (1) single receptors can recognize multiple odorants (2) a single odorant is typically recognized by multiple receptors and (3) that different odorants are recognized by different combinations of receptors thus indicating that the olfactory system uses a combinatorial coding scheme to encode the identities of odors. This explains how 1,000 or so receptors can describe many thousands of different odors. Buck and her colleagues also demonstrated that even slight changes in chemical structure activate different combinations of receptors. Thus, octanol smells like oranges, but the similar compound octanoic acid smells like sweat. Similarly, it was found that large amounts of a chemical bind to a wider variety of receptors than do small amounts of the same chemical. This may explain why a large whiff of the chemical indole smells putrid, while a trace of the same chemical smells flowery.

In 2014, Leslie Vosshall's group at The Rockefeller University carried out mixture discrimination testing to determine a lower limit of the number of olfactory stimuli that humans can discriminate. They estimated that Humans can discriminate more than 1 trillion odors (The actual number of distinguishable olfactory stimuli is likely to be even higher than 1.72 trillion).^44a

In 2014, Idan Frumin, Noam Sobel & Yoav Gilad^44b reviewed the work of Joel D Mainland et al entitled "The missense of smell: functional variability in the human odorant receptor repertoire" ^44c. "Mainland et al. found that function-altering polymorphisms in genes for olfactory receptor subtypes differ, on average, in 30% of those genes when comparing any two individuals. The human perception data provided by Mainland et al.8 indeed reveal individual differences in olfactory perception that are influenced by the genetic makeup of each individual, but they do not mirror the extent of the genetic variability. Even within the study itself, allelic differences for a particular single olfactory receptor accounted for only ~15% in perceptual variance of its odorant ligand. Given the hypothesized combinatorial nature of the olfactory code, some may argue that the perceptual variance explained by the genetics is not low, as we do not know how many different receptor subtypes respond to guaiacol. If many subtypes respond to guaiacol, then explaining 15% of the variance with a single receptor is a lot. However, if only few receptors respond to guaiacol, then 15% is less impressive. Moreover, although the genetic variability in OR10G4 accounted for a portion of the variability in perception of its main agonist guaiacol, it failed to account for perceptual variability in perception of its weaker agonists. This highlights a clear distinction between testing for receptor-odorant pairs in vitro, where an arbitrary cutoff is used to determine whether the interaction is significant, and testing for the effect of genetic variation in vivo, where redundancy can mask most differences. For this reason, the ultimate mapping of odorant perceptual space based on genetics might still be a very challenging task, even if we could de-orphan all of the olfactory receptor subtypes."

In 2015, Mainland et al.⁸¹ indicated - "Although the human olfactory system is capable of discriminating a vast number of odors, we do not currently understand what chemical features are encoded by olfactory receptors. In large part this is due to a paucity of data in a search space covering the interactions of hundreds of receptors with billions of odorous molecules. Of the approximately 400 intact human odorant receptors, only 10% have a published ligand. Here we used a heterologous luciferase assay to screen 73 odorants against a clone library of 511 human olfactory receptors. This dataset will allow other researchers to interrogate the combinatorial nature of olfactory coding."

In 2016, King-Wai Yau et al⁸⁰ demostrated that - "The electrical response of vertebrate olfactory receptor neurons to odorants consists of two components: an inward cyclic-nucleotide–gated, nonselective cation current and an inward calcium-activated chloride current. These two currents are causally and tightly coupled, making them difficult to be separated. We have now succeeded in cleanly separating these two currents and found the Cl current to be dominant whether the overall response is at threshold for signaling to the brain or has reached saturation. Thus, the Cl current appears to have an important role in signal amplification in olfaction across the stimulus range."

Combinatorial Process Visualization

For a novel "Shockwave" visualization of the "Combinatorial Process" that illustrates how odor molecules fit into scent receptors Click here. Note that, as with a chord played on a piano, some smells are triggered by a combination of different parts of the same odor molecule fitting into different receptors. (To view this you will need the Adobe Shockwave Player-which you can download from HERE.)

Human Olfactory Receptor Genes

On page 2 of this review, we describe briefly the recent identification & structural elucidation of human olfactory receptor genes by Lancet and co-workers^12h at the Weizmann Institute of Science Crown Human Genome Center in Israel which is now publicly availabe in the HORDE online database and the sophistcated work of Zozulya and co-workers at Senomyx in which the latter describe the identification and physical cloning of 347 putative human full-length odorant receptor genes that they believe represent essentially the complete repertoire of functional human odorant receptors.^12f Peter Mombaerts has also reviewed this subject⁶⁷.

The Human Vomeronasal Organ

The VNO has been known to be present in human fetuses and has been reported sporadically in adults since the eighteenth century, although many find this improbable. Most of the work on vomeronasal function has been in rodents, snakes and insects where pheromonic chemicals play a communication role in attraction & reproduction. Its presence and function (if it, indeed, functions) in humans has been a matter of debate. However, Savic et. al. have shown that women smelling an androgen-like compound activate the hypothalamus, with the center of gravity in the preoptic and ventromedial nuclei. Men, in contrast, activate the hypothalamus (center of gravity in paraventricular and dorsomedial nuclei) when smelling an estrogen-like substance. This sex-dissociated hypothalamic activation suggests a potential physiological substrate for a sex-differentiated behavioral response in humans.⁶⁹ Whether this provides indirect (or direct) evidence of VNO like descrimination in humans remains to be seen.

Mombaerts, Greer and co-workers⁷⁰, showed that the human genome contains at least one gene found in epithelial tissue in the nasal that closely resembles a family of mouse pheromone receptors—genes that are primarily involved in detecting odorless chemicals such as pheromones. "Until this report," Greer states, "the consensus was that humans do not have receptors that belong to this family of genes. Now the door is open to reconsidering the functional organization of the human olfactory system." Mombaerts doesn't rule out the possibility that more pheromone receptors will turn up in sequence data in the future, but he is confident that only a few more, if any, will emerge.

Enantiomeric Specificity in the Olfactory bulb

It is well accepted that in humans certain specific chemical enantiomers (optical anti-podes) (such as carvone, menthol, limonene, linalool, citronellol, 7-hydroxy citronellol, 1-octen-3-ol, delta-decalactone, gamma-decalactone, 2-methyl-4-propyl-1,3-oxathiane, p-menthene-8-thiol, nootakatone, patchoulol, alpha-damascone, alpha-ionone, 3-mercapto-2-methylpentanol, (E)- & (Z)-nerolidols, alpha-phellandrene, alpha-terpineol, the theaspiranes, the 2 isomeric & 4 chiral forms of whiskey lactone, 2-ethylhexanoic acid, cis-rose oxide, nerol oxide, ethyl 2-methylbutyrate, methyl 2-methylbutyrate, Jasmine lactone, ethyl 2-oxo-3-methylpentanoate, 2-methylbutyric acid, 2,4,6-trimethyl-4-phenyl-1,3-dioxane, methyl dihydrojasmonate, the1-(2',2',6'-trimethyl-1'-cyclohexyl)-3-hexanols, 2-ethyl-4,4-dimethyl-1-cyclohexanone, 2,5,6-trimethyl-2-heptanol, 2-methyl-4-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-pentenenitrile, the 2-methyl-4-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-penten-1-ols, the 3,3-dimethyl-5-(2',2',3'-trimethyl-3'-cyclopenten-1'-yl)-4-pen ten-2-ols, the 5,6,7,8-tetrahydro-3,5,5,6,7,8,8-heptamethyl-2-naphthalenecarbaldehydes, the 5,6,7,8-tetrahydro-3,5,5,6,7,8,8-heptamethyl-2-naphthalenecarbonitriles, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-ol , the ambroxides) can be distinguished as they possess varying degrees of olfactory differences.⁵⁴ Rubin & Katz also have shown that apparently the rat is able to discriminate a wide variety of enantiomers that are indistinguishable to humans.⁵⁵ Enantioselectivity of odor perception in honeybees has also recently been studied, but gave results more similar to human discrimination.⁵⁶ Leffingwell has published on the internet an extensive site that provides over 710 enantiomeric pairs of odorants that have differing odor properties. This site provides both 2-D and 3-D molecular structures along with odor descriptors, odor thresholds and original references.

The olfactory receptor gene superfamily of the mouse

As mentioned on page 2 of this review, in the January 22, 2002 issue of Nature Neuroscience^12j, Stuart Firestein with Xinmin Zhang at Columbia University identified the mouse OR genes from the nearly complete Celera mouse genome by a comprehensive data mining strategy. They found 1,296 mouse OR genes (including 20% pseudogenes). Human ORs cover a similar 'receptor space' as the mouse ORs, suggesting that the human olfactory system has retained the ability to recognize a broad spectrum of chemicals even though humans have lost nearly two-thirds of the OR genes as compared to mice.

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Publications of interest:

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 Last Updated on October 13, 2016

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